Please wait while the formulary information is being retrieved.
Drug overview for ADVIL (chlorpheniramine maleate/pseudoephedrine hcl/ibuprofen):
Generic name: CHLORPHENIRAMINE MALEATE/PSEUDOEPHEDRINE HCL/IBUPROFEN (EYE-bue-PROE-fen)
Drug class: Non-Steroidal Anti-Inflammatory (NSAID) and Salicylates
Therapeutic class: Analgesic, Anti-inflammatory or Antipyretic
Ibuprofen is a prototypical nonsteroidal anti-inflammatory agent (NSAIA) that also exhibits analgesic and antipyretic activity.
Ibuprofen is used orally for anti-inflammatory and analgesic effects in the symptomatic treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, and osteoarthritis. Ibuprofen also is used orally to relieve mild to moderate pain and for the management of primary dysmenorrhea. Ibuprofen has been used orally in the management of pericarditis+.
Ibuprofen also may be used orally for self-medication for analgesic effects to provide temporary relief of minor aches and pains, including those of arthritis and of dysmenorrhea, for relief of migraine headaches, and for its antipyretic effect to reduce fever. Ibuprofen is used IV to relieve mild to moderate pain, to relieve moderate to severe pain (in conjunction with opiates), and to reduce fever. Ibuprofen lysine is used IV in the treatment of patent ductus arteriosus (PDA) in premature neonates.
The potential benefits and risks of ibuprofen therapy as well as alternative therapies should be considered prior to initiating ibuprofen therapy. The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.
Generic name: CHLORPHENIRAMINE MALEATE/PSEUDOEPHEDRINE HCL/IBUPROFEN (EYE-bue-PROE-fen)
Drug class: Non-Steroidal Anti-Inflammatory (NSAID) and Salicylates
Therapeutic class: Analgesic, Anti-inflammatory or Antipyretic
Ibuprofen is a prototypical nonsteroidal anti-inflammatory agent (NSAIA) that also exhibits analgesic and antipyretic activity.
Ibuprofen is used orally for anti-inflammatory and analgesic effects in the symptomatic treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, and osteoarthritis. Ibuprofen also is used orally to relieve mild to moderate pain and for the management of primary dysmenorrhea. Ibuprofen has been used orally in the management of pericarditis+.
Ibuprofen also may be used orally for self-medication for analgesic effects to provide temporary relief of minor aches and pains, including those of arthritis and of dysmenorrhea, for relief of migraine headaches, and for its antipyretic effect to reduce fever. Ibuprofen is used IV to relieve mild to moderate pain, to relieve moderate to severe pain (in conjunction with opiates), and to reduce fever. Ibuprofen lysine is used IV in the treatment of patent ductus arteriosus (PDA) in premature neonates.
The potential benefits and risks of ibuprofen therapy as well as alternative therapies should be considered prior to initiating ibuprofen therapy. The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.
DRUG IMAGES
ADVIL 200 MG GEL CAPLET
The following indications for ADVIL (chlorpheniramine maleate/pseudoephedrine hcl/ibuprofen) have been approved by the FDA:
Indications:
Dysmenorrhea
Fever
Headache disorder
Juvenile idiopathic arthritis
Osteoarthritis
Pain
Rheumatoid arthritis
Professional Synonyms:
Arthritis deformans
Arthrosis deformans
Cephalgia
Cephalodynia
Degenerative arthritis
Degenerative joint disease
Degenerative polyarthritis
Difficult menses
Difficult menstruation
Febrile reaction
Febrile
Hypertrophic arthritis
Juvenile RA
Juvenile rheumatoid arthritis
Nodose rheumatism
Osteoarthrosis
Painful menses
Painful menstrual cramps
Pyrexia
Rheumatic arthritis
Rheumatic gout
Indications:
Dysmenorrhea
Fever
Headache disorder
Juvenile idiopathic arthritis
Osteoarthritis
Pain
Rheumatoid arthritis
Professional Synonyms:
Arthritis deformans
Arthrosis deformans
Cephalgia
Cephalodynia
Degenerative arthritis
Degenerative joint disease
Degenerative polyarthritis
Difficult menses
Difficult menstruation
Febrile reaction
Febrile
Hypertrophic arthritis
Juvenile RA
Juvenile rheumatoid arthritis
Nodose rheumatism
Osteoarthrosis
Painful menses
Painful menstrual cramps
Pyrexia
Rheumatic arthritis
Rheumatic gout
The following dosing information is available for ADVIL (chlorpheniramine maleate/pseudoephedrine hcl/ibuprofen):
The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed. Dosage of ibuprofen must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.
Patients receiving ibuprofen for self-medication should be advised to use the lowest effective dosage and not to exceed the recommended dosage or duration of therapy.
Dosage of ibuprofen lysine is expressed in terms of ibuprofen.
Patients should be warned that the risk of GI bleeding is increased when recommended durations of self-medication are exceeded and when more than one NSAIA are used concomitantly.
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines state that, in patients who are CYP2C9 poor metabolizers, ibuprofen should be initiated at a dosage that is 25-50% of the lowest recommended initial dosage and cautiously titrated to a clinically effective dosage, up to a dosage that is 25-50% of the maximum recommended dosage. Dosage should not be increased until steady-state concentrations are attained (at least 5 days following the initial dose in poor metabolizers). Alternatively, a drug that is not metabolized by CYP2C9 or is not substantially affected by CYP2C9 genetic variants in vivo should be considered.
In addition, CPIC guidelines state that, in patients who are CYP2C9 intermediate metabolizers with a diplotype functional activity score (AS) of 1, ibuprofen may be initiated at the lowest recommended initial dosage and cautiously titrated to a clinically effective dosage, up to the maximum recommended dosage. Intermediate metabolizers with an AS of 1.5 may receive dosages recommended for normal metabolizers.
These dosage recommendations apply to both nonprescription (over-the-counter, OTC) and prescription use of the drug. (See Pharmacogenomic Precautions under Cautions.)
Patients receiving ibuprofen for self-medication should be advised to use the lowest effective dosage and not to exceed the recommended dosage or duration of therapy.
Dosage of ibuprofen lysine is expressed in terms of ibuprofen.
Patients should be warned that the risk of GI bleeding is increased when recommended durations of self-medication are exceeded and when more than one NSAIA are used concomitantly.
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines state that, in patients who are CYP2C9 poor metabolizers, ibuprofen should be initiated at a dosage that is 25-50% of the lowest recommended initial dosage and cautiously titrated to a clinically effective dosage, up to a dosage that is 25-50% of the maximum recommended dosage. Dosage should not be increased until steady-state concentrations are attained (at least 5 days following the initial dose in poor metabolizers). Alternatively, a drug that is not metabolized by CYP2C9 or is not substantially affected by CYP2C9 genetic variants in vivo should be considered.
In addition, CPIC guidelines state that, in patients who are CYP2C9 intermediate metabolizers with a diplotype functional activity score (AS) of 1, ibuprofen may be initiated at the lowest recommended initial dosage and cautiously titrated to a clinically effective dosage, up to the maximum recommended dosage. Intermediate metabolizers with an AS of 1.5 may receive dosages recommended for normal metabolizers.
These dosage recommendations apply to both nonprescription (over-the-counter, OTC) and prescription use of the drug. (See Pharmacogenomic Precautions under Cautions.)
The potential benefits and risks of ibuprofen therapy as well as alternative therapies should be considered prior to initiating ibuprofen therapy. Ibuprofen is administered orally or IV. Ibuprofen lysine is administered IV.
Ibuprofen is administered by IV infusion over a period of at least 30 minutes in adults and at least 10 minutes in pediatric patients 6 months to 17 years of age. All patients receiving IV ibuprofen should be well hydrated. For self-medication in pediatric patients, ibuprofen is commercially available as oral drops, an oral suspension, chewable tablets, and film-coated tablets.
The calibrated dosing device provided by the manufacturer should be used by parents or caregivers for measurement of the dose of oral drops; the calibrated dosage cup provided by the manufacturer should be used by parents or caregivers for measurement of the dose of pediatric oral suspension. Ibuprofen oral drops generally are used in infants 6-23 months of age, the oral suspension and the 100-mg chewable tablets commonly are used in children 2-11 years of age, and the 100-mg film-coated tablets may be used in children 6-11 years of age. If GI disturbances occur, ibuprofen should be administered with meals or with milk or dosage should be reduced.
Tablets containing ibuprofen in fixed combination with famotidine should be swallowed whole, and should not be chewed, divided, crushed, or cut to provide a lower dose. For IV administration, ibuprofen injection concentrate containing 100 mg/mL must be diluted with a compatible IV solution (e.g., 0.9% sodium chloride injection, 5% dextrose injection, lactated Ringer's injection) to provide a solution containing 4 mg/mL (less-concentrated solutions are acceptable). IV administration of the undiluted concentrate can result in hemolysis.
The commercially available ibuprofen 4-mg/mL (800 mg in 200 mL) premixed injection should be used for administration of 800-mg doses only. Parenteral solutions of ibuprofen should be inspected visually for particulate matter and/or discoloration prior to administration whenever solution and container permit. The solution should not be used if opaque particles, discoloration, or other foreign particulate matter is present.
For IV administration, ibuprofen lysine injection should be diluted with an appropriate volume of dextrose injection or sodium chloride injection and administered within 30 minutes of preparation. The drug should be administered using the IV port that is nearest to the IV insertion site. The dose should be infused over a period of 15 minutes.
Care should be taken to avoid extravasation of the drug since it may be irritating to extravascular tissues. Ibuprofen lysine should not be infused simultaneously through the same IV line as parenteral nutrition solutions; if the same IV line must be used, infusion of the nutrition solution should be interrupted for 15 minutes before and after ibuprofen lysine administration, and patency of the IV line maintained by infusion of dextrose injection or sodium chloride injection. Parenteral solutions of ibuprofen lysine should be inspected visually for particulate matter and/or discoloration prior to administration whenever solution and container permit.
The solution should be discarded if particulate matter is observed. Ibuprofen lysine injection contains no preservatives and is intended for single use only; any unused portion should be discarded.
Ibuprofen is administered by IV infusion over a period of at least 30 minutes in adults and at least 10 minutes in pediatric patients 6 months to 17 years of age. All patients receiving IV ibuprofen should be well hydrated. For self-medication in pediatric patients, ibuprofen is commercially available as oral drops, an oral suspension, chewable tablets, and film-coated tablets.
The calibrated dosing device provided by the manufacturer should be used by parents or caregivers for measurement of the dose of oral drops; the calibrated dosage cup provided by the manufacturer should be used by parents or caregivers for measurement of the dose of pediatric oral suspension. Ibuprofen oral drops generally are used in infants 6-23 months of age, the oral suspension and the 100-mg chewable tablets commonly are used in children 2-11 years of age, and the 100-mg film-coated tablets may be used in children 6-11 years of age. If GI disturbances occur, ibuprofen should be administered with meals or with milk or dosage should be reduced.
Tablets containing ibuprofen in fixed combination with famotidine should be swallowed whole, and should not be chewed, divided, crushed, or cut to provide a lower dose. For IV administration, ibuprofen injection concentrate containing 100 mg/mL must be diluted with a compatible IV solution (e.g., 0.9% sodium chloride injection, 5% dextrose injection, lactated Ringer's injection) to provide a solution containing 4 mg/mL (less-concentrated solutions are acceptable). IV administration of the undiluted concentrate can result in hemolysis.
The commercially available ibuprofen 4-mg/mL (800 mg in 200 mL) premixed injection should be used for administration of 800-mg doses only. Parenteral solutions of ibuprofen should be inspected visually for particulate matter and/or discoloration prior to administration whenever solution and container permit. The solution should not be used if opaque particles, discoloration, or other foreign particulate matter is present.
For IV administration, ibuprofen lysine injection should be diluted with an appropriate volume of dextrose injection or sodium chloride injection and administered within 30 minutes of preparation. The drug should be administered using the IV port that is nearest to the IV insertion site. The dose should be infused over a period of 15 minutes.
Care should be taken to avoid extravasation of the drug since it may be irritating to extravascular tissues. Ibuprofen lysine should not be infused simultaneously through the same IV line as parenteral nutrition solutions; if the same IV line must be used, infusion of the nutrition solution should be interrupted for 15 minutes before and after ibuprofen lysine administration, and patency of the IV line maintained by infusion of dextrose injection or sodium chloride injection. Parenteral solutions of ibuprofen lysine should be inspected visually for particulate matter and/or discoloration prior to administration whenever solution and container permit.
The solution should be discarded if particulate matter is observed. Ibuprofen lysine injection contains no preservatives and is intended for single use only; any unused portion should be discarded.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| ADVIL 200 MG GEL CAPLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| GS IBUPROFEN 200 MG TABLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| GS IBUPROFEN 200 MG CAPLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| IBUPROFEN 200 MG TABLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| IBUPROFEN 200 MG CAPLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| MB IBUPROFEN 200 MG TABLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| SM IBUPROFEN 200 MG TABLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| SM IBUPROFEN 200 MG CAPLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| RA IBUPROFEN 200 MG TABLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| RA IBUPROFEN 200 MG CAPLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| KRO IBUPROFEN 200 MG CAPLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| KRO IBUPROFEN 200 MG TABLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| QC IBUPROFEN 200 MG CAPLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| QC IBUPROFEN 200 MG TABLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| EQL IBUPROFEN 200 MG TABLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| EQL IBUPROFEN 200 MG CAPLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| PUB IBUPROFEN 200 MG TABLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| GNP IBUPROFEN 200 MG TABLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| EQ IBUPROFEN 200 MG TABLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| EQ IBUPROFEN 200 MG CAPLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| CVS IBUPROFEN 200 MG TABLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| CVS IBUPROFEN 200 MG CAPLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| FT IBUPROFEN 200 MG TABLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| FT IBUPROFEN 200 MG CAPLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
| GNP IBUPROFEN 200 MG CAPLET | Maintenance | Adults take 1 tablet (200 mg) by oral route every 6 hours as needed with food |
The following drug interaction information is available for ADVIL (chlorpheniramine maleate/pseudoephedrine hcl/ibuprofen):
There are 4 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Ketorolac (Non-Injection)/NSAID; Aspirin (Greater Than 100 mg); Salicylates SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Possible additive or synergistic side effects.(1,2) CLINICAL EFFECTS: Concurrent use of multiple doses of ketorolac with other non-steroidal anti-inflammatory agents (NSAIDs), salicylates or aspirin may result in an increase in NSAID-related side effects such as bleeding or renal impairment.(1-3) PREDISPOSING FACTORS: Patients with pre-existing renal impairment may be at an increased risk of adverse effects from this interaction. The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., anticoagulants, antiplatelets, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. PATIENT MANAGEMENT: Manufacturers of ketorolac state that concurrent use of ketorolac with either other NSAIDs or aspirin is contraindicated.(1,2) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Conduct periodic monitoring of renal function, especially in patients with renal impairment. Instruct patients to report any signs and symptoms of bleeding, such as unusual bruising; red or black, tarry stools; acute abdominal or joint pain and/or swelling. DISCUSSION: Based upon similar pharmacodynamic effects and potentially cumulative risks of serious NSAID-related adverse events, manufacturers of ketorolac state the concurrent administration of ketorolac with other NSAIDs or aspirin is contraindicated.(1,2) |
KETOROLAC TROMETHAMINE, SPRIX |
| Selected Nephrotoxic Agents/Cidofovir SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Cidofovir is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1-3) CLINICAL EFFECTS: Concurrent use of cidofovir with nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The Australian,(1) UK,(2) and US(3) manufacturers of cidofovir state that concurrent administration of potentially nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin. These agents should be discontinued at least 7 days before the administration of cidofovir. DISCUSSION: The safety of cidofovir has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is the major toxicity of cidofovir.(1-3) |
CIDOFOVIR |
| Ketorolac (Injectable)/NSAIDs; Aspirin (Greater Than 100 mg); Salicylates SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Possible additive or synergistic side effects.(1) CLINICAL EFFECTS: Concurrent use of multiple doses of ketorolac with other non-steroidal anti-inflammatory agents (NSAIDs), salicylates or aspirin may result in an increase in NSAID-related side effects such as bleeding or renal impairment.(1-3) PREDISPOSING FACTORS: Patients with pre-existing renal impairment may be at an increased risk of adverse effects from this interaction. The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., anticoagulants, antiplatelets, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. PATIENT MANAGEMENT: The manufacturer of ketorolac states that concurrent use of ketorolac with either other NSAIDs, salicylates or aspirin is contraindicated.(1) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: Manufacturers of ketorolac state that concurrent use of ketorolac with either other NSAIDs, salicylates or aspirin is contraindicated.(1,2) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Conduct periodic monitoring of renal function, especially in patients with renal impairment. |
BUPIVACAINE-KETOROLAC-KETAMINE, KETOROLAC TROMETHAMINE, R.E.C.K.(ROPIV-EPI-CLON-KETOR), ROPIVACAINE-CLONIDINE-KETOROLC, ROPIVACAINE-KETOROLAC-KETAMINE, TORONOVA II SUIK, TORONOVA SUIK |
| Selected Nephrotoxic Agents/Bacitracin SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Bacitracin may cause renal failure due to glomerular and tubular necrosis. Concurrent administration of other nephrotoxic agents may result in additive renal toxicity.(1-3) CLINICAL EFFECTS: Concurrent use of bacitracin with other potentially nephrotoxic agents may result in renal toxicity.(1-3) PREDISPOSING FACTORS: Dehydration and high-dose bacitracin may predispose to adverse renal effects.(1) PATIENT MANAGEMENT: Health Canada states that bacitracin is contraindicated in patients with renal impairment, including those taking other nephrotoxic drugs.(1) The Canadian and US manufacturers of bacitracin state that concomitant use of bacitracin with other potentially nephrotoxic agents should be avoided.(2,3) DISCUSSION: Renal impairment is a major toxicity of bacitracin. Cases of nephrotoxicity have been reported when bacitracin was used off-label.(1-3) |
BACITRACIN, BACITRACIN MICRONIZED, BACITRACIN ZINC |
There are 13 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Methotrexate; Pralatrexate/NSAIDs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown. NSAID-induced inhibition of prostaglandin synthesis may decrease renal perfusion rate and therefore inhibit methotrexate and pralatrexate clearance. NSAIDs may also compete for renal secretion with methotrexate and pralatrexate. Since methotrexate is not extensively protein bound, displacement of methotrexate by NSAIDs is unlikely to have altered methotrexate kinetics. CLINICAL EFFECTS: Increased levels of methotrexate and pralatrexate, with increased effects, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia. PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions PATIENT MANAGEMENT: Avoid the use of NSAIDs with high dose methotrexate therapy.(1) If both drugs must be given, monitor methotrexate levels and patient response carefully. Consider extending leucovorin rescue duration. Use caution when administering NSAIDs with low dose methotrexate therapy. (1) Administration of NSAIDs with pralatrexate requires close monitoring for toxicity.(2) DISCUSSION: A retrospective review documented four cases of methotrexate toxicity during concurrent administration of ketoprofen and methotrexate in 36 patients. Three cases were fatalities.(3) In contrast, a four-way cross-over study in ten subjects found no effect on methotrexate oral or renal clearance by ketoprofen, piroxicam, or flurbiprofen.(4) In a study in 19 subjects, the concurrent administration of methotrexate and piroxicam resulted in a decrease in methotrexate maximum concentration (Cmax) but no other changes in methotrexate kinetics.(5) Another three-way cross-over study in six patients showed no effect by flurbiprofen or ibuprofen on methotrexate kinetics.(6) In contrast, administration of ibuprofen to nine patients resulted in a 39% decrease in methotrexate total clearance and a 40% decrease in methotrexate renal clearance.(7) Information on naproxen is also conflicting. In another arm of the earlier study (7), the administration of naproxen in nine patients decreased methotrexate total clearance by 22%, but had no significant effects on methotrexate renal clearance. In another study in nine subjects, methotrexate altered naproxen kinetics by greater than 30% in six subjects, although these changes were not statistically significant. Naproxen altered methotrexate kinetics by greater than 30% in four subjects, although these changes were also not statistically significant.(8) In contrast, the administration of naproxen with methotrexate in 15 subjects showed no significant effects on methotrexate oral or renal clearance.(9) A study in 19 subjects found that the concurrent administration of etodolac and methotrexate decreased methotrexate Cmax and increased methotrexate mean residence time. There were no changes in methotrexate clearance or area-under-curve (AUC) and no toxicity was observed.(10) A study in 12 patients showed no significant effects of sulindac on methotrexate kinetics unless one patient who had low baseline clearance of methotrexate was excluded from analysis.(11) A study in seven children examined the effects of the children's usual NSAID on methotrexate kinetics. NSAIDs were naproxen, tolmetin, and indomethacin. Methotrexate half-life increased during NSAID administration. There were no significant changes in methotrexate clearance, AUC or volume of distribution. There was inter-subject variably in response. In six of seven patients, NSAID administration increased methotrexate AUC 19-140%.(12) Case reports have documented an interaction between methotrexate and phenylbutazone (13), indomethacin (14), flurbiprofen (15), and naproxen (16,17); however, one naproxen report (16) is complicated by the fact that the patient took 27.5 mg methotrexate in one week instead of 2.5 mg three times weekly. Because of the conflicting data and wide patient variability, caution is warranted during concurrent administration of methotrexate and any NSAID. |
FOLOTYN, JYLAMVO, METHOTREXATE, METHOTREXATE SODIUM, OTREXUP, PRALATREXATE, RASUVO, TREXALL, XATMEP |
| Selected Immunosuppressants/NSAIDs; Salicylates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Cyclosporine increases the production of prostaglandin E2 and I2. Prostaglandin E2 has been shown to prevent cyclosporine -induced renal toxicity in animals. NSAIDS and salicylates may increase cyclosporine-induced renal toxicity by blocking the formation of prostaglandins. Concurrent use of everolimus, sirolimus or tacrolimus with NSAIDs or salicylates may result in additive nephrotoxicity. CLINICAL EFFECTS: Concurrent administration of cyclosporine, everolimus, sirolimus, or tacrolimus and a NSAID or salicylate may result in a decrease in renal function, with or without an alteration in immunosuppressant levels. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: If possible, avoid the concurrent use of NSAIDs or salicylates in patients maintained on cyclosporine, everolimus, sirolimus, or tacrolimus. If concurrent therapy is warranted, patients should be monitored for a decrease in renal function. The NSAID or salicylate may need to be discontinued. DISCUSSION: A decrease in renal function has been reported with concurrent cyclosporine and diclofenac, sulindac, mefenamic acid, ketoprofen, piroxicam, and naproxen. Decreasing the cyclosporine dose without discontinuing the NSAID does not appear to improve renal function. The use of agents which decrease renal function concurrently with everolimus, sirolimus or tacrolimus should be approached with caution. An observational study of 63 inpatient encounters for 57 transplant patients evaluated concurrent use between calcineurin inhibitor (CNI) therapy and NSAID use. Patients were matched to 126 transplant patients on CNI therapy without NSAID use. Patients who received at least one dose of NSAID had a 12.2% rate of treatment emergent acute kidney injury (AKI). The relative risk ratio for AKI in patient exposed to NSAID therapy was 2.20 (95% CI 0.74-6.54). An increase in 48 hour post NSAID exposure serum creatinine above baseline was documented in 65.9% of patients compared to 46% in the non NSAID group (p=0.016). Multivariate analysis revealed changes in serum creatinine at 48 hours after admission were independently associated with age (p=0.008) and NSAID use (p=0.026).(12) |
AFINITOR, AFINITOR DISPERZ, ASTAGRAF XL, CYCLOSPORINE, CYCLOSPORINE MODIFIED, ENVARSUS XR, EVEROLIMUS, FYARRO, GENGRAF, NEORAL, PROGRAF, SANDIMMUNE, SIROLIMUS, TACROLIMUS, TACROLIMUS XL, TORPENZ, ZORTRESS |
| Selected Anticoagulants (Vit K antagonists)/NSAIDs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown. Some NSAIDs may displace anticoagulants from plasma protein binding sites. NSAIDs also have the potential to produce gastrointestinal ulceration and bleeding. Some NSAIDs may impair platelet function and prolong bleeding times. CLINICAL EFFECTS: Concurrent use of anticoagulants and NSAIDs may increase the risk for bleeding. PREDISPOSING FACTORS: Bleeding risk may be increased in patients with renal impairment and in patients older than 75 years. The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., other anticoagulants, antiplatelets, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. PATIENT MANAGEMENT: If concurrent therapy with anticoagulants and NSAIDs is warranted, patients should be closely monitored for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: The effects of NSAIDs on the hypoprothrombinemic response to anticoagulants appears to vary between patients as well as with different NSAIDs. Documentation is frequently contradictory - while studies have shown several NSAIDs to have no effect on the pharmacokinetics of warfarin, case reports have documented increased effects with and without bleeding when these same NSAIDs were administered concurrently with warfarin. While celecoxib has been shown not to affect platelet aggregation or bleeding times and had no effects on the anticoagulant effect of warfarin in healthy subjects, increased prothrombin times and bleeding episodes, some of which were fatal, have been reported, predominantly in the elderly, in patients receiving concurrent therapy with celecoxib and warfarin. Rofecoxib has been shown to increase prothrombin times in subjects who received concurrent warfarin therapy. A post hoc analysis of nonselective NSAIDs in the RE-LY study (compared dabigatran 150 and 110 mg twice daily with warfarin in atrial fibrillation) assessed clinical outcomes by comparing nonselective NSAID use (at least once during trial) with no NSAID use in 2279 patients. The use of NSAIDs was associated an increased risk of major bleeding (hazard ratio (HR) 1.68), gastrointestinal major bleeding (HR 1.81), stroke or systemic embolism (HR 1.50), and hospitalization (HR 1.64).(22) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and sulindac resulted in a ratio of rate ratios (RR) (95% CI) of 3.7 (1.79-7.62); warfarin and etodolac ratio of RR 2.61 (1.6-4.25); warfarin and ibuprofen ratio of RR 1.94 (1.5-2.5); warfarin and naproxen ratio of RR 1.72 (1.35-2.19); warfarin and indomethacin ratio of RR 1.62 (1.03-2.55); warfarin and diclofenac ratio of RR 1.43 (1.07-1.92; warfarin and celecoxib ratio of RR 1.24 (1.02-1.53); and warfarin and meloxicam ratio of RR 1.23 (1.02-1.47).(23) In a nationwide cohort study, patients were evaluated for thromboembolic cardiovascular and clinically relevant bleeding events with concurrent antithrombotic and ongoing NSAID treatment. A total of 108,232 patients were followed for a mean of 2.3 +/- 1.8 years after diagnosis of myocardial infarction. Concomitant NSAID treatment significantly increased the risk for cardiovascular events (hazard ratio (HR) 6.96; 95% CI 6.24 - 6.77; p<0.001) and bleeding events (HR 4.08; 95% CI 3.51 - 4.73; p<0.001) compared to no NSAID treatment. NSAIDs were further evaluated and revealed the use of celecoxib (HR: 4.65; 95% CI: 3.17 to 6.82; p < 0.001, and 3.44; 95% CI: 2.20 to 5.39; p < 0.001, respectively) and meloxicam (HR: 3.03; 95% CI: 1.68 to 5.47; p < 0.001, and 2.80; 95% CI: 1.40 to 5.60; p < 0.001, respectively) had the lowest risk for cardiovascular and bleeding events, receptively. A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 8 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and NSAIDs (OR=1.83; 95% CI 1.29-2.59). Increased bleeding risk was seen in subgroup analyses with non-selective NSAIDs (OR=1.86; 95% CI 1.10-3.17) and COX-2 inhibitors (OR=1.81; 95% CI 1.3-2.52).(24) If concurrent therapy with anticoagulants and NSAIDs is warranted, it would be prudent to monitor patients closely for increased anticoagulant effects. |
ANISINDIONE, DICUMAROL, JANTOVEN, WARFARIN SODIUM |
| Pemetrexed/Selected NSAIDs; Aspirin (Greater Than 325 mg) SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: NSAIDs may decrease the clearance of pemetrexed.(1) This decreased clearance may be the result of chronic renal toxicity from NSAIDs or NSAIDs may compete with pemetrexed for tubular secretion.(2) CLINICAL EFFECTS: Concurrent use of pemetrexed and NSAIDs may result in elevated levels of and toxicity from pemetrexed, including myelosuppression, neutropenia, renal toxicity, and gastrointestinal toxicity.(1) PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with mild to moderate renal insufficiency (creatine clearance (CrCl) of 45 ml/min to 79 ml/min) and/or patients taking long acting NSAIDs. (1) PATIENT MANAGEMENT: In patients with normal renal function (CrCl equal to or greater than 80 ml/min), ibuprofen (400 mg 4 times daily) can be administered with pemetrexed. Aspirin in low to moderate doses (325 mg every 6 hours) does not affect the pharmacokinetics of pemetrexed.(1) In patients with mild to moderate renal insufficiency (CrCl from 45 ml/min to 79 ml/min), NSAIDs with short half-lives should be avoided for 2 days before, the day of, and 2 days after pemetrexed administration. Ibuprofen should be administered with caution in these patients.(1) NSAIDs and salicylates with long half-lives should be avoided for at least 5 days before, the day of, and 2 days following pemetrexed administration in all patients.(1,2) If NSAIDs are required, patients should be monitored for pemetrexed toxicity, especially myelosuppression, renal toxicity, and gastrointestinal toxicity.(1) DISCUSSION: In patients with normal renal function, ibuprofen (400 mg 4 times daily) decreased the clearance of pemetrexed by 20% and increased its area-under-curve (AUC) by 20%.(1) In a Phase I clinical trial, two patients receiving high dose pemetrexed therapy experienced severe toxicity, both were receiving a NSAID. Following these reports, all patients were required to stop aspirin or other NSAIDs 2 days before and not resume these agents until 2 days after pemetrexed.(2) In two randomized, controlled cross-over trials, 27 cancer patients with a creatinine clearance (CrCl) less than or equal to 60 ml/min received pemetrexed (500 mg/m2) infusion on Day 1 of a 21-day cycle and either aspirin 325 mg or ibuprofen 400 mg orally every 6 hours starting 2 days before pemetrexed administration. Coadministration of aspirin did not affect pemetrexed pharmacokinetics. Ibuprofen decreased the clearance of pemetrexed by 16%, increased its maximum concentration (Cmax) by 15%, and increased the AUC by 20%.(3) Aspirin products linked to this monograph are single ingredient aspirin products with greater than 325 mg strength, and aspirin combination products (e.g. opioid-aspirin or cough/cold/allergy products) with a reasonable likelihood of a total daily aspirin dose > or = 1,300 mg per day. |
ALIMTA, PEMETREXED, PEMETREXED DISODIUM, PEMFEXY, PEMRYDI RTU |
| Selected Platelet Aggregation Inhibitors/NSAIDs; Salicylates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Abciximab, cangrelor, cilostazol, clopidogrel, dipyridamole, eptifibatide, prasugrel, ticagrelor, vorapaxar and NSAIDs or salicylates inhibit platelet aggregation. CLINICAL EFFECTS: Concurrent use of platelet aggregation inhibitors and NSAIDs or salicylates may increase the risk of bleeding. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., anticoagulants, other antiplatelets, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. Risk increases as the number of risk factors increases. PATIENT MANAGEMENT: Use caution when administering platelet aggregation inhibitors with NSAIDs or salicylates.(1-5) It would be prudent to monitor patients more closely during concurrent therapy and to use the lowest NSAID or salicylate dose possible. If concurrent therapy is warranted, monitor patients for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The 2010 ACCF/ACG/AHA Consensus guidelines recommend the use of proton pump inhibitors (PPIs) in patients with multiple risk factors for GI bleeding who require antiplatelet therapy. However, esomeprazole and omeprazole should be avoided with clopidogrel as they are expected to reduce the effectiveness of clopidogrel. Use of other PPIs should be approached with caution, as they may reduce the effectiveness of clopidogrel. DISCUSSION: Because of the increased risk of bleeding, caution is warranted when using this combination. In a nationwide cohort study, patients were evaluated for thromboembolic cardiovascular and clinically relevant bleeding events with concurrent antithrombotic and ongoing NSAID treatment. A total of 108,232 patients were followed for a mean of 2.3 +/- 1.8 years after diagnosis of myocardial infarction. Concomitant NSAID treatment significantly increased the risk for cardiovascular events (hazard ratio (HR) 6.96; 95% CI 6.24 - 6.77; p<0.001) and bleeding events (HR 4.08; 95% CI 3.51 - 4.73; p<0.001) compared to no NSAID treatment. NSAIDs were further evaluated and revealed the use of celecoxib (HR: 4.65; 95% CI: 3.17 to 6.82; p < 0.001, and 3.44; 95% CI: 2.20 to 5.39; p < 0.001, respectively) and meloxicam (HR: 3.03; 95% CI: 1.68 to 5.47; p < 0.001, and 2.80; 95% CI: 1.40 to 5.60; p < 0.001, respectively) had the lowest risk for cardiovascular and bleeding events, receptively. |
ASPIRIN-DIPYRIDAMOLE ER, BRILINTA, CILOSTAZOL, CLOPIDOGREL, CLOPIDOGREL BISULFATE, DIPYRIDAMOLE, EFFIENT, EPTIFIBATIDE, KENGREAL, PLAVIX, PRASUGREL HCL, ZONTIVITY |
| Colistimethate/Selected Nephrotoxic Agents SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Colistimethate can cause nephrotoxicity.(1,2) Concurrent administration of other nephrotoxic agents may result in an increased risk of nephrotoxicity.(1) It is suspected that cephalothin interferes with the excretion of colistimethate resulting in enhanced nephrotoxicity.(2,3) CLINICAL EFFECTS: Concurrent use of colistimethate with other nephrotoxic agents may result in additive nephrotoxic effects. PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include higher cumulative doses of colistimethate, longer treatment duration, hypovolemia, and critical illness. PATIENT MANAGEMENT: Concurrent use of potentially nephrotoxic agents with colistimethate should be avoided.(1,2) If concurrent use is necessary, it should be undertaken with great caution.(1) DISCUSSION: In a case control study of 42 patients on intravenous colistimethate sodium, NSAIDs were identified as an independent risk factor for nephrotoxicity (OR 40.105, p=0.044).(4) In 4 case reports, patients developed elevated serum creatinine and blood urea nitrogen following concurrent colistimethate and cephalothin (3 patients) or when colistimethate followed cephalothin therapy (1 patient).(3) A literature review found that individual nephrotoxic agents, including aminoglycosides, vancomycin, amphotericin, IV contrast, diuretics, ACE inhibitors, ARBs, NSAIDs, and calcineurin inhibitors, were not consistently associated with additive nephrotoxicity when used with colistimethate. However, when multiple agents (at least 2 additional potential nephrotoxins) were used concurrently, there was a significant correlation to colistimethate nephrotoxicity.(5) |
COLISTIMETHATE, COLISTIMETHATE SODIUM, COLY-MYCIN M PARENTERAL |
| Sodium Phosphate Bowel Cleanser/NSAIDs; Salicylates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Bowel cleansing with sodium phosphate causes dehydration, decreased intravascular volume and hyperphosphatemia, which increases phosphate levels in the renal tubules. Abnormally high levels of calcium and phosphate in the renal tubules may precipitate out, resulting in renal injury.(1) CLINICAL EFFECTS: Use of sodium phosphate for bowel cleansing in patients maintained on nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of acute phosphate nephropathy, which is an acute kidney injury associated with deposits of calcium phosphate crystal in the renal tubules that may result in permanent renal function impairment. Acute phosphate nephropathy presents as acute kidney injury with minimal proteinuria and a bland urine sediment.(2) Use of oral sodium phosphate products at laxative doses has not been associated with acute kidney injury.(3) PREDISPOSING FACTORS: Patients who may be at an increased risk of acute phosphate nephropathy include those who are over age 55; are hypovolemic or have decreased intravascular volume; have baseline kidney disease, bowel obstruction, or active colitis; and who are using medications that affect renal perfusion or function (such as diuretics, ACE inhibitors, angiotension receptor blockers [ARBs]), and NSAIDs.(2) PATIENT MANAGEMENT: If possible, use an alternative agent for bowel cleansing.(1) Use sodium phosphate products with caution in patients taking medications that affect kidney function or perfusion, such as ACE inhibitors or ARBs. Obtain baseline and post-procedure labs (electrolytes, calcium, phosphate, BUN, creatinine, and [in smaller, frail individuals] glomerular filtration rate). Instruct patients to drink sufficient quantities of clear fluids before, during, and after bowel cleansing and to avoid other laxatives that contain sodium phosphate. Consider hospitalization and intravenous hydration during bowel cleansing to support frail patients who may be unable to drink an appropriate volume of fluid or who may be without assistance at home.(2) Use of an electrolyte solution for rehydration may decrease the risk of acute phosphate nephropathy.(4,5) DISCUSSION: Since May 2006, the FDA has received 20 reports of acute phosphate nephropathy associated with the use of Osmo Prep. Concomitant medications included ACE inhibitors or ARBs (11), diuretics (6), and NSAIDs (4).(2) In a retrospective review of colonoscopy patients, simultaneous use of ACE inhibitors or ARBs significantly increased the risk of acute kidney injury from oral sodium phosphate. Diuretic use was also a risk factor.(6) In a case series study of 21 cases of acute phosphate nephropathy in patients who had used oral sodium phosphate, 14 patients received an ACE inhibitor or ARB, 4 used a diuretic, and 3 used an NSAID.(7) Cases have also been reported with rectal products.(8) |
SODIUM PHOSPHATE DIBASIC, URIMAR-T, URNEVA |
| Dabigatran/NSAIDs; Salicylates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Dabigatran is a direct thrombin inhibitor and when taken with agents that effect platelet aggregation and/or other clotting factors increased bleeding episodes can occur.(1,2) CLINICAL EFFECTS: Concurrent use of dabigatran with NSAIDs or salicylates may result in additive or synergistic effects resulting in unwanted bleeding episodes.(1) PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-glycoprotein inhibitors, patient older than 74 years, coexisting conditions (e.g. recent trauma, thrombocytopenia, advanced liver disease), use of drugs associated with bleeding risk (e.g. other anticoagulants, antiplatelets, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)), and patient weight less than 50 kg. (1-3) Risk of GI bleed may be increased in patients who are of older age, in poor health status, who use alcohol or smoke, with longer duration of NSAID use, and with prior history of peptic ulcer disease and/or GI bleeding. PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy for signs of blood loss and promptly evaluate patients with any symptoms. Discontinue dabigatran in patients with active pathological bleeding.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: Dabigatran is a direct thrombin inhibitor and when taken with agents that effect platelet aggregation and/or other clotting factors increased bleeding episodes can occur.(1,2) A post hoc analysis of nonselective NSAIDs in the RE-LY study (compared dabigatran 150 and 110 mg twice daily with warfarin in atrial fibrillation) assessed clinical outcomes by comparing nonselective NSAID use (at least once during trial) with no NSAID use in 2279 patients. The use of NSAIDs was associated an increased risk of major bleeding (hazard ratio (HR) 1.68), gastrointestinal major bleeding (HR 1.81), stroke or systemic embolism (HR 1.50), and hospitalization (HR 1.64).(22) |
DABIGATRAN ETEXILATE, PRADAXA |
| Apixaban; Betrixaban; Edoxaban; Rivaroxaban/NSAIDs; Salicylates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of apixaban(1-4), betrixaban(7), edoxaban(5), or rivaroxaban(6) and nonsteroidal antiinflammatory agents (NSAIDs) or salicylates may result in additive increased risk of bleeding. CLINICAL EFFECTS: Concurrent use of apixaban(1), betrixaban(7), edoxaban(5), or rivaroxaban(2) with NSAIDs or salicylates may result in unwanted bleeding episodes. PREDISPOSING FACTORS: Bleeding risk may be increased in patients with renal impairment and in patients older than 75 years. The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., other anticoagulants, antiplatelets, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. PATIENT MANAGEMENT: Approach concurrent therapy with apixaban(1-4), betrixaban(7), edoxaban(5), or rivaroxaban(6) with caution. Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In a study, naproxen (500 mg) increased apixaban (10 mg) area-under-curve (AUC) and maximum concentration (Cmax) by 1.5-fold an 1.6-fold, respectively, with corresponding increases in clotting tests. There were no changes in the effect of naproxen on arachidonic acid-induced platelet aggregation, no clinically relevant changes in bleeding times, or naproxen pharmacokinetics.(1) In a single dose study, there were no pharmacokinetic or pharmacodynamic interactions between rivaroxaban and naproxen.(6) Although effects seen in the above studies were limited, NSAIDs are known to increase bleeding and may further increase the risk of bleeding with these agents.(1-6) In edoxaban clinical studies, concomitant use of low-dose aspirin (less than or equal to 100 mg/day) or thienopyridines, and NSAIDs was permitted and resulted in increased rates of clinically relevant bleeding.(5) In a study of 34 healthy subjects administered edoxaban 60 mg daily and naproxen 500 mg daily, bleeding time increased by 2.08-fold from baseline on the combination, compared to a 1.23-fold increase with naproxen alone and 1.7-fold increase on edoxaban alone.(8) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of apixaban and ibuprofen resulted in a ratio of rate ratios (RR) (95% CI) of 5.16 (3.0-8.85); apixaban and celecoxib ratio of RR 1.8 (1.06-3.06); rivaroxaban and etodolac ratio of RR 2.47 (1.18-4.22); rivaroxaban and naproxen ratio of RR 1.89 (1.12-1.43); and rivaroxaban and ibuprofen ratio of RR 1.68 (1.29-4.44).(9) |
ELIQUIS, SAVAYSA, XARELTO |
| Selected Nephrotoxic Agents/Foscarnet SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Foscarnet is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1) Concurrent intravenous pentamidine may also result in hypocalcemia.(1) CLINICAL EFFECTS: Concurrent use of foscarnet with nephrotoxic agents such as acyclovir, adefovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, non-steroidal anti-inflammatory agents, intravenous pentamidine, tacrolimus, tenofovir, vancomycin and voclosporin may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of foscarnet state that concurrent administration of potentially nephrotoxic agents such as acyclovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, tacrolimus, and intravenous pentamidine should be avoided.(1) Other nephrotoxic agents include adefovir, capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, non-steroidal anti-inflammatory agents, streptozocin, tenofovir, vancomycin and voclosporin. If concurrent therapy is warranted, monitor renal function closely. In patients receiving concurrent foscarnet and pentamidine, also monitor serum calcium levels and instruct patients to report severe muscle spasms, mental/mood changes, and/or seizures.(1) DISCUSSION: The safety of foscarnet has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is the major toxicity of foscarnet.(1) |
FOSCARNET SODIUM, FOSCAVIR |
| Inotersen/Non-Steroidal Anti-Inflammatory Drugs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inotersen causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia. Inotersen can also cause glomerulonephritis and renal toxicity. NSAIDs can impair thromboxane-dependent platelet aggregation by blocking the formation of thromboxane A2. Concurrent administration with NSAIDs may also result in additive or synergistic effects on renal function.(1) CLINICAL EFFECTS: Concurrent use of inotersen with NSAIDs may result in additive or synergistic effects, including fatal and non-fatal intracranial hemorrhage, or renal toxicity.(1) PREDISPOSING FACTORS: The risk for bleeding episodes may also be greater in patients greater than 60 years or have a prior history of major bleeding events. Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding. Patients with pre-existing renal impairment. PATIENT MANAGEMENT: Inotersen should be administered with caution in patients receiving NSAIDs. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Monitor platelet count frequently. If platelet count is less than 50, stop inotersen treatment and consider discontinuation of NSAID. Monitor for signs and symptoms of thrombocytopenia; such as, unusual or prolonged bleeding (petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness, or atypical severe headache. Monitor renal function closely. DISCUSSION: In a clinical study, platelet counts below 100 occurred in 25% of inotersen-treated patients, compared with 2% of patients on placebo. Platelet counts below 75 occurred in 14% of inotersen-treated patients, compared to no patients on placebo. In study 1 and its extension study, 39% of inotersen-treated patients with a baseline platelet count below 200 had a nadir platelet count below 75, compared to 6% of patients with baseline platelet counts 200 or higher. Three inotersen-treated patients (3%) had sudden severe thrombocytopenia (platelet count below 25). One patient experienced a fatal intracranial hemorrhage.(1) The safety of inotersen has not been studied in patients receiving other known potentially nephrotoxic agents.(1) Inotersen is only available through a Tegsedi REMS program because of the risk of severe thrombocytopenia and the risk of glomerulonephritis.(1) |
TEGSEDI |
| Caplacizumab/Anticoagulants; Antiplatelets SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Bleeding has been reported with the use of caplacizumab.(1) CLINICAL EFFECTS: Concurrent use of caplacizumab with either anticoagulants or antiplatelets may increase the risk of hemorrhage.(1) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. hemophilia, coagulation factor deficiencies). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Avoid the use of caplacizumab with anticoagulants and antiplatelets. Interrupt caplacizumab therapy if clinically significant bleeding occurs. Patients may require von Willebrand factor concentrate to rapidly correct hemostasis. If caplacizumab is restarted, closely monitor for signs of bleeding.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: Bleeding has been reported with caplacizumab. In clinical studies, severe bleeding adverse reactions of epistaxis, gingival bleeding, upper gastrointestinal hemorrhage, and metrorrhagia were each reported in 1% of patients. Overall, bleeding events occurred in approximately 58% of patients on caplacizumab versus 43% of patients on placebo.(1) In post-marketing reports, cases of life-threatening and fatal bleeding were reported with caplacizumab.(1) |
CABLIVI |
| Alprostadil/Acetaminophen; NSAIDs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Alprostadil is a prostaglandin E1 product used to maintain patency of a patent ductus arteriosus (PDA).(1) Acetaminophen and nonsteroidal anti-inflammatory (NSAID) agents inhibit prostaglandins and may be used for PDA closure in addition to pain/fever management.(2-4) CLINICAL EFFECTS: Simultaneous administration of acetaminophen or NSAIDs may result in decreased clinical effects from alprostadil, including reduction in PDA.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concurrent administration of acetaminophen or NSAIDs in patients on alprostadil for maintaining patency of a patent ductus arteriosus (PDA).(1) DISCUSSION: NSAIDs and acetaminophen are used as management for patent ductus arteriosus (PDA) closure.(2-4) Alprostadil is used to maintain patency of a PDA.(1) In a case report, a 37-week gestational age neonate with cardiac defects required alprostadil therapy for PDA patency. After multiple doses of acetaminophen for pain, an echocardiogram showed reduction of the PDA requiring increased doses of alprostadil. Additional acetaminophen was discontinued. Follow up echocardiogram showed successful reversal of PDA reduction and alprostadil dose was reduced.(5) |
ALPROSTADIL, PROSTAGLANDIN E1, PROSTIN VR PEDIATRIC |
There are 30 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| NSAIDs/Corticosteroids SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of NSAIDs and corticosteroids result in additive risk of GI ulceration. CLINICAL EFFECTS: Concurrent use of NSAIDs and corticosteroids may increase the incidence and/or severity of GI irritation or ulceration, including increasing the risk for bleeding. PREDISPOSING FACTORS: Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased by concurrent use of anticoagulants, antiplatelets, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs); with longer duration of NSAID use; and with prior history of peptic ulcer disease and/or GI bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia, advanced liver disease). PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy carefully for signs of gastrointestinal ulceration. Use the lowest effective NSAID dose for the shortest duration possible. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report signs of GI bleeding such as black, tarry stools; "coffee ground" vomit; nausea; or stomach/abdominal pain. DISCUSSION: Concurrent use of NSAIDs and corticosteroids increase the risk of GI bleeding. |
ACTIVE INJECTION KIT D, AGAMREE, ALDOSTERONE, ALKINDI SPRINKLE, ANUCORT-HC, ANUSOL-HC, BECLOMETHASONE DIPROPIONATE, BETA 1, BETALOAN SUIK, BETAMETHASONE ACETATE MICRO, BETAMETHASONE ACETATE-SOD PHOS, BETAMETHASONE DIPROPIONATE, BETAMETHASONE SOD PHOS-ACETATE, BETAMETHASONE SOD PHOS-WATER, BETAMETHASONE SODIUM PHOSPHATE, BETAMETHASONE VALERATE, BSP 0820, BUDESONIDE, BUDESONIDE DR, BUDESONIDE EC, BUDESONIDE ER, BUDESONIDE MICRONIZED, CELESTONE, CLOBETASOL PROPIONATE MICRO, CORTEF, CORTENEMA, CORTIFOAM, CORTISONE ACETATE, DEFLAZACORT, DEPO-MEDROL, DESONIDE MICRONIZED, DESOXIMETASONE, DESOXYCORTICOSTERONE ACETATE, DEXABLISS, DEXAMETHASONE, DEXAMETHASONE ACETATE, DEXAMETHASONE ACETATE MICRO, DEXAMETHASONE INTENSOL, DEXAMETHASONE ISONICOTINATE, DEXAMETHASONE MICRONIZED, DEXAMETHASONE SOD PHOS-WATER, DEXAMETHASONE SODIUM PHOSPHATE, DEXAMETHASONE-0.9% NACL, DEXONTO, DMT SUIK, DOUBLEDEX, EMFLAZA, EOHILIA, FLUDROCORTISONE ACETATE, FLUNISOLIDE, FLUOCINOLONE ACETONIDE, FLUOCINOLONE ACETONIDE MICRO, FLUOCINONIDE MICRONIZED, FLUTICASONE PROPIONATE, FLUTICASONE PROPIONATE MICRO, HEMADY, HEMMOREX-HC, HEXATRIONE, HYDROCORTISONE, HYDROCORTISONE ACETATE, HYDROCORTISONE SOD SUCCINATE, HYDROCORTISONE-PRAMOXINE, KENALOG-10, KENALOG-40, KENALOG-80, LIDOCIDEX-I, MAS CARE-PAK, MEDROL, MEDROLOAN II SUIK, MEDROLOAN SUIK, METHYLPRED DP, METHYLPREDNISOLONE, METHYLPREDNISOLONE AC MICRO, METHYLPREDNISOLONE ACETATE, METHYLPREDNISOLONE SODIUM SUCC, MILLIPRED, MILLIPRED DP, MOMETASONE FUROATE, ORAPRED ODT, ORTIKOS, PEDIAPRED, PREDNISOLONE, PREDNISOLONE ACETATE MICRONIZE, PREDNISOLONE MICRONIZED, PREDNISOLONE SODIUM PHOS ODT, PREDNISOLONE SODIUM PHOSPHATE, PREDNISONE, PREDNISONE INTENSOL, PREDNISONE MICRONIZED, PRO-C-DURE 5, PRO-C-DURE 6, PROCTOCORT, RAYOS, SOLU-CORTEF, SOLU-MEDROL, TAPERDEX, TARPEYO, TRIAMCINOLONE, TRIAMCINOLONE ACETONIDE, TRIAMCINOLONE DIACETATE, TRIAMCINOLONE DIACETATE MICRO, TRILOAN II SUIK, TRILOAN SUIK, UCERIS, VERIPRED 20, ZCORT, ZILRETTA |
| NSAIDs; Salicylates/Loop Diuretics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: During concurrent administration of a loop diuretic and a nonsteroidal anti-inflammatory drug (NSAID), patients may retain sodium as a result of NSAID-induced prostaglandin inhibition. CLINICAL EFFECTS: The pharmacological effects of loop diuretics may be decreased due to reduced antihypertensive and diuretic actions. Concurrent use of NSAIDs with loop diuretics and renin-angiotensin system (RAS) inhibitors may result in increased risk of acute kidney injury (AKI). PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individuals susceptibility to AKI. PATIENT MANAGEMENT: Monitor patients for a decrease in the effects of the loop diuretic. It may be necessary to administer a higher dose of the diuretic or an alternative anti-inflammatory agent. Concurrent use of NSAIDs with loop diuretics and RAS inhibitors should be used with caution and monitored closely for signs of AKI. DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, RAS inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(19,20) In an observational study, current use of a triple therapy with a diuretic, RAS inhibitor, and NSAID, was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46). (21) Administration of indomethacin alone has been reported to decrease sodium excretion and increase blood pressure. In patients receiving a loop diuretic (e.g., bumetanide, furosemide), these effects interfere with clinical management. Several NSAIDs have been shown to interact with loop diuretics interfering with the pharmacological effects of the diuretic. In volunteers on sodium restricted diets, ibuprofen and indomethacin inhibited furosemide diuresis. |
BUMETANIDE, EDECRIN, ETHACRYNATE SODIUM, ETHACRYNIC ACID, FUROSCIX, FUROSEMIDE, FUROSEMIDE-0.9% NACL, LASIX, SOAANZ, TORSEMIDE |
| NSAIDs; Salicylates/Lithium SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Decreased renal excretion of lithium, possibly resulting from NSAID-induced prostaglandin inhibition. CLINICAL EFFECTS: May observe increased lithium toxicity. PREDISPOSING FACTORS: Risk factors for lithium toxicity include: renal impairment or worsening of existing renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics). Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors. PATIENT MANAGEMENT: The magnitude of this interaction is highly variable. Patients with predisposing factors, e.g. dehydration, renal impairment, or concurrent use of other agents which may impair lithium elimination, are expected to have a higher risk for lithium toxicity. If both drugs are administered, monitor plasma lithium levels and observe the patient for signs and symptoms of lithium toxicity or changes in renal function. Full effects of the addition or an increase in NSAID dose may not be seen for one to two weeks. Adjust the dose of lithium accordingly. If lithium is to be started in a patient stabilized on chronic NSAID therapy, consider starting with a lower lithium dose and titrate slowly as half-life may be prolonged. Monitor lithium concentrations until stabilized on the combination. Counsel the patient to contact their prescriber before starting an OTC NSAID. Assure that patients are familiar with signs and symptoms of lithium toxicity (e.g. new or worsening tremor, nausea/vomiting, diarrhea, ataxia, or altered mental status) and to report signs and symptoms of toxicity. DISCUSSION: Numerous studies and case reports have been documented that administration of a NSAID to a patient stabilized on lithium therapy may result in increased serum lithium levels and possible toxicity. Full effects may take 1 to 2 weeks to develop and may persist for a week after the NSAID is discontinued. |
LITHIUM CARBONATE, LITHIUM CARBONATE ER, LITHIUM CITRATE, LITHIUM CITRATE TETRAHYDRATE, LITHOBID |
| Angiotensin II Receptor Blocker (ARB)/NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Angiotensin II receptor blockers (ARBs) can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate. NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and may negate any decrease in blood pressure. CLINICAL EFFECTS: Concurrent use of ARBs with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion. Concurrent use of ARBs with NSAIDs and diuretics may result in increased risk of acute kidney injury (AKI). PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and use of diuretics can lead to hypovolemia and increased risk of AKI. PATIENT MANAGEMENT: Patients maintained on ARBs should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of ARBs. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent ARB therapy. Concurrent use of ARBs with NSAIDs and diuretics should be used with caution and monitored for signs of AKI. DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(22,23) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(24) In a population based cohort study, the concurrent use of NSAIDs with renin-angiotensin system (RAS) inhibitors in 5,710 hypertensive patients stabilized on antihypertensive therapy required hypertension treatment intensification. Adjusted hazard ratios (HR) for hypertension treatment intensification were 1.34 [95% CI 1.05-1.71] for NSAIDs in general, 1.79 (95% CI 1.15-2.78) for diclofenac and 2.02 (95% CI 1.09-3.77) for piroxicam. There were significant interactions between NSAIDs and angiotensin converting enzyme inhibitors (ACE inhibitors; HR 4.09, 95% CI 2.02-8.27) or angiotensin receptor blockers (ARBs; HR 3.62, 95% CI 1.80-7.31), but not with other antihypertensive drugs. |
AMLODIPINE-OLMESARTAN, AMLODIPINE-VALSARTAN, AMLODIPINE-VALSARTAN-HCTZ, ATACAND, ATACAND HCT, AVALIDE, AVAPRO, AZOR, BENICAR, BENICAR HCT, CANDESARTAN CILEXETIL, CANDESARTAN-HYDROCHLOROTHIAZID, COZAAR, DIOVAN, DIOVAN HCT, EDARBI, EDARBYCLOR, ENTRESTO, ENTRESTO SPRINKLE, EPROSARTAN MESYLATE, EXFORGE, EXFORGE HCT, HYZAAR, IRBESARTAN, IRBESARTAN-HYDROCHLOROTHIAZIDE, LOSARTAN POTASSIUM, LOSARTAN-HYDROCHLOROTHIAZIDE, MICARDIS, MICARDIS HCT, OLMESARTAN MEDOXOMIL, OLMESARTAN-AMLODIPINE-HCTZ, OLMESARTAN-HYDROCHLOROTHIAZIDE, TELMISARTAN, TELMISARTAN-AMLODIPINE, TELMISARTAN-HYDROCHLOROTHIAZID, TRIBENZOR, VALSARTAN, VALSARTAN-HYDROCHLOROTHIAZIDE |
| NSAIDs; Aspirin (Non-Cardioprotective)/Beta-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Unknown; however, possibly related to inhibition of prostaglandin by NSAIDs. CLINICAL EFFECTS: The antihypertensive action of beta-blockers may be decreased. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor patient's blood pressure and adjust the dose of the beta-blocker as needed. DISCUSSION: Concurrent administration of beta-blockers and NSAIDs has been associated with a clinically significant loss in antihypertensive response. The magnitude of the effect of NSAIDs on control of blood pressure by beta-blockers needs to be determined for each anti-inflammatory agent. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
ACEBUTOLOL HCL, ATENOLOL, ATENOLOL-CHLORTHALIDONE, BETAPACE, BETAPACE AF, BETAXOLOL HCL, BISOPROLOL FUMARATE, BISOPROLOL-HYDROCHLOROTHIAZIDE, BREVIBLOC, BYSTOLIC, CARVEDILOL, CARVEDILOL ER, COREG, COREG CR, CORGARD, ESMOLOL HCL, ESMOLOL HCL-SODIUM CHLORIDE, ESMOLOL HCL-WATER, HEMANGEOL, INDERAL LA, INDERAL XL, INNOPRAN XL, LABETALOL HCL, LABETALOL HCL-DEXTROSE, LABETALOL HCL-NACL, LABETALOL HCL-WATER, NADOLOL, NEBIVOLOL HCL, PINDOLOL, PROPRANOLOL HCL, PROPRANOLOL HCL ER, PROPRANOLOL-HYDROCHLOROTHIAZID, SOTALOL, SOTALOL AF, SOTALOL HCL, SOTYLIZE, TENORETIC 100, TENORETIC 50, TENORMIN, TIMOLOL MALEATE |
| Triamterene; Amiloride/Selected NSAIDs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown; however, nonsteroidal anti-inflammatory (NSAID) inhibition of prostaglandins may allow triamterene or amiloride- induced nephrotoxicity or hyperkalemia to occur in some patients. CLINICAL EFFECTS: Possible renal failure or hyperkalemia. PREDISPOSING FACTORS: Preexisting renal impairment. PATIENT MANAGEMENT: When possible, avoid concurrent therapy with triamterene or amiloride with NSAIDs. If these agents are used concurrently, monitor renal function and serum electrolytes. If decreased renal function or hyperkalemia develops, discontinue both agents. DISCUSSION: Acute renal failure and hyperkalemia have been reported in patients receiving concurrent therapy with therapeutic doses of triamterene or amiloride with NSAIDs. Although a majority of these reports have involved indomethacin, other NSAIDs have been implicated (diclofenac, flurbiprofen, and ibuprofen). |
AMILORIDE HCL, AMILORIDE-HYDROCHLOROTHIAZIDE, DYRENIUM, TRIAMTERENE, TRIAMTERENE-HYDROCHLOROTHIAZID |
| Digoxin/Ibuprofen; Indomethacin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism of this interaction is unknown, but it may involve decreased digoxin renal excretion. CLINICAL EFFECTS: Increased levels of digoxin which may result in digoxin toxicity. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, hallucinations, visual disturbances, and arrhythmias. PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity. PATIENT MANAGEMENT: Digoxin levels should be monitored and patients should be monitored for signs of digoxin toxicity during concurrent therapy. The dosage of digoxin may need to be decreased by 15-30% or the frequency of administration may be reduced. DISCUSSION: Although the documentation for this interaction is conflicting, caution is warranted. One study in 12 patients reported that serum digoxin levels were significantly increased (mean 59%) after concurrent administration of ibuprofen (1600 to 1800 mg/day) for seven days. However, there was no significant difference in digoxin levels after 28 days of concomitant therapy. In another study in eight patients, there was no significant change in digoxin serum concentration during concurrent administration of ibuprofen. Indomethacin-induced digoxin toxicity in three premature infants has been reported in one study. In another study, administration of indomethacin to 11 preterm infants who received intravenous digoxin followed by oral maintenance doses of digoxin resulted in a significant increase of digoxin serum concentration by 40.6% with a significant decrease in urine output by 47.7%. The digoxin half-life increased 125.5%. This study recommended decreasing the digoxin dosage by 50% when indomethacin is added to digoxin therapy in preterm infants until further assessments of urine output and digoxin levels are obtained. There are two case reports of digoxin toxicity in neonates following the addition of indomethacin to therapy. Administration of indomethacin to ten patients maintained on digoxin resulted in a 39.7% increase in digoxin concentrations. In contrast, the concurrent administration of indomethacin and digoxin in six healthy adults did not result in a significant pharmacokinetic or pharmacodynamic interaction. However, indomethacin did tend to elevate serum digoxin levels, strengthen the digoxin-induced decrease in ECG parameters and heart rate, and reduce the positive inotropic action of digoxin. In another study involving six healthy adults, the administration of indomethacin for three days followed by a single infusion of digoxin (750 mcg) did not affect any pharmacokinetic or pharmacodynamic parameters of digoxin. |
DIGITEK, DIGOXIN, DIGOXIN MICRONIZED, LANOXIN, LANOXIN PEDIATRIC |
| Selected NSAIDs/Selected CYP2C9 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The major metabolic pathway for many non-steroidal anti-inflammatory agents (NSAIDs) is CYP2C9. Inhibitors of CYP2C9 include: amiodarone, asciminib, cannabidiol, diosmin, fluconazole, ketoconazole, miconazole, nitisinone, oxandrolone, piperine, voriconazole, and zafirlukast.(1,2) CLINICAL EFFECTS: Concurrent use of NSAIDs with inhibitors of CYP2C9 may result in increased levels of and adverse effects from NSAIDs, including increased risk for bleeding. NSAIDs linked to this monograph are celecoxib, diclofenac, flurbiprofen, ibuprofen, meloxicam, naproxen, parecoxib, piroxicam and valdecoxib. PREDISPOSING FACTORS: Higher doses of either agent would be expected to increase the risk for serious adverse effects such as gastrointestinal bleeding (GIB) or renal failure. Patients who smoke, are elderly, debilitated, dehydrated, have renal impairment, or who have a history of GIB due to NSAIDs are also at increased risk for serious adverse events.(3-7) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Patients on routine NSAID therapy when an inhibitor of CYP2C9 is started should be evaluated for patient-specific risk factors for NSAID toxicity. Based upon this risk assessment, consider dose reduction of the NSAID or close monitoring for adverse effects. For a patient already receiving a CYP2C9 inhibitor when an NSAID is started, consider initiating the NSAID at a lower than usual dose, particularly when predisposing risk factors for harm are present. The manufacturer of celecoxib recommends that celecoxib be introduced at the lowest recommended dose in patients receiving fluconazole therapy.(3) The manufacturer of fluconazole states that half the dose of celecoxib may be necessary when fluconazole is added.(4) It would be prudent to follow this recommendation with other CYP2C9 inhibitors and to decrease the dose of celecoxib in patients in whom CYP2C9 inhibitors are added to celecoxib therapy. The manufacturer of diclofenac-misoprostol states that the total daily dose of diclofenac should not exceed the lowest recommended dose of 50 mg twice daily in patients taking CYP2C9 inhibitors.(5) It would be prudent to use the lowest recommended dose of other diclofenac formulations in patients taking CYP2C9 inhibitors. The manufacturer of parecoxib states that the dose of parecoxib should be reduced in those patients who are receiving fluconazole therapy.(6) It would be prudent to follow this recommendation with other CYP2C9 inhibitors. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: The concomitant administration of celecoxib and fluconazole (200 mg daily) resulted in a 2-fold increase in celecoxib plasma concentration.(3) In vitro studies in human hepatocytes found that amiodarone inhibited diclofenac metabolism.(7) In two separate studies, single doses of diclofenac (50 mg) or ibuprofen (400 mg) were coadministered with the last dose of voriconazole (400 mg q12h on Day 1, followed by 200 mg q12h on Day 2). Voriconazole increased the mean AUC of diclofenac by 78% and increased the AUC of the active isomer of ibuprofen by 100%.(8-10) Coadministration of diosmin increased diclofenac levels by 63%.(2) Coadministration of flurbiprofen or ibuprofen with fluconazole increased the AUC of flurbiprofen by 81% and of the active ibuprofen by 82% compared with either agent alone.(4) Concurrent voriconazole increased meloxicam AUC by 47%.(11,12) The concurrent administration of fluconazole and parecoxib resulted in increases in the area-under-curve (AUC) and maximum concentration (Cmax) of valdecoxib (the active metabolite of parecoxib) by 62% and 19%, respectively.(6) In a study, single dose diclofenac (50mg) given concurrently with the last dose of voriconazole (400 mg every 12 hours on Day 1, 200 mg every 12 hours on Day 2) increased Cmax and AUC by 2.1-fold and 1.8-fold, respectively. (5) Inhibitors of CYP2C9 include: amiodarone, asciminib, cannabidiol, diosmin, fluconazole, ketoconazole, miconazole, nitisinone, oxandrolone, piperine, voriconazole, and zafirlukast.(1,2) |
ACCOLATE, AMIODARONE HCL, AMIODARONE HCL-D5W, DIFLUCAN, EPIDIOLEX, FLUCONAZOLE, FLUCONAZOLE-NACL, KETOCONAZOLE, MICONAZOLE, MICONAZOLE NITRATE, NEXTERONE, NITISINONE, NITYR, ORAVIG, ORFADIN, OXANDRIN, OXANDROLONE, PACERONE, SCEMBLIX, VFEND, VFEND IV, VORICONAZOLE, ZAFIRLUKAST |
| Selected NSAIDs/Probenecid SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Probenecid may inhibit the renal tubular secretion of some NSAIDs. Probenecid may also prevent biliary clearance of NSAIDs. CLINICAL EFFECTS: The decreased clearance of NSAIDs may lead to increased blood levels and an increase in adverse effects. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for an increase in NSAID-related adverse effects, including renal insufficiency. The dose of the NSAID may need to be decreased or probenecid may need to be discontinued. DISCUSSION: Probenecid has been reported to increase the blood levels of indomethacin by 2-fold to 6-fold.(1,2) Probenecid has been reported to increase levels of oral ketoprofen by 93%;(3) however, no effect was seen on intramuscular ketoprofen in another study.(4) Probenecid has also been shown to increase naproxen levels.(5) Probenecid has been shown to increase the maximum concentration (Cmax) of tenoxicam. No other pharmacokinetic parameters were affected.(6) This interaction may result in clinical benefits in some patients. |
PROBENECID, PROBENECID-COLCHICINE |
| Heparins/NSAIDs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Heparin inhibits thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin.(1) NSAIDs inhibit coagulation by interfering with platelet-aggregation, while inhibition of prostaglandin synthesis increases the risk for gastrointestinal bleeding. CLINICAL EFFECTS: Concurrent use of heparin and an NSAID may increase the risk for bleeding.(1,2) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., other anticoagulants, antiplatelets, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. PATIENT MANAGEMENT: Manufacturers recommend caution and monitoring when using this combination of drugs.(1,2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: Based upon drug mechanisms of action, careful monitoring would be prudent. |
AA 2%-D5W-CALCIUM-HEPARIN, AA 6%-D10W-CALCIUM-HEPARIN, ARIXTRA, ELMIRON, ENOXAPARIN SODIUM, ENOXILUV, FONDAPARINUX SODIUM, FRAGMIN, HEPARIN SODIUM, HEPARIN SODIUM IN 0.45% NACL, HEPARIN SODIUM-0.45% NACL, HEPARIN SODIUM-0.9% NACL, HEPARIN SODIUM-D5W, LOVENOX, PENTOSAN POLYSULFATE SODIUM |
| SSRIs; SNRIs/Selected NSAIDs; Aspirin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets. CLINICAL EFFECTS: Concurrent use of a selective serotonin reuptake inhibitor(1-7,13) or a serotonin-norepinephrine reuptake inhibitor(8-10) and a NSAID may result in bleeding. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., anticoagulants, antiplatelets, or corticosteroids. Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(15) PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-7,13) or serotonin-norepinephrine reuptake inhibitors(8-10) and NSAIDs should be used concurrently with caution. Patients should be warned about the increased risk of bleeding and be educated about signs and symptoms of bleeding.(1-11,13) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anti-platelet agents in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(11) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(12) |
CELEXA, CITALOPRAM HBR, CYMBALTA, DESVENLAFAXINE ER, DESVENLAFAXINE SUCCINATE ER, DRIZALMA SPRINKLE, DULOXETINE HCL, DULOXICAINE, EFFEXOR XR, ESCITALOPRAM OXALATE, FETZIMA, FLUOXETINE DR, FLUOXETINE HCL, FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER, LEXAPRO, OLANZAPINE-FLUOXETINE HCL, PAROXETINE CR, PAROXETINE ER, PAROXETINE HCL, PAROXETINE MESYLATE, PAXIL, PAXIL CR, PRISTIQ, PROZAC, SAVELLA, SERTRALINE HCL, SYMBYAX, TRINTELLIX, VENLAFAXINE BESYLATE ER, VENLAFAXINE HCL, VENLAFAXINE HCL ER, VIIBRYD, VILAZODONE HCL, ZOLOFT |
| Selected Nephrotoxic Agents/Cisplatin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The nephrotoxic effects of aminoglycosides or non-steroidal anti-inflammatory drugs (NSAIDs) may be additive to those of cisplatin. CLINICAL EFFECTS: The concurrent administration of amikacin, gentamicin, tobramycin, or NSAIDs with cisplatin may result in additive nephrotoxic effects.(1,2,5,6) PREDISPOSING FACTORS: Pre-existing renal insufficiency, advanced age, dehydration may increase the risk of nephrotoxicity.(1,5,6) PATIENT MANAGEMENT: The US labeling for aminoglycosides and cisplatin states that the concurrent use of aminoglycosides and cisplatin should be avoided.(1,3,4,6) Inform patients that concurrent cisplatin and aminoglycosides or NSAIDs can cause nephrotoxicity and that renal function and electrolyte monitoring during treatment is necessary.(2) DISCUSSION: The US manufacturers of amikacin, gentamicin and tobramycin state that since the nephrotoxic effects of these medications may be additive, avoid concurrent or sequential use of other neurotoxic and/or nephrotoxic agents including cisplatin.(1,3,6) |
CISPLATIN, KEMOPLAT |
| Drospirenone/NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Drospirenone has antimineralocorticoid activity and may cause hyperkalemia. NSAIDs may also increase potassium levels.(1) CLINICAL EFFECTS: Concurrent use of drospirenone and NSAIDs may result in hyperkalemia.(1) PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium supplements, ACE inhibitors, angiotensin II receptor antagonists, heparin, and potassium-sparing diuretics may increase potassium levels.(1) PATIENT MANAGEMENT: Patients receiving drospirenone with a NSAID should have their serum potassium level checked during the first treatment cycle.(1) DISCUSSION: Drospirenone has antimineralocorticoid activity comparable to 25 mg of spironolactone and may result in hyperkalemia. Concurrent use of NSAIDs may also increase potassium levels.(1) Occasional or chronic use of NSAIDs was not restricted in clinical trials of drospirenone.(1) |
ANGELIQ, BEYAZ, DROSPIRENONE-ETH ESTRA-LEVOMEF, DROSPIRENONE-ETHINYL ESTRADIOL, JASMIEL, LO-ZUMANDIMINE, LORYNA, NEXTSTELLIS, NIKKI, OCELLA, SAFYRAL, SLYND, SYEDA, TYDEMY, VESTURA, YASMIN 28, YAZ, ZARAH, ZUMANDIMINE |
| Tenofovir/Selected Nephrotoxic Agents SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Tenofovir and other nephrotoxic agents may result in additive or synergistic effects on renal function and increase nephrotoxicity risk.(1) CLINICAL EFFECTS: Concurrent use of tenofovir and other nephrotoxic agents may result in renal toxicity and acute renal failure.(1) Reports of acute renal failure and Fanconi syndrome have been reported with tenofovir use.(2,3) However, this has been reported in 3 case reports and the renal failure may have been complicated by other pre-existing conditions.(2) PREDISPOSING FACTORS: Pre-existing renal dysfunction, long duration of use, low body weight, concomitant use of drugs that may increase tenofovir levels may increase the risk of nephrotoxicity.(1) PATIENT MANAGEMENT: The US prescribing information for tenofovir recommends avoiding concurrent or recent use of a nephrotoxic agent.(3) Evaluate renal function prior to initiation of concurrent therapy and continue renal function monitoring during therapy. Dose adjustments may be required for impaired renal function. Tenofovir should be avoided with high-dose or multiple NSAIDs. Alternatives to NSAIDs should be considered in patients at risk for renal dysfunction.(3) Patients receiving concurrent NSAIDs with tenofovir should be monitored for possible renal toxicity.(1,2) The dosing interval should be adjusted in patients with a baseline creatinine clearance of less than 50 ml/min.(1-3) DISCUSSION: From March 18, 2003 to December 1, 2005, Health Canada received 10 reports of nephrotoxic reactions with tenofovir. Three of these occurred following the addition of a NSAID to tenofovir therapy. In the first report, a patient maintained on tenofovir for 29 months developed acute renal failure and acute tubular necrosis requiring dialysis 5 days after beginning indomethacin (100 mg rectally twice daily). In the second report, a patient maintained on tenofovir for 7 months developed acute renal failure and acute tubular necrosis after taking 90 tablets of naproxen (375 mg) over 2 months. The patient died. In the third report, a patient maintained on tenofovir for over a year developed acute renal failure and nephrotic syndrome after 2 months of valdecoxib (20 mg daily) therapy. Symptoms subsided following discontinuation of valdecoxib.(1) |
ATRIPLA, BIKTARVY, CIMDUO, COMPLERA, DELSTRIGO, DESCOVY, EFAVIRENZ-EMTRIC-TENOFOV DISOP, EFAVIRENZ-LAMIVU-TENOFOV DISOP, EMTRICITABINE-TENOFOVIR DISOP, GENVOYA, ODEFSEY, STRIBILD, SYMFI, SYMFI LO, SYMTUZA, TENOFOVIR DISOPROXIL FUMARATE, TRUVADA, VEMLIDY, VIREAD |
| Aspirin (for Cardioprotection)/Selected NSAIDs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Some non-steroidal anti-inflammatory agents (NSAIDs) are reversible inhibitors of cyclooxygenase and aspirin is an irreversible inhibitor. If these NSAIDs are given before aspirin, the aspirin will not be able to bind to the cyclooxygenase site, which will result in a lack of effect. CLINICAL EFFECTS: The antiplatelet and cardioprotective effect of aspirin may be decreased with the concurrent use of some NSAIDs, particularly during the washout period of the NSAID. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Consideration should be given to use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or a non-NSAID analgesic if appropriate. If an NSAID must be used, cardioprotective doses of aspirin should be administered before taking any NSAIDs. Single doses of ibuprofen should be given at least 8 hours before or at least 2 hours after immediate release aspirin. The administration of other NSAIDs should be separated from aspirin by at least 2 hours. DISCUSSION: The cardioprotective effect from aspirin is based on the antiplatelet effects. The irreversible inhibition of cyclooxygenase mediates the antiplatelet effects. Administration of a reversible inhibitor or cyclooxygenase blocks the irreversible effect of aspirin on the platelets. This effect has been seen with celecoxib, flufenamic acid, ibuprofen, indomethacin, naproxen, nimesulide, oxaprozin, piroxicam, and tiaprofenic acid but not with diclofenac, etoricoxib, ketorolac, meloxicam, or sulindac. In a study of 80 healthy volunteers, aspirin antiplatelet activity, measured by % thromboxane B2 inhibition (TxB2), was decreased when naproxen 220 mg daily was given simultaneously with or 30 minutes before aspirin 81 mg daily for 10 days (98.7% aspirin alone vs 93.1% and 87.7% naproxen and aspirin). The interaction persisted at least 1 day following discontinuation of naproxen but was normalized by the 3rd day. In a nationwide cohort study, patients were evaluated for thromboembolic cardiovascular and clinically relevant bleeding events with concurrent antithrombotic and ongoing NSAID treatment. A total of 108,232 patients were followed for a mean of 2.3 +/- 1.8 years after diagnosis of myocardial infarction. Concomitant NSAID treatment significantly increased the risk for cardiovascular events (hazard ratio (HR) 6.96; 95% CI 6.24 - 6.77; p<0.001) and bleeding events (HR 4.08; 95% CI 3.51 - 4.73; p<0.001) compared to no NSAID treatment. NSAIDs were further evaluated and revealed the use of celecoxib (HR: 4.65; 95% CI: 3.17 to 6.82; p < 0.001, and 3.44; 95% CI: 2.20 to 5.39; p < 0.001, respectively) and meloxicam (HR: 3.03; 95% CI: 1.68 to 5.47; p < 0.001, and 2.80; 95% CI: 1.40 to 5.60; p < 0.001, respectively) had the lowest risk for cardiovascular and bleeding events, receptively. |
ACETYL SALICYLIC ACID, ASPIRIN, ASPIRIN-DIPYRIDAMOLE ER, DURLAZA |
| Erlotinib/NSAIDs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. CLINICAL EFFECTS: Concurrent use of NSAIDs may increase the risk of gastrointestinal bleeding and/or perforation in patients receiving erlotinib. Fatalities have been reported.(1) PREDISPOSING FACTORS: Patients with a history of peptic ulceration or diverticular disease or who are receiving concomitant anti-angiogenic, corticosteroids, and/or taxane-based chemotherapy may be an increased risk of gastrointestinal perforation.(1) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding. PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy for signs of gastrointestinal bleeding and/or perforation. Discontinue erlotinib in patients who develop gastrointestinal perforation.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: Infrequent cases of gastrointestinal bleeding were reported during erlotinib trials. Some cases were associated with NSAID administration.(1) In a phase II trial of concurrent bevacizumab plus erlotinib, 2 of 13 patients suffered fatal gastrointestinal perforations.(2) In another phase II trial of concurrent bevacizumab with erlotinib, 1 of 104 patients died of gastrointestinal perforation.(3) |
ERLOTINIB HCL, TARCEVA |
| Selected Nephrotoxic Agents/Adefovir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Recommended doses of adefovir have been associated with delayed nephrotoxicity.(1-4) Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1) CLINICAL EFFECTS: Concurrent use of adefovir with nephrotoxic agents such as intravenous aminoglycosides, amphotericin B, cyclosporine, tacrolimus,tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, intravenous pentamidine, and streptozocin. PREDISPOSING FACTORS: Patients with pre-existing renal impairment(1,2) or receiving multiple nephrotoxic agents appear to be at greater risk for nephrotoxicity. PATIENT MANAGEMENT: Evaluate renal function prior to initiation of concurrent therapy and continue renal function monitoring during therapy. Dose adjustments may be required for impaired renal function. Weigh the risks and benefits of concurrent therapy in patients with treatment-emergent nephrotoxicity. DISCUSSION: Because of the known risks for adefovir nephrotoxicity, particularly at higher than recommended doses, the safety of adefovir has not been studied in patients receiving other known potentially nephrotoxic agents. |
ADEFOVIR DIPIVOXIL, HEPSERA |
| Ibrutinib/Selected Anticoagulants; Antiplatelets SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ibrutinib administration lowers platelet count in the majority of patients.(1,2) In addition, ibrutinib has been shown to inhibit collagen-mediated platelet aggregation.(3-4) Bleeding has been reported with the use of ibrutinib,(1-4) anticoagulants, or antiplatelets alone. CLINICAL EFFECTS: Concurrent use of ibrutinib with either anticoagulants or antiplatelets may increase the risk of hemorrhage. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: The Canadian product monograph for ibrutinib recommends concurrent use with anticoagulants or antiplatelets should be approached with caution. If therapeutic anticoagulation is required, consider temporarily withholding ibrutinib therapy until stable anticoagulation in achieved.(2) The US prescribing information for ibrutinib states patients receiving concurrent therapy with ibrutinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in International Normalized Ratio (INR). Carefully weigh the risks vs. benefits of concurrent therapy in patients with significant thrombocytopenia. If a bleeding event occurs, follow manufacturer instructions for ibrutinib dose adjustment.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: Bleeding has been reported with ibrutinib alone.(1-3) Across 27 clinical trials, grade 3 or higher bleeding events, e.g. subdural hematoma, gastrointestinal bleeding or hematuria, have occurred in up to 4% of patients, with 0.4% fatality. Grade 3 or 4 thrombocytopenia occurred in 5-19% of patients. Bleeding events of any grade occurred in 39% of patients treated with ibrutinib.(1) Concurrent use of anticoagulants or antiplatelets has been reported to increase the risk for major bleeding. In clinical trials, major bleeding occurred in 3.1% of patients taking ibrutinib without concurrent anticoagulants or antiplatelets, 4.4% of patients on concurrent antiplatelets with or without anticoagulants, and 6.1% of patients on concurrent anticoagulants with or without antiplatelets.(1) In an open-label, phase 2 trial of patients with relapsed/refractory mantle cell lymphoma on ibrutinib, 61 patients (55%) on concurrent anticoagulants or antiplatelets had a higher rate of bleeding (69% any grade, 8% grade 3-4) than patients not on anticoagulants or antiplatelets (28% any grade, 4% grade 3-4).(5) A retrospective trial found a hazard ratio of 20 (95% CI, 2.1-200) for patients on ibrutinib with concurrent anticoagulants and antiplatelets. There was a trend towards an increased bleeding risk in patients on either anticoagulants or antiplatelets, but this was not statistically significant on multivariate analysis.(6) A case report of 2 patients with chronic lymphocytic leukemia (CLL) on ibrutinib and dabigatran demonstrated no stroke nor bleeding events during the mean 11.5 month follow-up.(7) A case report of 4 patients with lymphoproliferative disease on concurrent dabigatran and ibrutinib demonstrated no stroke nor major bleeding events. 1 patient experienced grade 2 conjunctival hemorrhage whilst on both ibrutinib and dabigatran. The anticoagulant was withheld and successfully re-initiated at a lower dose with no further bleeding events.(8) |
IMBRUVICA |
| Aldosterone Receptor Antagonists/NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown; however, nonsteroidal anti-inflammatory (NSAID) inhibition of prostaglandins may allow eplerenone, finerenone, or spironolactone-induced nephrotoxicity or hyperkalemia to occur in some patients.(1-3) In some patients, NSAIDs may reduce the diuretic, natriuretic and antihypertensive effects of eplerenone, finerenone, or spironolactone.(1-3) CLINICAL EFFECTS: Concurrent use of eplerenone, finerenone, or spironolactone with NSAIDs may result in renal failure or hyperkalemia. The effects of the diuretic, natriuretic, or antihypertensive effects of eplerenone, finerenone, or spironolactone may be decreased.(1-3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: When possible, avoid concurrent therapy with eplerenone, finerenone, or spironolactone with NSAIDs. If these agents are used concurrently, monitor renal function and serum electrolytes. If decreased renal function or hyperkalemia develops, discontinue both agents. The manufacturer of eplerenone recommends checking serum potassium and serum creatinine within 3-7 days of concurrent therapy with NSAIDs.(1) The manufacturer of spironolactone states concurrent use with NSAIDs may lead to severe hyperkalemia and extreme caution should be used during concurrent therapy.(2) DISCUSSION: Although acute renal failure and hyperkalemia have only been reported in studies and case reports involving indomethacin, diclofenac, flurbiprofen, and ibuprofen with either triamterene or amiloride, the proposed mechanism suggests that all nonsteroidal anti-inflammatory agents may be capable of this interaction with all potassium-sparing diuretics. Patients receiving diuretics are at an increased risk of NSAID-induced renal failure. |
ALDACTONE, CAROSPIR, EPLERENONE, INSPRA, KERENDIA, SPIRONOLACTONE, SPIRONOLACTONE-HCTZ |
| Selected Nephrotoxic Agents/Immune Globulin IV (IGIV) SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, can cause renal dysfunction, acute renal failure, osmotic nephrosis, and/or death. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1-4) CLINICAL EFFECTS: Concurrent use of Immune Globulin Intravenous (IGIV) products with nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, non-steroidal anti-inflammatory agents, tenofovir, and vancomycin may result in renal toxicity.(1-4) Other nephrotoxic agents include capreomycin, gallium nitrate, and streptozocin. PREDISPOSING FACTORS: Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs.(1-4) Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose.(3-4) PATIENT MANAGEMENT: For patients at risk of renal dysfunction or renal failure, the US manufacturers of Immune Globulin Intravenous (IGIV) products recommends administration at the minimum dose and infusion rate practicable; ensure adequate hydration in patients before administration; and monitor renal function and urine output with assessment of blood urea nitrogen (BUN) and serum creatinine before initial infusion and at regular intervals during therapy.(1-3) Concurrent administration of potentially nephrotoxic agents should be avoided.(1) Review prescribing information for IGIV product to be administered for sucrose content. If concurrent therapy is warranted, monitor renal function closely. In high risk patients, consider selecting an IGIV product that does not contain sucrose. DISCUSSION: The safety of Immune Globulin Intravenous (IGIV) has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is a major toxicity of IGIV products.(1-3) A review of the FDA renal adverse events (RAEs) (i.e. acute renal failure or insufficiency) from June 1985 to November 1998 identified 120 reports worldwide associated with IGIV administration. In the US, the FDA received 88 reports of cases with clinical and/or laboratory findings consistent with RAE (i.e. increased serum creatinine, oliguria, and acute renal failure). Patient cases involved a median age of 60.5 years and 55% were male. Of the 54 patients who developed acute renal failure, 65% were greater than 65 years, 56% had diabetes, and 26% had prior renal insufficiency; 59% had one, 35% had two, and 6% had three of these conditions. Upon review of the IGIV product received, 90% of cases received sucrose-containing IGIV products with the remaining patients receiving either maltose- or glucose-containing products. Approximately 40% of affected patients required dialysis and RAE may have contributed to death in 15% of patients.(4) |
ALYGLO, BIVIGAM, CUTAQUIG, CUVITRU, FLEBOGAMMA DIF, GAMMAGARD LIQUID, GAMMAGARD S-D, GAMMAKED, GAMMAPLEX, GAMUNEX-C, HIZENTRA, HYQVIA, HYQVIA IG COMPONENT, OCTAGAM, PANZYGA, PRIVIGEN, XEMBIFY |
| Desmopressin/Agents with Hyponatremia Risk SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Carbamazepine, chlorpromazine, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants increase the risk of hyponatremia.(1-3) CLINICAL EFFECTS: Concurrent use may increase the risk of hyponatremia with desmopressin.(1-3) PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (glucocorticoids, loop diuretics). PATIENT MANAGEMENT: The concurrent use of agents with a risk of hyponatremia with desmopressin may increase the risk of hyponatremia. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1) DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4) |
DDAVP, DESMOPRESSIN ACETATE, NOCDURNA |
| Aliskiren/NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. It is believed to be related to inhibition of prostaglandin synthesis by the NSAIDs. Use of an NSAID in combination with aliskiren, whose hypotensive effects may be related to the increase in hypotensive prostaglandins, may negate any decrease in blood pressure. CLINICAL EFFECTS: Concurrent use of aliskiren with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients maintained on aliskiren should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of aliskiren. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent aliskiren therapy. DISCUSSION: Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. Studies have shown that sulindac does not affect the antihypertensive effects of captopril and enalapril. |
ALISKIREN, TEKTURNA |
| ACE Inhibitors/Selected NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: ACE inhibitors can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate. NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and may negate any decrease in blood pressure. CLINICAL EFFECTS: Concurrent use of ACE inhibitors with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion. Concurrent use of ACE inhibitors with NSAIDs and diuretics may result in increased risk of acute kidney injury (AKI). PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individuals susceptibility to AKI. PATIENT MANAGEMENT: Patients maintained on ACE inhibitors should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of ACE inhibitors. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent ACE inhibitor therapy. Concurrent use of ACE inhibitors with NSAIDs and diuretics should be used with caution and monitored closely for signs of AKI. DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(30,31) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(32) Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. Studies have shown that sulindac does not affect the antihypertensive effects of captopril and enalapril. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
ACCUPRIL, ACCURETIC, ALTACE, AMLODIPINE BESYLATE-BENAZEPRIL, BENAZEPRIL HCL, BENAZEPRIL-HYDROCHLOROTHIAZIDE, CAPTOPRIL, CAPTOPRIL-HYDROCHLOROTHIAZIDE, ENALAPRIL MALEATE, ENALAPRIL-HYDROCHLOROTHIAZIDE, ENALAPRILAT, EPANED, FOSINOPRIL SODIUM, FOSINOPRIL-HYDROCHLOROTHIAZIDE, LISINOPRIL, LISINOPRIL-HYDROCHLOROTHIAZIDE, LOTENSIN, LOTENSIN HCT, LOTREL, MOEXIPRIL HCL, PERINDOPRIL ERBUMINE, PRESTALIA, QBRELIS, QUINAPRIL HCL, QUINAPRIL-HYDROCHLOROTHIAZIDE, RAMIPRIL, TRANDOLAPRIL, TRANDOLAPRIL-VERAPAMIL ER, VASERETIC, VASOTEC, ZESTORETIC, ZESTRIL |
| Fruquintinib; Surufatinib/Anticoagulants; Antiplatelets SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Bleeding has been reported with the use of fruquintinib and surufatinib.(1,2) CLINICAL EFFECTS: Concurrent use of fruquintinib or surufatinib with either anticoagulants or antiplatelets may increase the risk of hemorrhage.(1,2) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Patients receiving concurrent therapy with fruquintinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in International Normalized Ratio (INR). If a serious bleeding event occurs, the manufacturer recommends permanent discontinuation of fruquintinib.(1) Patients receiving concurrent therapy with surufatinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in INR.If a serious bleeding event occurs, the manufacturer recommends permanent discontinuation of surufatinib.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: Bleeding has been reported with fruquintinib in three randomized, double-blinded, placebo-controlled clinical trials. The incidence of grade 1 and grade 2 bleeding events was 28.2%, including gastrointestinal bleeding (10.9%), hematuria (10.6%), and epistaxis (7.5%). The incidence of grade 3 or higher bleeding events was 2.1% and included gastrointestinal bleeding (1.6%) and hemoptysis (0.5%).(1) Bleeding has been reported with surufatinib in clinical trials. Grade 1 and 2 bleeding events included gastrointestinal bleeding, blood in the urine, and gum bleeding. The incidence of grade 3 or greater bleeding events was 4.5%, including gastrointestinal hemorrhage (1.9%), and cerebral hemorrhage (1.1%). Fatalities due to bleeding were reported in 0.3% of patients. The incidence of permanent discontinuation due to bleeding was 2.6% and the incidence of suspension of surufatinib due to bleeding was 3.8%.(2) |
FRUZAQLA |
| Plasminogen/Anticoagulants; Antiplatelets SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Bleeding has been reported with the use of plasminogen.(1) CLINICAL EFFECTS: Concurrent use of plasminogen with either anticoagulants or antiplatelets may increase the risk of active bleeding during plasminogen therapy, including bleeding from mucosal disease-related lesions that may manifest as gastrointestinal (GI) bleeding, hemoptysis, epistaxis, vaginal bleeding, or hematuria.(1) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Patients receiving concurrent therapy with plasminogen and anticoagulants and/or antiplatelets should be closely monitored during plasminogen therapy for active bleeding from mucosal disease-related lesions, including GI bleeding, hemoptysis, epistaxis, vaginal bleeding, or hematuria.(1) Prior to initiation of treatment with plasminogen, confirm healing of lesions or wounds suspected as a source of a recent bleeding event. Monitor patients during and for 4 hours after infusion when administering plasminogen with concurrent anticoagulants, antiplatelet drugs, or other agents which may interfere with normal coagulation.(1) If patient experiences uncontrolled bleeding (defined as any gastrointestinal bleeding or bleeding from any other site that persists longer than 30 minutes), seek emergency care and discontinue plasminogen immediately.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: Plasminogen has not been studied in patients at an increased risk of bleeding. Bleeding has been reported with plasminogen in a two single-arm, open-label clinical trials as well as in compassionate use programs. The incidence of hemorrhage in patients with Plasminogen Deficiency Type 1 was 16% (3/19 patients).(1) One of the bleeding events occurred two days after receiving the second dose of plasminogen in a patient with a recent history of GI bleeding due to gastric ulcers. The patient received plasminogen through a compassionate use program and the dose was 6.6 mg/kg body weight every 2 days. Endoscopy showed multiple ulcers with one actively bleeding ulcer near the pylorus.(1) |
RYPLAZIM |
| Tisotumab/Anticoagulants; Antiplatelets SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Bleeding, including hemorrhage, has been reported with the use of tisotumab.(1) CLINICAL EFFECTS: Concurrent use of tisotumab with either anticoagulants, antiplatelets, or NSAIDs may increase the risk of hemorrhage.(1) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Patients receiving concurrent therapy with tisotumab and anticoagulants, antiplatelets, and/or NSAIDs should be closely monitored for signs and symptoms of bleeding and changes in platelet count or International Normalized Ratio (INR). For patients experiencing pulmonary or central nervous system (CNS) hemorrhage, permanently discontinue tisotumab. For grade 2 or greater hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage. After resolution, either resume treatment or permanently discontinue tisotumab.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: Hemorrhage occurred in 62% of patients with cervical cancer treated with tisotumab across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients.(1) |
TIVDAK |
| Sparsentan/NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Sparsentan is an endothelin and angiotensin II receptor antagonist.(1) Angiotensin II receptor blockers can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate. NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction. CLINICAL EFFECTS: Concurrent use of sparsentan with NSAIDs (including selective COX-2 inhibitors) may result in renal hypoperfusion and deterioration of renal clearance, including possible acute kidney injury (AKI). These effects are usually reversible.(1) PREDISPOSING FACTORS: Patients older than 75 years old, with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion (including from diuretic use and dehydration) may be at greater risk for AKI.(1-3) PATIENT MANAGEMENT: Monitor for signs of worsening renal function if an NSAID (including selective COX-2 inhibitors) is used concurrently with sparsentan. If renal function deteriorates, the NSAID may need to be discontinued.(1) DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(2,3) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(4) |
FILSPARI |
| NSAIDs; Aspirin (Non-Cardioprotective)/Metoprolol SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Unknown; however, possibly related to inhibition of prostaglandin by NSAIDs. CLINICAL EFFECTS: The antihypertensive action of metoprolol may be decreased. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor patient's blood pressure and adjust the dose of metoprolol as needed. DISCUSSION: Concurrent administration of metoprolol and NSAIDs has been associated with a clinically significant loss in antihypertensive response. The magnitude of the effect of NSAIDs on control of blood pressure by beta-blockers needs to be determined for each anti-inflammatory agent. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
KAPSPARGO SPRINKLE, LOPRESSOR, METOPROLOL SUCCINATE, METOPROLOL TARTRATE, METOPROLOL-HYDROCHLOROTHIAZIDE, TOPROL XL |
| NSAIDs; Salicylates/Minoxidil SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Oral minoxidil functions as a direct-acting peripheral vasodilator, lowering elevated systolic and diastolic blood pressure by reducing resistance in peripheral blood vessels. This triggers a compensatory increase in cardiac output and renin secretion and results in sodium and water retention. NSAIDs inhibit prostaglandin synthesis and also result in sodium and water retention.(1,2) CLINICAL EFFECTS: The risk of heart failure may increase with oral minoxidil and NSAIDs due to their combined effects on blood vessel dilation, fluid retention, and altered sodium balance. Minoxidil efficacy may be compromised.(1,2) PREDISPOSING FACTORS: Higher doses of oral minoxidil have been associated with serious adverse events, including hypotensive syncope, pericarditis, pericardial effusion, and myocardial infarction.(1-5) PATIENT MANAGEMENT: Closely monitor body weight, fluid and electrolyte balance, and blood pressure when using oral minoxidil and NSAIDs concurrently. Minoxidil tablets should be co-administered with an appropriate diuretic to prevent fluid retention and potential congestive heart failure. A high-ceiling (loop) diuretic is often necessary alongside vigilant monitoring of body weight. Without concurrent diuretic use, minoxidil may lead to the retention of salt and water within a few days.(1,2) DISCUSSION: While the manufacturer of minoxidil does not provide specific recommendations regarding NSAID co-administration, it emphasizes the necessity of combining minoxidil with a beta-blocker to prevent tachycardia and increased myocardial workload. Additionally, concurrent use with a diuretic is recommended to avert serious fluid accumulation and potential congestive heart failure. NSAID labeling warns about fluid retention, edema, an elevated risk of heart failure, and potential drug interactions with beta-blockers and diuretics which can result in a blunting of the antihypertensive and cardiovascular effects of these agents.(1-5) |
MINOXIDIL |
| T Cell Immunotherapies/NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: NSAIDs augment the immune system. Concurrent use with NSAIDs may interfere with the activity of CAR-T cell immunotherapies.(1) CLINICAL EFFECTS: NSAIDs may decrease the efficacy of CAR-T cell immunotherapies.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: NSAIDs should be used with caution with or after CAR-T cell immunotherapy.(1) DISCUSSION: An in vitro study showed aspirin and celecoxib negatively affected CD19.CAR-T cells through their effects on the induction of apoptosis, reduction of activation, and impairment of proliferation.(1) |
ABECMA, AMTAGVI, BREYANZI, BREYANZI CD4 COMPONENT, BREYANZI CD8 COMPONENT, CARVYKTI, KYMRIAH, TECARTUS, TECELRA, YESCARTA |
The following contraindication information is available for ADVIL (chlorpheniramine maleate/pseudoephedrine hcl/ibuprofen):
Drug contraindication overview.
Ibuprofen is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to the drug or any ingredient in the formulation. NSAIAs generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, often fatal, anaphylactic reactions may occur in such patients. Although NSAIAs generally are contraindicated in these patients, the drugs have occasionally been used in NSAIA-sensitive patients who have undergone desensitization.
Because patients with asthma may have aspirin-sensitivity asthma, patients with asthma but without known aspirin sensitivity who are receiving ibuprofen should be monitored for changes in manifestations of asthma. In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad. Patients who are considering use of ibuprofen for self-medication should be advised that ibuprofen is contraindicated in patients who have experienced asthma, urticaria, or other sensitivity reaction to other analgesics or antipyretics.
For further discussion of cross-sensitivity of NSAIAs, see Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08.04.24.
NSAIAs are contraindicated in the setting of CABG surgery. Ibuprofen lysine is contraindicated in neonates with congenital heart disease when patency of the ductus arteriosus is necessary for adequate pulmonary or systemic blood flow (e.g., neonates with pulmonary atresia, severe tetralogy of Fallot, or severe coarctation of the aorta); in premature neonates with suspected necrotizing enterocolitis; in neonates with proven or suspected, untreated infection; and in neonates with substantially impaired renal function.
Ibuprofen is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to the drug or any ingredient in the formulation. NSAIAs generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, often fatal, anaphylactic reactions may occur in such patients. Although NSAIAs generally are contraindicated in these patients, the drugs have occasionally been used in NSAIA-sensitive patients who have undergone desensitization.
Because patients with asthma may have aspirin-sensitivity asthma, patients with asthma but without known aspirin sensitivity who are receiving ibuprofen should be monitored for changes in manifestations of asthma. In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad. Patients who are considering use of ibuprofen for self-medication should be advised that ibuprofen is contraindicated in patients who have experienced asthma, urticaria, or other sensitivity reaction to other analgesics or antipyretics.
For further discussion of cross-sensitivity of NSAIAs, see Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08.04.24.
NSAIAs are contraindicated in the setting of CABG surgery. Ibuprofen lysine is contraindicated in neonates with congenital heart disease when patency of the ductus arteriosus is necessary for adequate pulmonary or systemic blood flow (e.g., neonates with pulmonary atresia, severe tetralogy of Fallot, or severe coarctation of the aorta); in premature neonates with suspected necrotizing enterocolitis; in neonates with proven or suspected, untreated infection; and in neonates with substantially impaired renal function.
There are 7 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Aspirin exacerbated respiratory disease |
| Cerebrovascular accident |
| History of kidney donation |
| History of roux-en-Y gastric bypass |
| Post-operative from CABG surgery |
| Pregnancy |
| Renal transplant |
There are 12 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Acute myocardial infarction |
| Alcohol use disorder |
| Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min |
| Chronic kidney disease stage 5 (failure) GFr<15 ml/min |
| CYp2c9 intermediate metabolizer (activity score 1) |
| CYp2c9 poor metabolizer |
| Gastrointestinal hemorrhage |
| Gastrointestinal perforation |
| Gastrointestinal ulcer |
| Increased risk of bleeding |
| Systemic mastocytosis |
| Thrombotic disorder |
There are 6 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Chronic heart failure |
| Disease of liver |
| Hypertension |
| Increased risk of bleeding due to coagulation disorder |
| Kidney disease with likely reduction in glomerular filtration rate (GFr) |
| Tobacco smoker |
The following adverse reaction information is available for ADVIL (chlorpheniramine maleate/pseudoephedrine hcl/ibuprofen):
Adverse reaction overview.
No enhanced Common Adverse Effects information available for this drug.
No enhanced Common Adverse Effects information available for this drug.
There are 81 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Skin rash |
Body fluid retention Edema Pruritus of skin Tinnitus |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Abnormal vaginal bleeding Acute cognitive impairment Acute myocardial infarction Acute pancreatitis Agranulocytosis Allergic dermatitis Altered mental status Anaphylaxis Anemia Angioedema Aphthous stomatitis Aplastic anemia Bloody stools Bloody vomit Blurred vision Bronchospastic pulmonary disease Bullous dermatitis Cardiac arrhythmia Cerebrovascular accident Chest pain Chest tightness Chronic heart failure Conjunctivitis Cystitis Depression Diplopia DRESS syndrome Drug-induced hepatitis Dry eye Dyspnea Eosinophilia Epistaxis Erythema multiforme Esophageal ulcer Exfoliative dermatitis Gastric ulcer Gastritis Gastrointestinal hemorrhage Gastrointestinal perforation Gastrointestinal ulcer Hallucinations Hematuria Hemolytic anemia Hepatitis Hyperkalemia Hypertension IgA vasculitis Jaundice Kidney disease with reduction in glomerular filtration rate (GFr) Laryngeal edema Leukopenia Lupus-like syndrome Mood changes Nephrotoxicity Neutropenic disorder Non-infective meningitis Pancytopenia Peptic ulcer Peripheral neuropathy Polyuria Renal failure Renal papillary necrosis Renal tubular necrosis Rhinitis Scotomata Serum sickness Stevens-johnson syndrome Thrombocytopenic disorder Toxic amblyopia Toxic epidermal necrolysis Urticaria Vasculitis Visual changes Wheezing Worsening of chronic heart failure |
There are 25 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Dizziness Heartburn Nausea |
Body fluid retention Edema Pruritus of skin Tinnitus |
| Rare/Very Rare |
|---|
|
Drowsy Ecchymosis Flushing Hearing loss Insomnia Mouth irritation Palpitations Skin photosensitivity Symptoms of anxiety Tachycardia Xerostomia |
The following precautions are available for ADVIL (chlorpheniramine maleate/pseudoephedrine hcl/ibuprofen):
No enhanced Pediatric Use information available for this drug.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| Ibuprofen (Oral) | 1 Day – 179 Days | Safety and efficacy for children less than 6 months not established. |
Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used. Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.
Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks of gestation. Known effects of NSAIAs on the human fetus during the third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis. Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.
Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy. Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation. A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.
Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis. Deaths associated with neonatal renal failure have been reported. Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.
These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use. Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain. Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.
In animal studies, inhibitors of prostaglandin synthesis, such as ibuprofen, were associated with increased pre- and post-implantation losses. Prostaglandins also have an important role in fetal kidney development. In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.
There are no adequate and well-controlled studies of ibuprofen in pregnant women. In animal reproduction studies, no clear developmental effects were observed in rabbits or rats given ibuprofen throughout the gestational period at dosages up to 0.4 or 0.5
times, respectively, the maximum recommended human dosage (MRHD). An increase in membranous ventricular septal defects was reported in rats given ibuprofen on gestation days 9 and 10 at a dosage of 0.8 times the MRHD.
The effects of ibuprofen on labor and delivery are unknown. In studies in rats, drugs that inhibit prostaglandin synthesis, including NSAIAs, delayed parturition and increased the incidence of stillbirth.
Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks of gestation. Known effects of NSAIAs on the human fetus during the third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis. Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.
Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy. Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation. A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.
Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis. Deaths associated with neonatal renal failure have been reported. Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.
These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use. Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain. Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.
In animal studies, inhibitors of prostaglandin synthesis, such as ibuprofen, were associated with increased pre- and post-implantation losses. Prostaglandins also have an important role in fetal kidney development. In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.
There are no adequate and well-controlled studies of ibuprofen in pregnant women. In animal reproduction studies, no clear developmental effects were observed in rabbits or rats given ibuprofen throughout the gestational period at dosages up to 0.4 or 0.5
times, respectively, the maximum recommended human dosage (MRHD). An increase in membranous ventricular septal defects was reported in rats given ibuprofen on gestation days 9 and 10 at a dosage of 0.8 times the MRHD.
The effects of ibuprofen on labor and delivery are unknown. In studies in rats, drugs that inhibit prostaglandin synthesis, including NSAIAs, delayed parturition and increased the incidence of stillbirth.
| Drug/Drug Class | Severity | Precaution Description | Pregnancy Category Description |
|---|---|---|---|
| Ibuprofen | 1 | Not recommended near or after 20 weeks gestation | Contraindicated or not recommended. Existing fda teratogenicity category (if available) is augmented by information supporting a more severe warning. |
Limited data indicate that ibuprofen is distributed into milk, resulting in infant exposures of 0.06-0.6% of the maternal weight-adjusted daily dosage.
Adverse effects on breast-fed infants or effects on milk production have not been reported to date. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for ibuprofen and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.
No Known Risk
No known risk. This drug has no known risks to nursing infants and does not adversely affect lactation.
Adverse effects on breast-fed infants or effects on milk production have not been reported to date. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for ibuprofen and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.
No Known Risk
No known risk. This drug has no known risks to nursing infants and does not adversely affect lactation.
| Drug Name | Excretion Potential | Effect on Infant | Notes |
|---|---|---|---|
| Ibuprofen | Excreted.This drug is known to be excreted in human breast milk. | This drug has been shown not to have an adverse effect on the nursing infant. | Low levels in breast milk, with no known resulting adverse effect on infant |
No enhanced Geriatric Use information available for this drug.
Precaution Exists
Geriatric management or monitoring precaution exists.
Precaution Exists
Geriatric management or monitoring precaution exists.
| Drug Name | Narrative | REN | HEP | CARDIO | NEURO | PULM | ENDO |
|---|---|---|---|---|---|---|---|
| Ibuprofen | Gastrointestinal-Risk for ulceration or serious GI bleed; highest with history of PUD or GI bleed. Renal-Risk of AKI and exacerbation of CKD. Avoid with CrCl <30 mL/min. Cardiovascular-May exacerbate pre-existing hypertension or CHF. Risk of MI and stroke. This risk may occur early in treatment and increases with duration of use. Risk for reinfarction with minimal NSAID use post-MI. Contraindicated with CABG. Hepatic-Elevated hepatic transaminases may occur with chronic use. | Y | Y | Y | N | N | N |
The following prioritized warning is available for ADVIL (chlorpheniramine maleate/pseudoephedrine hcl/ibuprofen):
WARNING: Nonsteroidal anti-inflammatory drugs (including ibuprofen) may rarely increase the risk for a heart attack or stroke. This effect can happen at any time while taking this drug but is more likely if you take it for a long time. The risk may be greater in older adults or if you have heart disease or increased risk for heart disease (for example, due to smoking, family history of heart disease, or conditions such as high blood pressure or diabetes).
Do not take this drug right before or after heart bypass surgery (CABG). This drug may rarely cause serious (rarely fatal) bleeding from the stomach or intestines. This effect can occur without warning at any time while taking this drug.
Older adults may be at higher risk for this effect. Stop taking ibuprofen and get medical help right away if you notice any of these rare but serious side effects: stomach/abdominal pain that doesn't go away, black/tarry stools, vomit that looks like coffee grounds, chest/jaw/left arm pain, shortness of breath, unusual sweating, confusion, weakness on one side of the body, trouble speaking, sudden vision changes. Talk to your doctor or pharmacist about the benefits and risks of taking this drug.
WARNING: Nonsteroidal anti-inflammatory drugs (including ibuprofen) may rarely increase the risk for a heart attack or stroke. This effect can happen at any time while taking this drug but is more likely if you take it for a long time. The risk may be greater in older adults or if you have heart disease or increased risk for heart disease (for example, due to smoking, family history of heart disease, or conditions such as high blood pressure or diabetes).
Do not take this drug right before or after heart bypass surgery (CABG). This drug may rarely cause serious (rarely fatal) bleeding from the stomach or intestines. This effect can occur without warning at any time while taking this drug.
Older adults may be at higher risk for this effect. Stop taking ibuprofen and get medical help right away if you notice any of these rare but serious side effects: stomach/abdominal pain that doesn't go away, black/tarry stools, vomit that looks like coffee grounds, chest/jaw/left arm pain, shortness of breath, unusual sweating, confusion, weakness on one side of the body, trouble speaking, sudden vision changes. Talk to your doctor or pharmacist about the benefits and risks of taking this drug.
The following icd codes are available for ADVIL (chlorpheniramine maleate/pseudoephedrine hcl/ibuprofen)'s list of indications:
| Dysmenorrhea | |
| N94.4 | Primary dysmenorrhea |
| N94.5 | Secondary dysmenorrhea |
| N94.6 | Dysmenorrhea, unspecified |
| Fever | |
| R50 | Fever of other and unknown origin |
| R50.2 | Drug induced fever |
| R50.8 | Other specified fever |
| R50.81 | Fever presenting with conditions classified elsewhere |
| R50.82 | Postprocedural fever |
| R50.83 | Postvaccination fever |
| R50.84 | Febrile nonhemolytic transfusion reaction |
| R50.9 | Fever, unspecified |
| Headache disorder | |
| G43 | Migraine |
| G43.0 | Migraine without aura |
| G43.00 | Migraine without aura, not intractable |
| G43.009 | Migraine without aura, not intractable, without status migrainosus |
| G43.01 | Migraine without aura, intractable |
| G43.019 | Migraine without aura, intractable, without status migrainosus |
| G43.1 | Migraine with aura |
| G43.10 | Migraine with aura, not intractable |
| G43.109 | Migraine with aura, not intractable, without status migrainosus |
| G43.11 | Migraine with aura, intractable |
| G43.119 | Migraine with aura, intractable, without status migrainosus |
| G43.4 | Hemiplegic migraine |
| G43.40 | Hemiplegic migraine, not intractable |
| G43.409 | Hemiplegic migraine, not intractable, without status migrainosus |
| G43.41 | Hemiplegic migraine, intractable |
| G43.419 | Hemiplegic migraine, intractable, without status migrainosus |
| G43.5 | Persistent migraine aura without cerebral infarction |
| G43.50 | Persistent migraine aura without cerebral infarction, not intractable |
| G43.509 | Persistent migraine aura without cerebral infarction, not intractable, without status migrainosus |
| G43.51 | Persistent migraine aura without cerebral infarction, intractable |
| G43.519 | Persistent migraine aura without cerebral infarction, intractable, without status migrainosus |
| G43.6 | Persistent migraine aura with cerebral infarction |
| G43.60 | Persistent migraine aura with cerebral infarction, not intractable |
| G43.609 | Persistent migraine aura with cerebral infarction, not intractable, without status migrainosus |
| G43.61 | Persistent migraine aura with cerebral infarction, intractable |
| G43.619 | Persistent migraine aura with cerebral infarction, intractable, without status migrainosus |
| G43.7 | Chronic migraine without aura |
| G43.70 | Chronic migraine without aura, not intractable |
| G43.709 | Chronic migraine without aura, not intractable, without status migrainosus |
| G43.71 | Chronic migraine without aura, intractable |
| G43.719 | Chronic migraine without aura, intractable, without status migrainosus |
| G43.8 | Other migraine |
| G43.80 | Other migraine, not intractable |
| G43.809 | Other migraine, not intractable, without status migrainosus |
| G43.81 | Other migraine, intractable |
| G43.819 | Other migraine, intractable, without status migrainosus |
| G43.82 | Menstrual migraine, not intractable |
| G43.829 | Menstrual migraine, not intractable, without status migrainosus |
| G43.83 | Menstrual migraine, intractable |
| G43.839 | Menstrual migraine, intractable, without status migrainosus |
| G43.9 | Migraine, unspecified |
| G43.90 | Migraine, unspecified, not intractable |
| G43.909 | Migraine, unspecified, not intractable, without status migrainosus |
| G43.91 | Migraine, unspecified, intractable |
| G43.919 | Migraine, unspecified, intractable, without status migrainosus |
| G43.B | Ophthalmoplegic migraine |
| G43.B0 | Ophthalmoplegic migraine, not intractable |
| G43.B1 | Ophthalmoplegic migraine, intractable |
| G43.C | Periodic headache syndromes in child or adult |
| G43.C0 | Periodic headache syndromes in child or adult, not intractable |
| G43.C1 | Periodic headache syndromes in child or adult, intractable |
| G43.D | Abdominal migraine |
| G43.D0 | Abdominal migraine, not intractable |
| G43.D1 | Abdominal migraine, intractable |
| G43.E | Chronic migraine with aura |
| G43.E0 | Chronic migraine with aura, not intractable |
| G43.E09 | Chronic migraine with aura, not intractable, without status migrainosus |
| G43.E1 | Chronic migraine with aura, intractable |
| G43.E19 | Chronic migraine with aura, intractable, without status migrainosus |
| G44 | Other headache syndromes |
| G44.0 | Cluster headaches and other trigeminal autonomic cephalgias (TAc) |
| G44.00 | Cluster headache syndrome, unspecified |
| G44.001 | Cluster headache syndrome, unspecified, intractable |
| G44.009 | Cluster headache syndrome, unspecified, not intractable |
| G44.01 | Episodic cluster headache |
| G44.011 | Episodic cluster headache, intractable |
| G44.019 | Episodic cluster headache, not intractable |
| G44.02 | Chronic cluster headache |
| G44.021 | Chronic cluster headache, intractable |
| G44.029 | Chronic cluster headache, not intractable |
| G44.03 | Episodic paroxysmal hemicrania |
| G44.031 | Episodic paroxysmal hemicrania, intractable |
| G44.039 | Episodic paroxysmal hemicrania, not intractable |
| G44.04 | Chronic paroxysmal hemicrania |
| G44.041 | Chronic paroxysmal hemicrania, intractable |
| G44.049 | Chronic paroxysmal hemicrania, not intractable |
| G44.05 | Short lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCt) |
| G44.051 | Short lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCt), intractable |
| G44.059 | Short lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCt), not intractable |
| G44.09 | Other trigeminal autonomic cephalgias (TAc) |
| G44.091 | Other trigeminal autonomic cephalgias (TAc), intractable |
| G44.099 | Other trigeminal autonomic cephalgias (TAc), not intractable |
| G44.1 | Vascular headache, not elsewhere classified |
| G44.2 | Tension-type headache |
| G44.20 | Tension-type headache, unspecified |
| G44.201 | Tension-type headache, unspecified, intractable |
| G44.209 | Tension-type headache, unspecified, not intractable |
| G44.21 | Episodic tension-type headache |
| G44.211 | Episodic tension-type headache, intractable |
| G44.219 | Episodic tension-type headache, not intractable |
| G44.22 | Chronic tension-type headache |
| G44.221 | Chronic tension-type headache, intractable |
| G44.229 | Chronic tension-type headache, not intractable |
| G44.3 | Post-traumatic headache |
| G44.30 | Post-traumatic headache, unspecified |
| G44.301 | Post-traumatic headache, unspecified, intractable |
| G44.309 | Post-traumatic headache, unspecified, not intractable |
| G44.31 | Acute post-traumatic headache |
| G44.311 | Acute post-traumatic headache, intractable |
| G44.319 | Acute post-traumatic headache, not intractable |
| G44.32 | Chronic post-traumatic headache |
| G44.321 | Chronic post-traumatic headache, intractable |
| G44.329 | Chronic post-traumatic headache, not intractable |
| G44.4 | Drug-induced headache, not elsewhere classified |
| G44.40 | Drug-induced headache, not elsewhere classified, not intractable |
| G44.41 | Drug-induced headache, not elsewhere classified, intractable |
| G44.5 | Complicated headache syndromes |
| G44.51 | Hemicrania continua |
| G44.52 | New daily persistent headache (NDPh) |
| G44.53 | Primary thunderclap headache |
| G44.59 | Other complicated headache syndrome |
| G44.8 | Other specified headache syndromes |
| G44.81 | Hypnic headache |
| G44.82 | Headache associated with sexual activity |
| G44.83 | Primary cough headache |
| G44.84 | Primary exertional headache |
| G44.85 | Primary stabbing headache |
| G44.89 | Other headache syndrome |
| R51 | Headache |
| R51.9 | Headache, unspecified |
| Juvenile idiopathic arthritis | |
| M08.0 | Unspecified juvenile rheumatoid arthritis |
| M08.00 | Unspecified juvenile rheumatoid arthritis of unspecified site |
| M08.01 | Unspecified juvenile rheumatoid arthritis, shoulder |
| M08.011 | Unspecified juvenile rheumatoid arthritis, right shoulder |
| M08.012 | Unspecified juvenile rheumatoid arthritis, left shoulder |
| M08.019 | Unspecified juvenile rheumatoid arthritis, unspecified shoulder |
| M08.02 | Unspecified juvenile rheumatoid arthritis of elbow |
| M08.021 | Unspecified juvenile rheumatoid arthritis, right elbow |
| M08.022 | Unspecified juvenile rheumatoid arthritis, left elbow |
| M08.029 | Unspecified juvenile rheumatoid arthritis, unspecified elbow |
| M08.03 | Unspecified juvenile rheumatoid arthritis, wrist |
| M08.031 | Unspecified juvenile rheumatoid arthritis, right wrist |
| M08.032 | Unspecified juvenile rheumatoid arthritis, left wrist |
| M08.039 | Unspecified juvenile rheumatoid arthritis, unspecified wrist |
| M08.04 | Unspecified juvenile rheumatoid arthritis, hand |
| M08.041 | Unspecified juvenile rheumatoid arthritis, right hand |
| M08.042 | Unspecified juvenile rheumatoid arthritis, left hand |
| M08.049 | Unspecified juvenile rheumatoid arthritis, unspecified hand |
| M08.05 | Unspecified juvenile rheumatoid arthritis, hip |
| M08.051 | Unspecified juvenile rheumatoid arthritis, right hip |
| M08.052 | Unspecified juvenile rheumatoid arthritis, left hip |
| M08.059 | Unspecified juvenile rheumatoid arthritis, unspecified hip |
| M08.06 | Unspecified juvenile rheumatoid arthritis, knee |
| M08.061 | Unspecified juvenile rheumatoid arthritis, right knee |
| M08.062 | Unspecified juvenile rheumatoid arthritis, left knee |
| M08.069 | Unspecified juvenile rheumatoid arthritis, unspecified knee |
| M08.07 | Unspecified juvenile rheumatoid arthritis, ankle and foot |
| M08.071 | Unspecified juvenile rheumatoid arthritis, right ankle and foot |
| M08.072 | Unspecified juvenile rheumatoid arthritis, left ankle and foot |
| M08.079 | Unspecified juvenile rheumatoid arthritis, unspecified ankle and foot |
| M08.08 | Unspecified juvenile rheumatoid arthritis, vertebrae |
| M08.09 | Unspecified juvenile rheumatoid arthritis, multiple sites |
| M08.0A | Unspecified juvenile rheumatoid arthritis, other specified site |
| M08.2 | Juvenile rheumatoid arthritis with systemic onset |
| M08.20 | Juvenile rheumatoid arthritis with systemic onset, unspecified site |
| M08.21 | Juvenile rheumatoid arthritis with systemic onset, shoulder |
| M08.211 | Juvenile rheumatoid arthritis with systemic onset, right shoulder |
| M08.212 | Juvenile rheumatoid arthritis with systemic onset, left shoulder |
| M08.219 | Juvenile rheumatoid arthritis with systemic onset, unspecified shoulder |
| M08.22 | Juvenile rheumatoid arthritis with systemic onset, elbow |
| M08.221 | Juvenile rheumatoid arthritis with systemic onset, right elbow |
| M08.222 | Juvenile rheumatoid arthritis with systemic onset, left elbow |
| M08.229 | Juvenile rheumatoid arthritis with systemic onset, unspecified elbow |
| M08.23 | Juvenile rheumatoid arthritis with systemic onset, wrist |
| M08.231 | Juvenile rheumatoid arthritis with systemic onset, right wrist |
| M08.232 | Juvenile rheumatoid arthritis with systemic onset, left wrist |
| M08.239 | Juvenile rheumatoid arthritis with systemic onset, unspecified wrist |
| M08.24 | Juvenile rheumatoid arthritis with systemic onset, hand |
| M08.241 | Juvenile rheumatoid arthritis with systemic onset, right hand |
| M08.242 | Juvenile rheumatoid arthritis with systemic onset, left hand |
| M08.249 | Juvenile rheumatoid arthritis with systemic onset, unspecified hand |
| M08.25 | Juvenile rheumatoid arthritis with systemic onset, hip |
| M08.251 | Juvenile rheumatoid arthritis with systemic onset, right hip |
| M08.252 | Juvenile rheumatoid arthritis with systemic onset, left hip |
| M08.259 | Juvenile rheumatoid arthritis with systemic onset, unspecified hip |
| M08.26 | Juvenile rheumatoid arthritis with systemic onset, knee |
| M08.261 | Juvenile rheumatoid arthritis with systemic onset, right knee |
| M08.262 | Juvenile rheumatoid arthritis with systemic onset, left knee |
| M08.269 | Juvenile rheumatoid arthritis with systemic onset, unspecified knee |
| M08.27 | Juvenile rheumatoid arthritis with systemic onset, ankle and foot |
| M08.271 | Juvenile rheumatoid arthritis with systemic onset, right ankle and foot |
| M08.272 | Juvenile rheumatoid arthritis with systemic onset, left ankle and foot |
| M08.279 | Juvenile rheumatoid arthritis with systemic onset, unspecified ankle and foot |
| M08.28 | Juvenile rheumatoid arthritis with systemic onset, vertebrae |
| M08.29 | Juvenile rheumatoid arthritis with systemic onset, multiple sites |
| M08.2A | Juvenile rheumatoid arthritis with systemic onset, other specified site |
| M08.3 | Juvenile rheumatoid polyarthritis (seronegative) |
| M08.4 | Pauciarticular juvenile rheumatoid arthritis |
| M08.40 | Pauciarticular juvenile rheumatoid arthritis, unspecified site |
| M08.41 | Pauciarticular juvenile rheumatoid arthritis, shoulder |
| M08.411 | Pauciarticular juvenile rheumatoid arthritis, right shoulder |
| M08.412 | Pauciarticular juvenile rheumatoid arthritis, left shoulder |
| M08.419 | Pauciarticular juvenile rheumatoid arthritis, unspecified shoulder |
| M08.42 | Pauciarticular juvenile rheumatoid arthritis, elbow |
| M08.421 | Pauciarticular juvenile rheumatoid arthritis, right elbow |
| M08.422 | Pauciarticular juvenile rheumatoid arthritis, left elbow |
| M08.429 | Pauciarticular juvenile rheumatoid arthritis, unspecified elbow |
| M08.43 | Pauciarticular juvenile rheumatoid arthritis, wrist |
| M08.431 | Pauciarticular juvenile rheumatoid arthritis, right wrist |
| M08.432 | Pauciarticular juvenile rheumatoid arthritis, left wrist |
| M08.439 | Pauciarticular juvenile rheumatoid arthritis, unspecified wrist |
| M08.44 | Pauciarticular juvenile rheumatoid arthritis, hand |
| M08.441 | Pauciarticular juvenile rheumatoid arthritis, right hand |
| M08.442 | Pauciarticular juvenile rheumatoid arthritis, left hand |
| M08.449 | Pauciarticular juvenile rheumatoid arthritis, unspecified hand |
| M08.45 | Pauciarticular juvenile rheumatoid arthritis, hip |
| M08.451 | Pauciarticular juvenile rheumatoid arthritis, right hip |
| M08.452 | Pauciarticular juvenile rheumatoid arthritis, left hip |
| M08.459 | Pauciarticular juvenile rheumatoid arthritis, unspecified hip |
| M08.46 | Pauciarticular juvenile rheumatoid arthritis, knee |
| M08.461 | Pauciarticular juvenile rheumatoid arthritis, right knee |
| M08.462 | Pauciarticular juvenile rheumatoid arthritis, left knee |
| M08.469 | Pauciarticular juvenile rheumatoid arthritis, unspecified knee |
| M08.47 | Pauciarticular juvenile rheumatoid arthritis, ankle and foot |
| M08.471 | Pauciarticular juvenile rheumatoid arthritis, right ankle and foot |
| M08.472 | Pauciarticular juvenile rheumatoid arthritis, left ankle and foot |
| M08.479 | Pauciarticular juvenile rheumatoid arthritis, unspecified ankle and foot |
| M08.48 | Pauciarticular juvenile rheumatoid arthritis, vertebrae |
| M08.4A | Pauciarticular juvenile rheumatoid arthritis, other specified site |
| Osteoarthritis | |
| M15 | Polyosteoarthritis |
| M15.0 | Primary generalized (osteo)arthritis |
| M15.1 | Heberden's nodes (with arthropathy) |
| M15.2 | Bouchard's nodes (with arthropathy) |
| M15.3 | Secondary multiple arthritis |
| M15.4 | Erosive (osteo)arthritis |
| M15.8 | Other polyosteoarthritis |
| M15.9 | Polyosteoarthritis, unspecified |
| M16 | Osteoarthritis of hip |
| M16.0 | Bilateral primary osteoarthritis of hip |
| M16.1 | Unilateral primary osteoarthritis of hip |
| M16.10 | Unilateral primary osteoarthritis, unspecified hip |
| M16.11 | Unilateral primary osteoarthritis, right hip |
| M16.12 | Unilateral primary osteoarthritis, left hip |
| M16.2 | Bilateral osteoarthritis resulting from hip dysplasia |
| M16.3 | Unilateral osteoarthritis resulting from hip dysplasia |
| M16.30 | Unilateral osteoarthritis resulting from hip dysplasia, unspecified hip |
| M16.31 | Unilateral osteoarthritis resulting from hip dysplasia, right hip |
| M16.32 | Unilateral osteoarthritis resulting from hip dysplasia, left hip |
| M16.4 | Bilateral post-traumatic osteoarthritis of hip |
| M16.5 | Unilateral post-traumatic osteoarthritis of hip |
| M16.50 | Unilateral post-traumatic osteoarthritis, unspecified hip |
| M16.51 | Unilateral post-traumatic osteoarthritis, right hip |
| M16.52 | Unilateral post-traumatic osteoarthritis, left hip |
| M16.6 | Other bilateral secondary osteoarthritis of hip |
| M16.7 | Other unilateral secondary osteoarthritis of hip |
| M16.9 | Osteoarthritis of hip, unspecified |
| M17 | Osteoarthritis of knee |
| M17.0 | Bilateral primary osteoarthritis of knee |
| M17.1 | Unilateral primary osteoarthritis of knee |
| M17.10 | Unilateral primary osteoarthritis, unspecified knee |
| M17.11 | Unilateral primary osteoarthritis, right knee |
| M17.12 | Unilateral primary osteoarthritis, left knee |
| M17.2 | Bilateral post-traumatic osteoarthritis of knee |
| M17.3 | Unilateral post-traumatic osteoarthritis of knee |
| M17.30 | Unilateral post-traumatic osteoarthritis, unspecified knee |
| M17.31 | Unilateral post-traumatic osteoarthritis, right knee |
| M17.32 | Unilateral post-traumatic osteoarthritis, left knee |
| M17.4 | Other bilateral secondary osteoarthritis of knee |
| M17.5 | Other unilateral secondary osteoarthritis of knee |
| M17.9 | Osteoarthritis of knee, unspecified |
| M18 | Osteoarthritis of first carpometacarpal joint |
| M18.0 | Bilateral primary osteoarthritis of first carpometacarpal joints |
| M18.1 | Unilateral primary osteoarthritis of first carpometacarpal joint |
| M18.10 | Unilateral primary osteoarthritis of first carpometacarpal joint, unspecified hand |
| M18.11 | Unilateral primary osteoarthritis of first carpometacarpal joint, right hand |
| M18.12 | Unilateral primary osteoarthritis of first carpometacarpal joint, left hand |
| M18.2 | Bilateral post-traumatic osteoarthritis of first carpometacarpal joints |
| M18.3 | Unilateral post-traumatic osteoarthritis of first carpometacarpal joint |
| M18.30 | Unilateral post-traumatic osteoarthritis of first carpometacarpal joint, unspecified hand |
| M18.31 | Unilateral post-traumatic osteoarthritis of first carpometacarpal joint, right hand |
| M18.32 | Unilateral post-traumatic osteoarthritis of first carpometacarpal joint, left hand |
| M18.4 | Other bilateral secondary osteoarthritis of first carpometacarpal joints |
| M18.5 | Other unilateral secondary osteoarthritis of first carpometacarpal joint |
| M18.50 | Other unilateral secondary osteoarthritis of first carpometacarpal joint, unspecified hand |
| M18.51 | Other unilateral secondary osteoarthritis of first carpometacarpal joint, right hand |
| M18.52 | Other unilateral secondary osteoarthritis of first carpometacarpal joint, left hand |
| M18.9 | Osteoarthritis of first carpometacarpal joint, unspecified |
| M19 | Other and unspecified osteoarthritis |
| M19.0 | Primary osteoarthritis of other joints |
| M19.01 | Primary osteoarthritis, shoulder |
| M19.011 | Primary osteoarthritis, right shoulder |
| M19.012 | Primary osteoarthritis, left shoulder |
| M19.019 | Primary osteoarthritis, unspecified shoulder |
| M19.02 | Primary osteoarthritis, elbow |
| M19.021 | Primary osteoarthritis, right elbow |
| M19.022 | Primary osteoarthritis, left elbow |
| M19.029 | Primary osteoarthritis, unspecified elbow |
| M19.03 | Primary osteoarthritis, wrist |
| M19.031 | Primary osteoarthritis, right wrist |
| M19.032 | Primary osteoarthritis, left wrist |
| M19.039 | Primary osteoarthritis, unspecified wrist |
| M19.04 | Primary osteoarthritis, hand |
| M19.041 | Primary osteoarthritis, right hand |
| M19.042 | Primary osteoarthritis, left hand |
| M19.049 | Primary osteoarthritis, unspecified hand |
| M19.07 | Primary osteoarthritis ankle and foot |
| M19.071 | Primary osteoarthritis, right ankle and foot |
| M19.072 | Primary osteoarthritis, left ankle and foot |
| M19.079 | Primary osteoarthritis, unspecified ankle and foot |
| M19.09 | Primary osteoarthritis, other specified site |
| M19.1 | Post-traumatic osteoarthritis of other joints |
| M19.11 | Post-traumatic osteoarthritis, shoulder |
| M19.111 | Post-traumatic osteoarthritis, right shoulder |
| M19.112 | Post-traumatic osteoarthritis, left shoulder |
| M19.119 | Post-traumatic osteoarthritis, unspecified shoulder |
| M19.12 | Post-traumatic osteoarthritis, elbow |
| M19.121 | Post-traumatic osteoarthritis, right elbow |
| M19.122 | Post-traumatic osteoarthritis, left elbow |
| M19.129 | Post-traumatic osteoarthritis, unspecified elbow |
| M19.13 | Post-traumatic osteoarthritis, wrist |
| M19.131 | Post-traumatic osteoarthritis, right wrist |
| M19.132 | Post-traumatic osteoarthritis, left wrist |
| M19.139 | Post-traumatic osteoarthritis, unspecified wrist |
| M19.14 | Post-traumatic osteoarthritis, hand |
| M19.141 | Post-traumatic osteoarthritis, right hand |
| M19.142 | Post-traumatic osteoarthritis, left hand |
| M19.149 | Post-traumatic osteoarthritis, unspecified hand |
| M19.17 | Post-traumatic osteoarthritis, ankle and foot |
| M19.171 | Post-traumatic osteoarthritis, right ankle and foot |
| M19.172 | Post-traumatic osteoarthritis, left ankle and foot |
| M19.179 | Post-traumatic osteoarthritis, unspecified ankle and foot |
| M19.19 | Post-traumatic osteoarthritis, other specified site |
| M19.2 | Secondary osteoarthritis of other joints |
| M19.21 | Secondary osteoarthritis, shoulder |
| M19.211 | Secondary osteoarthritis, right shoulder |
| M19.212 | Secondary osteoarthritis, left shoulder |
| M19.219 | Secondary osteoarthritis, unspecified shoulder |
| M19.22 | Secondary osteoarthritis, elbow |
| M19.221 | Secondary osteoarthritis, right elbow |
| M19.222 | Secondary osteoarthritis, left elbow |
| M19.229 | Secondary osteoarthritis, unspecified elbow |
| M19.23 | Secondary osteoarthritis, wrist |
| M19.231 | Secondary osteoarthritis, right wrist |
| M19.232 | Secondary osteoarthritis, left wrist |
| M19.239 | Secondary osteoarthritis, unspecified wrist |
| M19.24 | Secondary osteoarthritis, hand |
| M19.241 | Secondary osteoarthritis, right hand |
| M19.242 | Secondary osteoarthritis, left hand |
| M19.249 | Secondary osteoarthritis, unspecified hand |
| M19.27 | Secondary osteoarthritis, ankle and foot |
| M19.271 | Secondary osteoarthritis, right ankle and foot |
| M19.272 | Secondary osteoarthritis, left ankle and foot |
| M19.279 | Secondary osteoarthritis, unspecified ankle and foot |
| M19.29 | Secondary osteoarthritis, other specified site |
| M19.9 | Osteoarthritis, unspecified site |
| M19.90 | Unspecified osteoarthritis, unspecified site |
| M19.91 | Primary osteoarthritis, unspecified site |
| M19.92 | Post-traumatic osteoarthritis, unspecified site |
| M19.93 | Secondary osteoarthritis, unspecified site |
| Pain | |
| G43 | Migraine |
| G43.0 | Migraine without aura |
| G43.00 | Migraine without aura, not intractable |
| G43.001 | Migraine without aura, not intractable, with status migrainosus |
| G43.009 | Migraine without aura, not intractable, without status migrainosus |
| G43.01 | Migraine without aura, intractable |
| G43.011 | Migraine without aura, intractable, with status migrainosus |
| G43.019 | Migraine without aura, intractable, without status migrainosus |
| G43.1 | Migraine with aura |
| G43.10 | Migraine with aura, not intractable |
| G43.101 | Migraine with aura, not intractable, with status migrainosus |
| G43.109 | Migraine with aura, not intractable, without status migrainosus |
| G43.11 | Migraine with aura, intractable |
| G43.111 | Migraine with aura, intractable, with status migrainosus |
| G43.119 | Migraine with aura, intractable, without status migrainosus |
| G43.4 | Hemiplegic migraine |
| G43.40 | Hemiplegic migraine, not intractable |
| G43.401 | Hemiplegic migraine, not intractable, with status migrainosus |
| G43.409 | Hemiplegic migraine, not intractable, without status migrainosus |
| G43.41 | Hemiplegic migraine, intractable |
| G43.411 | Hemiplegic migraine, intractable, with status migrainosus |
| G43.419 | Hemiplegic migraine, intractable, without status migrainosus |
| G43.5 | Persistent migraine aura without cerebral infarction |
| G43.50 | Persistent migraine aura without cerebral infarction, not intractable |
| G43.501 | Persistent migraine aura without cerebral infarction, not intractable, with status migrainosus |
| G43.509 | Persistent migraine aura without cerebral infarction, not intractable, without status migrainosus |
| G43.51 | Persistent migraine aura without cerebral infarction, intractable |
| G43.511 | Persistent migraine aura without cerebral infarction, intractable, with status migrainosus |
| G43.519 | Persistent migraine aura without cerebral infarction, intractable, without status migrainosus |
| G43.6 | Persistent migraine aura with cerebral infarction |
| G43.60 | Persistent migraine aura with cerebral infarction, not intractable |
| G43.601 | Persistent migraine aura with cerebral infarction, not intractable, with status migrainosus |
| G43.609 | Persistent migraine aura with cerebral infarction, not intractable, without status migrainosus |
| G43.61 | Persistent migraine aura with cerebral infarction, intractable |
| G43.611 | Persistent migraine aura with cerebral infarction, intractable, with status migrainosus |
| G43.619 | Persistent migraine aura with cerebral infarction, intractable, without status migrainosus |
| G43.7 | Chronic migraine without aura |
| G43.70 | Chronic migraine without aura, not intractable |
| G43.701 | Chronic migraine without aura, not intractable, with status migrainosus |
| G43.709 | Chronic migraine without aura, not intractable, without status migrainosus |
| G43.71 | Chronic migraine without aura, intractable |
| G43.711 | Chronic migraine without aura, intractable, with status migrainosus |
| G43.719 | Chronic migraine without aura, intractable, without status migrainosus |
| G43.8 | Other migraine |
| G43.80 | Other migraine, not intractable |
| G43.801 | Other migraine, not intractable, with status migrainosus |
| G43.809 | Other migraine, not intractable, without status migrainosus |
| G43.81 | Other migraine, intractable |
| G43.811 | Other migraine, intractable, with status migrainosus |
| G43.819 | Other migraine, intractable, without status migrainosus |
| G43.82 | Menstrual migraine, not intractable |
| G43.821 | Menstrual migraine, not intractable, with status migrainosus |
| G43.829 | Menstrual migraine, not intractable, without status migrainosus |
| G43.83 | Menstrual migraine, intractable |
| G43.831 | Menstrual migraine, intractable, with status migrainosus |
| G43.839 | Menstrual migraine, intractable, without status migrainosus |
| G43.9 | Migraine, unspecified |
| G43.90 | Migraine, unspecified, not intractable |
| G43.901 | Migraine, unspecified, not intractable, with status migrainosus |
| G43.909 | Migraine, unspecified, not intractable, without status migrainosus |
| G43.91 | Migraine, unspecified, intractable |
| G43.911 | Migraine, unspecified, intractable, with status migrainosus |
| G43.919 | Migraine, unspecified, intractable, without status migrainosus |
| G43.B | Ophthalmoplegic migraine |
| G43.B0 | Ophthalmoplegic migraine, not intractable |
| G43.B1 | Ophthalmoplegic migraine, intractable |
| G43.C | Periodic headache syndromes in child or adult |
| G43.C0 | Periodic headache syndromes in child or adult, not intractable |
| G43.C1 | Periodic headache syndromes in child or adult, intractable |
| G43.D | Abdominal migraine |
| G43.D0 | Abdominal migraine, not intractable |
| G43.D1 | Abdominal migraine, intractable |
| G43.E | Chronic migraine with aura |
| G43.E0 | Chronic migraine with aura, not intractable |
| G43.E01 | Chronic migraine with aura, not intractable, with status migrainosus |
| G43.E09 | Chronic migraine with aura, not intractable, without status migrainosus |
| G43.E1 | Chronic migraine with aura, intractable |
| G43.E11 | Chronic migraine with aura, intractable, with status migrainosus |
| G43.E19 | Chronic migraine with aura, intractable, without status migrainosus |
| G44 | Other headache syndromes |
| G44.00 | Cluster headache syndrome, unspecified |
| G44.001 | Cluster headache syndrome, unspecified, intractable |
| G44.009 | Cluster headache syndrome, unspecified, not intractable |
| G44.01 | Episodic cluster headache |
| G44.011 | Episodic cluster headache, intractable |
| G44.019 | Episodic cluster headache, not intractable |
| G44.02 | Chronic cluster headache |
| G44.021 | Chronic cluster headache, intractable |
| G44.029 | Chronic cluster headache, not intractable |
| G44.03 | Episodic paroxysmal hemicrania |
| G44.031 | Episodic paroxysmal hemicrania, intractable |
| G44.039 | Episodic paroxysmal hemicrania, not intractable |
| G44.04 | Chronic paroxysmal hemicrania |
| G44.041 | Chronic paroxysmal hemicrania, intractable |
| G44.049 | Chronic paroxysmal hemicrania, not intractable |
| G44.05 | Short lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCt) |
| G44.051 | Short lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCt), intractable |
| G44.059 | Short lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCt), not intractable |
| G44.1 | Vascular headache, not elsewhere classified |
| G44.2 | Tension-type headache |
| G44.20 | Tension-type headache, unspecified |
| G44.201 | Tension-type headache, unspecified, intractable |
| G44.209 | Tension-type headache, unspecified, not intractable |
| G44.21 | Episodic tension-type headache |
| G44.211 | Episodic tension-type headache, intractable |
| G44.219 | Episodic tension-type headache, not intractable |
| G44.22 | Chronic tension-type headache |
| G44.221 | Chronic tension-type headache, intractable |
| G44.229 | Chronic tension-type headache, not intractable |
| G44.3 | Post-traumatic headache |
| G44.30 | Post-traumatic headache, unspecified |
| G44.301 | Post-traumatic headache, unspecified, intractable |
| G44.309 | Post-traumatic headache, unspecified, not intractable |
| G44.31 | Acute post-traumatic headache |
| G44.311 | Acute post-traumatic headache, intractable |
| G44.319 | Acute post-traumatic headache, not intractable |
| G44.32 | Chronic post-traumatic headache |
| G44.321 | Chronic post-traumatic headache, intractable |
| G44.329 | Chronic post-traumatic headache, not intractable |
| G44.4 | Drug-induced headache, not elsewhere classified |
| G44.40 | Drug-induced headache, not elsewhere classified, not intractable |
| G44.41 | Drug-induced headache, not elsewhere classified, intractable |
| G44.5 | Complicated headache syndromes |
| G44.51 | Hemicrania continua |
| G44.52 | New daily persistent headache (NDPh) |
| G44.53 | Primary thunderclap headache |
| G44.59 | Other complicated headache syndrome |
| G44.8 | Other specified headache syndromes |
| G44.81 | Hypnic headache |
| G44.82 | Headache associated with sexual activity |
| G44.83 | Primary cough headache |
| G44.84 | Primary exertional headache |
| G44.85 | Primary stabbing headache |
| G44.86 | Cervicogenic headache |
| G44.89 | Other headache syndrome |
| G50.1 | Atypical facial pain |
| G89 | Pain, not elsewhere classified |
| G89.0 | Central pain syndrome |
| G89.1 | Acute pain, not elsewhere classified |
| G89.11 | Acute pain due to trauma |
| G89.12 | Acute post-thoracotomy pain |
| G89.18 | Other acute postprocedural pain |
| G89.2 | Chronic pain, not elsewhere classified |
| G89.21 | Chronic pain due to trauma |
| G89.22 | Chronic post-thoracotomy pain |
| G89.28 | Other chronic postprocedural pain |
| G89.29 | Other chronic pain |
| G89.3 | Neoplasm related pain (acute) (chronic) |
| G89.4 | Chronic pain syndrome |
| G90.5 | Complex regional pain syndrome I (CRPS i) |
| G90.50 | Complex regional pain syndrome i, unspecified |
| G90.51 | Complex regional pain syndrome I of upper limb |
| G90.511 | Complex regional pain syndrome I of right upper limb |
| G90.512 | Complex regional pain syndrome I of left upper limb |
| G90.513 | Complex regional pain syndrome I of upper limb, bilateral |
| G90.519 | Complex regional pain syndrome I of unspecified upper limb |
| G90.52 | Complex regional pain syndrome I of lower limb |
| G90.521 | Complex regional pain syndrome I of right lower limb |
| G90.522 | Complex regional pain syndrome I of left lower limb |
| G90.523 | Complex regional pain syndrome I of lower limb, bilateral |
| G90.529 | Complex regional pain syndrome I of unspecified lower limb |
| G90.59 | Complex regional pain syndrome I of other specified site |
| H57.1 | Ocular pain |
| H57.10 | Ocular pain, unspecified eye |
| H57.11 | Ocular pain, right eye |
| H57.12 | Ocular pain, left eye |
| H57.13 | Ocular pain, bilateral |
| H92 | Otalgia and effusion of ear |
| H92.0 | Otalgia |
| H92.01 | Otalgia, right ear |
| H92.02 | Otalgia, left ear |
| H92.03 | Otalgia, bilateral |
| H92.09 | Otalgia, unspecified ear |
| K14.6 | Glossodynia |
| M25.5 | Pain in joint |
| M25.50 | Pain in unspecified joint |
| M25.51 | Pain in shoulder |
| M25.511 | Pain in right shoulder |
| M25.512 | Pain in left shoulder |
| M25.519 | Pain in unspecified shoulder |
| M25.52 | Pain in elbow |
| M25.521 | Pain in right elbow |
| M25.522 | Pain in left elbow |
| M25.529 | Pain in unspecified elbow |
| M25.53 | Pain in wrist |
| M25.531 | Pain in right wrist |
| M25.532 | Pain in left wrist |
| M25.539 | Pain in unspecified wrist |
| M25.54 | Pain in joints of hand |
| M25.541 | Pain in joints of right hand |
| M25.542 | Pain in joints of left hand |
| M25.549 | Pain in joints of unspecified hand |
| M25.55 | Pain in hip |
| M25.551 | Pain in right hip |
| M25.552 | Pain in left hip |
| M25.559 | Pain in unspecified hip |
| M25.56 | Pain in knee |
| M25.561 | Pain in right knee |
| M25.562 | Pain in left knee |
| M25.569 | Pain in unspecified knee |
| M25.57 | Pain in ankle and joints of foot |
| M25.571 | Pain in right ankle and joints of right foot |
| M25.572 | Pain in left ankle and joints of left foot |
| M25.579 | Pain in unspecified ankle and joints of unspecified foot |
| M25.59 | Pain in other specified joint |
| M26.62 | Arthralgia of temporomandibular joint |
| M26.621 | Arthralgia of right temporomandibular joint |
| M26.622 | Arthralgia of left temporomandibular joint |
| M26.623 | Arthralgia of bilateral temporomandibular joint |
| M26.629 | Arthralgia of temporomandibular joint, unspecified side |
| M54 | Dorsalgia |
| M54.2 | Cervicalgia |
| M54.4 | Lumbago with sciatica |
| M54.40 | Lumbago with sciatica, unspecified side |
| M54.41 | Lumbago with sciatica, right side |
| M54.42 | Lumbago with sciatica, left side |
| M54.5 | Low back pain |
| M54.50 | Low back pain, unspecified |
| M54.51 | Vertebrogenic low back pain |
| M54.59 | Other low back pain |
| M54.6 | Pain in thoracic spine |
| M54.8 | Other dorsalgia |
| M54.89 | Other dorsalgia |
| M54.9 | Dorsalgia, unspecified |
| M77.4 | Metatarsalgia |
| M77.40 | Metatarsalgia, unspecified foot |
| M77.41 | Metatarsalgia, right foot |
| M77.42 | Metatarsalgia, left foot |
| M79.1 | Myalgia |
| M79.10 | Myalgia, unspecified site |
| M79.11 | Myalgia of mastication muscle |
| M79.12 | Myalgia of auxiliary muscles, head and neck |
| M79.18 | Myalgia, other site |
| M79.6 | Pain in limb, hand, foot, fingers and toes |
| M79.60 | Pain in limb, unspecified |
| M79.601 | Pain in right arm |
| M79.602 | Pain in left arm |
| M79.603 | Pain in arm, unspecified |
| M79.604 | Pain in right leg |
| M79.605 | Pain in left leg |
| M79.606 | Pain in leg, unspecified |
| M79.609 | Pain in unspecified limb |
| M79.62 | Pain in upper arm |
| M79.621 | Pain in right upper arm |
| M79.622 | Pain in left upper arm |
| M79.629 | Pain in unspecified upper arm |
| M79.63 | Pain in forearm |
| M79.631 | Pain in right forearm |
| M79.632 | Pain in left forearm |
| M79.639 | Pain in unspecified forearm |
| M79.64 | Pain in hand and fingers |
| M79.641 | Pain in right hand |
| M79.642 | Pain in left hand |
| M79.643 | Pain in unspecified hand |
| M79.644 | Pain in right finger(s) |
| M79.645 | Pain in left finger(s) |
| M79.646 | Pain in unspecified finger(s) |
| M79.65 | Pain in thigh |
| M79.651 | Pain in right thigh |
| M79.652 | Pain in left thigh |
| M79.659 | Pain in unspecified thigh |
| M79.66 | Pain in lower leg |
| M79.661 | Pain in right lower leg |
| M79.662 | Pain in left lower leg |
| M79.669 | Pain in unspecified lower leg |
| M79.67 | Pain in foot and toes |
| M79.671 | Pain in right foot |
| M79.672 | Pain in left foot |
| M79.673 | Pain in unspecified foot |
| M79.674 | Pain in right toe(s) |
| M79.675 | Pain in left toe(s) |
| M79.676 | Pain in unspecified toe(s) |
| N23 | Unspecified renal colic |
| N64.4 | Mastodynia |
| N94 | Pain and other conditions associated with female genital organs and menstrual cycle |
| N94.0 | Mittelschmerz |
| N94.3 | Premenstrual tension syndrome |
| N94.4 | Primary dysmenorrhea |
| N94.5 | Secondary dysmenorrhea |
| N94.6 | Dysmenorrhea, unspecified |
| R07 | Pain in throat and chest |
| R07.0 | Pain in throat |
| R07.1 | Chest pain on breathing |
| R07.2 | Precordial pain |
| R07.81 | Pleurodynia |
| R07.82 | Intercostal pain |
| R07.89 | Other chest pain |
| R07.9 | Chest pain, unspecified |
| R10 | Abdominal and pelvic pain |
| R10.0 | Acute abdomen |
| R10.1 | Pain localized to upper abdomen |
| R10.10 | Upper abdominal pain, unspecified |
| R10.11 | Right upper quadrant pain |
| R10.12 | Left upper quadrant pain |
| R10.2 | Pelvic and perineal pain |
| R10.3 | Pain localized to other parts of lower abdomen |
| R10.30 | Lower abdominal pain, unspecified |
| R10.31 | Right lower quadrant pain |
| R10.32 | Left lower quadrant pain |
| R10.33 | Periumbilical pain |
| R10.8 | Other abdominal pain |
| R10.83 | Colic |
| R10.84 | Generalized abdominal pain |
| R10.9 | Unspecified abdominal pain |
| R51 | Headache |
| R51.0 | Headache with orthostatic component, not elsewhere classified |
| R51.9 | Headache, unspecified |
| R52 | Pain, unspecified |
| R68.84 | Jaw pain |
| T82.84 | Pain due to cardiac and vascular prosthetic devices, implants and grafts |
| T82.847 | Pain due to cardiac prosthetic devices, implants and grafts |
| T82.847A | Pain due to cardiac prosthetic devices, implants and grafts, initial encounter |
| T82.847D | Pain due to cardiac prosthetic devices, implants and grafts, subsequent encounter |
| T82.848 | Pain due to vascular prosthetic devices, implants and grafts |
| T82.848A | Pain due to vascular prosthetic devices, implants and grafts, initial encounter |
| T82.848D | Pain due to vascular prosthetic devices, implants and grafts, subsequent encounter |
| T83.84 | Pain due to genitourinary prosthetic devices, implants and grafts |
| T83.84xA | Pain due to genitourinary prosthetic devices, implants and grafts, initial encounter |
| T83.84xD | Pain due to genitourinary prosthetic devices, implants and grafts, subsequent encounter |
| T84.84 | Pain due to internal orthopedic prosthetic devices, implants and grafts |
| T84.84xA | Pain due to internal orthopedic prosthetic devices, implants and grafts, initial encounter |
| T84.84xD | Pain due to internal orthopedic prosthetic devices, implants and grafts, subsequent encounter |
| T85.84 | Pain due to internal prosthetic devices, implants and grafts, not elsewhere classified |
| T85.840 | Pain due to nervous system prosthetic devices, implants and grafts |
| T85.840A | Pain due to nervous system prosthetic devices, implants and grafts, initial encounter |
| T85.840D | Pain due to nervous system prosthetic devices, implants and grafts, subsequent encounter |
| T85.848 | Pain due to other internal prosthetic devices, implants and grafts |
| T85.848A | Pain due to other internal prosthetic devices, implants and grafts, initial encounter |
| T85.848D | Pain due to other internal prosthetic devices, implants and grafts, subsequent encounter |
| Rheumatoid arthritis | |
| M05 | Rheumatoid arthritis with rheumatoid factor |
| M05.0 | Felty's syndrome |
| M05.00 | Felty's syndrome, unspecified site |
| M05.01 | Felty's syndrome, shoulder |
| M05.011 | Felty's syndrome, right shoulder |
| M05.012 | Felty's syndrome, left shoulder |
| M05.019 | Felty's syndrome, unspecified shoulder |
| M05.02 | Felty's syndrome, elbow |
| M05.021 | Felty's syndrome, right elbow |
| M05.022 | Felty's syndrome, left elbow |
| M05.029 | Felty's syndrome, unspecified elbow |
| M05.03 | Felty's syndrome, wrist |
| M05.031 | Felty's syndrome, right wrist |
| M05.032 | Felty's syndrome, left wrist |
| M05.039 | Felty's syndrome, unspecified wrist |
| M05.04 | Felty's syndrome, hand |
| M05.041 | Felty's syndrome, right hand |
| M05.042 | Felty's syndrome, left hand |
| M05.049 | Felty's syndrome, unspecified hand |
| M05.05 | Felty's syndrome, hip |
| M05.051 | Felty's syndrome, right hip |
| M05.052 | Felty's syndrome, left hip |
| M05.059 | Felty's syndrome, unspecified hip |
| M05.06 | Felty's syndrome, knee |
| M05.061 | Felty's syndrome, right knee |
| M05.062 | Felty's syndrome, left knee |
| M05.069 | Felty's syndrome, unspecified knee |
| M05.07 | Felty's syndrome, ankle and foot |
| M05.071 | Felty's syndrome, right ankle and foot |
| M05.072 | Felty's syndrome, left ankle and foot |
| M05.079 | Felty's syndrome, unspecified ankle and foot |
| M05.09 | Felty's syndrome, multiple sites |
| M05.1 | Rheumatoid lung disease with rheumatoid arthritis |
| M05.10 | Rheumatoid lung disease with rheumatoid arthritis of unspecified site |
| M05.11 | Rheumatoid lung disease with rheumatoid arthritis of shoulder |
| M05.111 | Rheumatoid lung disease with rheumatoid arthritis of right shoulder |
| M05.112 | Rheumatoid lung disease with rheumatoid arthritis of left shoulder |
| M05.119 | Rheumatoid lung disease with rheumatoid arthritis of unspecified shoulder |
| M05.12 | Rheumatoid lung disease with rheumatoid arthritis of elbow |
| M05.121 | Rheumatoid lung disease with rheumatoid arthritis of right elbow |
| M05.122 | Rheumatoid lung disease with rheumatoid arthritis of left elbow |
| M05.129 | Rheumatoid lung disease with rheumatoid arthritis of unspecified elbow |
| M05.13 | Rheumatoid lung disease with rheumatoid arthritis of wrist |
| M05.131 | Rheumatoid lung disease with rheumatoid arthritis of right wrist |
| M05.132 | Rheumatoid lung disease with rheumatoid arthritis of left wrist |
| M05.139 | Rheumatoid lung disease with rheumatoid arthritis of unspecified wrist |
| M05.14 | Rheumatoid lung disease with rheumatoid arthritis of hand |
| M05.141 | Rheumatoid lung disease with rheumatoid arthritis of right hand |
| M05.142 | Rheumatoid lung disease with rheumatoid arthritis of left hand |
| M05.149 | Rheumatoid lung disease with rheumatoid arthritis of unspecified hand |
| M05.15 | Rheumatoid lung disease with rheumatoid arthritis of hip |
| M05.151 | Rheumatoid lung disease with rheumatoid arthritis of right hip |
| M05.152 | Rheumatoid lung disease with rheumatoid arthritis of left hip |
| M05.159 | Rheumatoid lung disease with rheumatoid arthritis of unspecified hip |
| M05.16 | Rheumatoid lung disease with rheumatoid arthritis of knee |
| M05.161 | Rheumatoid lung disease with rheumatoid arthritis of right knee |
| M05.162 | Rheumatoid lung disease with rheumatoid arthritis of left knee |
| M05.169 | Rheumatoid lung disease with rheumatoid arthritis of unspecified knee |
| M05.17 | Rheumatoid lung disease with rheumatoid arthritis of ankle and foot |
| M05.171 | Rheumatoid lung disease with rheumatoid arthritis of right ankle and foot |
| M05.172 | Rheumatoid lung disease with rheumatoid arthritis of left ankle and foot |
| M05.179 | Rheumatoid lung disease with rheumatoid arthritis of unspecified ankle and foot |
| M05.19 | Rheumatoid lung disease with rheumatoid arthritis of multiple sites |
| M05.2 | Rheumatoid vasculitis with rheumatoid arthritis |
| M05.20 | Rheumatoid vasculitis with rheumatoid arthritis of unspecified site |
| M05.21 | Rheumatoid vasculitis with rheumatoid arthritis of shoulder |
| M05.211 | Rheumatoid vasculitis with rheumatoid arthritis of right shoulder |
| M05.212 | Rheumatoid vasculitis with rheumatoid arthritis of left shoulder |
| M05.219 | Rheumatoid vasculitis with rheumatoid arthritis of unspecified shoulder |
| M05.22 | Rheumatoid vasculitis with rheumatoid arthritis of elbow |
| M05.221 | Rheumatoid vasculitis with rheumatoid arthritis of right elbow |
| M05.222 | Rheumatoid vasculitis with rheumatoid arthritis of left elbow |
| M05.229 | Rheumatoid vasculitis with rheumatoid arthritis of unspecified elbow |
| M05.23 | Rheumatoid vasculitis with rheumatoid arthritis of wrist |
| M05.231 | Rheumatoid vasculitis with rheumatoid arthritis of right wrist |
| M05.232 | Rheumatoid vasculitis with rheumatoid arthritis of left wrist |
| M05.239 | Rheumatoid vasculitis with rheumatoid arthritis of unspecified wrist |
| M05.24 | Rheumatoid vasculitis with rheumatoid arthritis of hand |
| M05.241 | Rheumatoid vasculitis with rheumatoid arthritis of right hand |
| M05.242 | Rheumatoid vasculitis with rheumatoid arthritis of left hand |
| M05.249 | Rheumatoid vasculitis with rheumatoid arthritis of unspecified hand |
| M05.25 | Rheumatoid vasculitis with rheumatoid arthritis of hip |
| M05.251 | Rheumatoid vasculitis with rheumatoid arthritis of right hip |
| M05.252 | Rheumatoid vasculitis with rheumatoid arthritis of left hip |
| M05.259 | Rheumatoid vasculitis with rheumatoid arthritis of unspecified hip |
| M05.26 | Rheumatoid vasculitis with rheumatoid arthritis of knee |
| M05.261 | Rheumatoid vasculitis with rheumatoid arthritis of right knee |
| M05.262 | Rheumatoid vasculitis with rheumatoid arthritis of left knee |
| M05.269 | Rheumatoid vasculitis with rheumatoid arthritis of unspecified knee |
| M05.27 | Rheumatoid vasculitis with rheumatoid arthritis of ankle and foot |
| M05.271 | Rheumatoid vasculitis with rheumatoid arthritis of right ankle and foot |
| M05.272 | Rheumatoid vasculitis with rheumatoid arthritis of left ankle and foot |
| M05.279 | Rheumatoid vasculitis with rheumatoid arthritis of unspecified ankle and foot |
| M05.29 | Rheumatoid vasculitis with rheumatoid arthritis of multiple sites |
| M05.3 | Rheumatoid heart disease with rheumatoid arthritis |
| M05.30 | Rheumatoid heart disease with rheumatoid arthritis of unspecified site |
| M05.31 | Rheumatoid heart disease with rheumatoid arthritis of shoulder |
| M05.311 | Rheumatoid heart disease with rheumatoid arthritis of right shoulder |
| M05.312 | Rheumatoid heart disease with rheumatoid arthritis of left shoulder |
| M05.319 | Rheumatoid heart disease with rheumatoid arthritis of unspecified shoulder |
| M05.32 | Rheumatoid heart disease with rheumatoid arthritis of elbow |
| M05.321 | Rheumatoid heart disease with rheumatoid arthritis of right elbow |
| M05.322 | Rheumatoid heart disease with rheumatoid arthritis of left elbow |
| M05.329 | Rheumatoid heart disease with rheumatoid arthritis of unspecified elbow |
| M05.33 | Rheumatoid heart disease with rheumatoid arthritis of wrist |
| M05.331 | Rheumatoid heart disease with rheumatoid arthritis of right wrist |
| M05.332 | Rheumatoid heart disease with rheumatoid arthritis of left wrist |
| M05.339 | Rheumatoid heart disease with rheumatoid arthritis of unspecified wrist |
| M05.34 | Rheumatoid heart disease with rheumatoid arthritis of hand |
| M05.341 | Rheumatoid heart disease with rheumatoid arthritis of right hand |
| M05.342 | Rheumatoid heart disease with rheumatoid arthritis of left hand |
| M05.349 | Rheumatoid heart disease with rheumatoid arthritis of unspecified hand |
| M05.35 | Rheumatoid heart disease with rheumatoid arthritis of hip |
| M05.351 | Rheumatoid heart disease with rheumatoid arthritis of right hip |
| M05.352 | Rheumatoid heart disease with rheumatoid arthritis of left hip |
| M05.359 | Rheumatoid heart disease with rheumatoid arthritis of unspecified hip |
| M05.36 | Rheumatoid heart disease with rheumatoid arthritis of knee |
| M05.361 | Rheumatoid heart disease with rheumatoid arthritis of right knee |
| M05.362 | Rheumatoid heart disease with rheumatoid arthritis of left knee |
| M05.369 | Rheumatoid heart disease with rheumatoid arthritis of unspecified knee |
| M05.37 | Rheumatoid heart disease with rheumatoid arthritis of ankle and foot |
| M05.371 | Rheumatoid heart disease with rheumatoid arthritis of right ankle and foot |
| M05.372 | Rheumatoid heart disease with rheumatoid arthritis of left ankle and foot |
| M05.379 | Rheumatoid heart disease with rheumatoid arthritis of unspecified ankle and foot |
| M05.39 | Rheumatoid heart disease with rheumatoid arthritis of multiple sites |
| M05.4 | Rheumatoid myopathy with rheumatoid arthritis |
| M05.40 | Rheumatoid myopathy with rheumatoid arthritis of unspecified site |
| M05.41 | Rheumatoid myopathy with rheumatoid arthritis of shoulder |
| M05.411 | Rheumatoid myopathy with rheumatoid arthritis of right shoulder |
| M05.412 | Rheumatoid myopathy with rheumatoid arthritis of left shoulder |
| M05.419 | Rheumatoid myopathy with rheumatoid arthritis of unspecified shoulder |
| M05.42 | Rheumatoid myopathy with rheumatoid arthritis of elbow |
| M05.421 | Rheumatoid myopathy with rheumatoid arthritis of right elbow |
| M05.422 | Rheumatoid myopathy with rheumatoid arthritis of left elbow |
| M05.429 | Rheumatoid myopathy with rheumatoid arthritis of unspecified elbow |
| M05.43 | Rheumatoid myopathy with rheumatoid arthritis of wrist |
| M05.431 | Rheumatoid myopathy with rheumatoid arthritis of right wrist |
| M05.432 | Rheumatoid myopathy with rheumatoid arthritis of left wrist |
| M05.439 | Rheumatoid myopathy with rheumatoid arthritis of unspecified wrist |
| M05.44 | Rheumatoid myopathy with rheumatoid arthritis of hand |
| M05.441 | Rheumatoid myopathy with rheumatoid arthritis of right hand |
| M05.442 | Rheumatoid myopathy with rheumatoid arthritis of left hand |
| M05.449 | Rheumatoid myopathy with rheumatoid arthritis of unspecified hand |
| M05.45 | Rheumatoid myopathy with rheumatoid arthritis of hip |
| M05.451 | Rheumatoid myopathy with rheumatoid arthritis of right hip |
| M05.452 | Rheumatoid myopathy with rheumatoid arthritis of left hip |
| M05.459 | Rheumatoid myopathy with rheumatoid arthritis of unspecified hip |
| M05.46 | Rheumatoid myopathy with rheumatoid arthritis of knee |
| M05.461 | Rheumatoid myopathy with rheumatoid arthritis of right knee |
| M05.462 | Rheumatoid myopathy with rheumatoid arthritis of left knee |
| M05.469 | Rheumatoid myopathy with rheumatoid arthritis of unspecified knee |
| M05.47 | Rheumatoid myopathy with rheumatoid arthritis of ankle and foot |
| M05.471 | Rheumatoid myopathy with rheumatoid arthritis of right ankle and foot |
| M05.472 | Rheumatoid myopathy with rheumatoid arthritis of left ankle and foot |
| M05.479 | Rheumatoid myopathy with rheumatoid arthritis of unspecified ankle and foot |
| M05.49 | Rheumatoid myopathy with rheumatoid arthritis of multiple sites |
| M05.5 | Rheumatoid polyneuropathy with rheumatoid arthritis |
| M05.50 | Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified site |
| M05.51 | Rheumatoid polyneuropathy with rheumatoid arthritis of shoulder |
| M05.511 | Rheumatoid polyneuropathy with rheumatoid arthritis of right shoulder |
| M05.512 | Rheumatoid polyneuropathy with rheumatoid arthritis of left shoulder |
| M05.519 | Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified shoulder |
| M05.52 | Rheumatoid polyneuropathy with rheumatoid arthritis of elbow |
| M05.521 | Rheumatoid polyneuropathy with rheumatoid arthritis of right elbow |
| M05.522 | Rheumatoid polyneuropathy with rheumatoid arthritis of left elbow |
| M05.529 | Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified elbow |
| M05.53 | Rheumatoid polyneuropathy with rheumatoid arthritis of wrist |
| M05.531 | Rheumatoid polyneuropathy with rheumatoid arthritis of right wrist |
| M05.532 | Rheumatoid polyneuropathy with rheumatoid arthritis of left wrist |
| M05.539 | Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified wrist |
| M05.54 | Rheumatoid polyneuropathy with rheumatoid arthritis of hand |
| M05.541 | Rheumatoid polyneuropathy with rheumatoid arthritis of right hand |
| M05.542 | Rheumatoid polyneuropathy with rheumatoid arthritis of left hand |
| M05.549 | Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified hand |
| M05.55 | Rheumatoid polyneuropathy with rheumatoid arthritis of hip |
| M05.551 | Rheumatoid polyneuropathy with rheumatoid arthritis of right hip |
| M05.552 | Rheumatoid polyneuropathy with rheumatoid arthritis of left hip |
| M05.559 | Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified hip |
| M05.56 | Rheumatoid polyneuropathy with rheumatoid arthritis of knee |
| M05.561 | Rheumatoid polyneuropathy with rheumatoid arthritis of right knee |
| M05.562 | Rheumatoid polyneuropathy with rheumatoid arthritis of left knee |
| M05.569 | Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified knee |
| M05.57 | Rheumatoid polyneuropathy with rheumatoid arthritis of ankle and foot |
| M05.571 | Rheumatoid polyneuropathy with rheumatoid arthritis of right ankle and foot |
| M05.572 | Rheumatoid polyneuropathy with rheumatoid arthritis of left ankle and foot |
| M05.579 | Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified ankle and foot |
| M05.59 | Rheumatoid polyneuropathy with rheumatoid arthritis of multiple sites |
| M05.6 | Rheumatoid arthritis with involvement of other organs and systems |
| M05.60 | Rheumatoid arthritis of unspecified site with involvement of other organs and systems |
| M05.61 | Rheumatoid arthritis of shoulder with involvement of other organs and systems |
| M05.611 | Rheumatoid arthritis of right shoulder with involvement of other organs and systems |
| M05.612 | Rheumatoid arthritis of left shoulder with involvement of other organs and systems |
| M05.619 | Rheumatoid arthritis of unspecified shoulder with involvement of other organs and systems |
| M05.62 | Rheumatoid arthritis of elbow with involvement of other organs and systems |
| M05.621 | Rheumatoid arthritis of right elbow with involvement of other organs and systems |
| M05.622 | Rheumatoid arthritis of left elbow with involvement of other organs and systems |
| M05.629 | Rheumatoid arthritis of unspecified elbow with involvement of other organs and systems |
| M05.63 | Rheumatoid arthritis of wrist with involvement of other organs and systems |
| M05.631 | Rheumatoid arthritis of right wrist with involvement of other organs and systems |
| M05.632 | Rheumatoid arthritis of left wrist with involvement of other organs and systems |
| M05.639 | Rheumatoid arthritis of unspecified wrist with involvement of other organs and systems |
| M05.64 | Rheumatoid arthritis of hand with involvement of other organs and systems |
| M05.641 | Rheumatoid arthritis of right hand with involvement of other organs and systems |
| M05.642 | Rheumatoid arthritis of left hand with involvement of other organs and systems |
| M05.649 | Rheumatoid arthritis of unspecified hand with involvement of other organs and systems |
| M05.65 | Rheumatoid arthritis of hip with involvement of other organs and systems |
| M05.651 | Rheumatoid arthritis of right hip with involvement of other organs and systems |
| M05.652 | Rheumatoid arthritis of left hip with involvement of other organs and systems |
| M05.659 | Rheumatoid arthritis of unspecified hip with involvement of other organs and systems |
| M05.66 | Rheumatoid arthritis of knee with involvement of other organs and systems |
| M05.661 | Rheumatoid arthritis of right knee with involvement of other organs and systems |
| M05.662 | Rheumatoid arthritis of left knee with involvement of other organs and systems |
| M05.669 | Rheumatoid arthritis of unspecified knee with involvement of other organs and systems |
| M05.67 | Rheumatoid arthritis of ankle and foot with involvement of other organs and systems |
| M05.671 | Rheumatoid arthritis of right ankle and foot with involvement of other organs and systems |
| M05.672 | Rheumatoid arthritis of left ankle and foot with involvement of other organs and systems |
| M05.679 | Rheumatoid arthritis of unspecified ankle and foot with involvement of other organs and systems |
| M05.69 | Rheumatoid arthritis of multiple sites with involvement of other organs and systems |
| M05.7 | Rheumatoid arthritis with rheumatoid factor without organ or systems involvement |
| M05.70 | Rheumatoid arthritis with rheumatoid factor of unspecified site without organ or systems involvement |
| M05.71 | Rheumatoid arthritis with rheumatoid factor of shoulder without organ or systems involvement |
| M05.711 | Rheumatoid arthritis with rheumatoid factor of right shoulder without organ or systems involvement |
| M05.712 | Rheumatoid arthritis with rheumatoid factor of left shoulder without organ or systems involvement |
| M05.719 | Rheumatoid arthritis with rheumatoid factor of unspecified shoulder without organ or systems involvement |
| M05.72 | Rheumatoid arthritis with rheumatoid factor of elbow without organ or systems involvement |
| M05.721 | Rheumatoid arthritis with rheumatoid factor of right elbow without organ or systems involvement |
| M05.722 | Rheumatoid arthritis with rheumatoid factor of left elbow without organ or systems involvement |
| M05.729 | Rheumatoid arthritis with rheumatoid factor of unspecified elbow without organ or systems involvement |
| M05.73 | Rheumatoid arthritis with rheumatoid factor of wrist without organ or systems involvement |
| M05.731 | Rheumatoid arthritis with rheumatoid factor of right wrist without organ or systems involvement |
| M05.732 | Rheumatoid arthritis with rheumatoid factor of left wrist without organ or systems involvement |
| M05.739 | Rheumatoid arthritis with rheumatoid factor of unspecified wrist without organ or systems involvement |
| M05.74 | Rheumatoid arthritis with rheumatoid factor of hand without organ or systems involvement |
| M05.741 | Rheumatoid arthritis with rheumatoid factor of right hand without organ or systems involvement |
| M05.742 | Rheumatoid arthritis with rheumatoid factor of left hand without organ or systems involvement |
| M05.749 | Rheumatoid arthritis with rheumatoid factor of unspecified hand without organ or systems involvement |
| M05.75 | Rheumatoid arthritis with rheumatoid factor of hip without organ or systems involvement |
| M05.751 | Rheumatoid arthritis with rheumatoid factor of right hip without organ or systems involvement |
| M05.752 | Rheumatoid arthritis with rheumatoid factor of left hip without organ or systems involvement |
| M05.759 | Rheumatoid arthritis with rheumatoid factor of unspecified hip without organ or systems involvement |
| M05.76 | Rheumatoid arthritis with rheumatoid factor of knee without organ or systems involvement |
| M05.761 | Rheumatoid arthritis with rheumatoid factor of right knee without organ or systems involvement |
| M05.762 | Rheumatoid arthritis with rheumatoid factor of left knee without organ or systems involvement |
| M05.769 | Rheumatoid arthritis with rheumatoid factor of unspecified knee without organ or systems involvement |
| M05.77 | Rheumatoid arthritis with rheumatoid factor of ankle and foot without organ or systems involvement |
| M05.771 | Rheumatoid arthritis with rheumatoid factor of right ankle and foot without organ or systems involvement |
| M05.772 | Rheumatoid arthritis with rheumatoid factor of left ankle and foot without organ or systems involvement |
| M05.779 | Rheumatoid arthritis with rheumatoid factor of unspecified ankle and foot without organ or systems involvement |
| M05.79 | Rheumatoid arthritis with rheumatoid factor of multiple sites without organ or systems involvement |
| M05.7A | Rheumatoid arthritis with rheumatoid factor of other specified site without organ or systems involvement |
| M05.8 | Other rheumatoid arthritis with rheumatoid factor |
| M05.80 | Other rheumatoid arthritis with rheumatoid factor of unspecified site |
| M05.81 | Other rheumatoid arthritis with rheumatoid factor of shoulder |
| M05.811 | Other rheumatoid arthritis with rheumatoid factor of right shoulder |
| M05.812 | Other rheumatoid arthritis with rheumatoid factor of left shoulder |
| M05.819 | Other rheumatoid arthritis with rheumatoid factor of unspecified shoulder |
| M05.82 | Other rheumatoid arthritis with rheumatoid factor of elbow |
| M05.821 | Other rheumatoid arthritis with rheumatoid factor of right elbow |
| M05.822 | Other rheumatoid arthritis with rheumatoid factor of left elbow |
| M05.829 | Other rheumatoid arthritis with rheumatoid factor of unspecified elbow |
| M05.83 | Other rheumatoid arthritis with rheumatoid factor of wrist |
| M05.831 | Other rheumatoid arthritis with rheumatoid factor of right wrist |
| M05.832 | Other rheumatoid arthritis with rheumatoid factor of left wrist |
| M05.839 | Other rheumatoid arthritis with rheumatoid factor of unspecified wrist |
| M05.84 | Other rheumatoid arthritis with rheumatoid factor of hand |
| M05.841 | Other rheumatoid arthritis with rheumatoid factor of right hand |
| M05.842 | Other rheumatoid arthritis with rheumatoid factor of left hand |
| M05.849 | Other rheumatoid arthritis with rheumatoid factor of unspecified hand |
| M05.85 | Other rheumatoid arthritis with rheumatoid factor of hip |
| M05.851 | Other rheumatoid arthritis with rheumatoid factor of right hip |
| M05.852 | Other rheumatoid arthritis with rheumatoid factor of left hip |
| M05.859 | Other rheumatoid arthritis with rheumatoid factor of unspecified hip |
| M05.86 | Other rheumatoid arthritis with rheumatoid factor of knee |
| M05.861 | Other rheumatoid arthritis with rheumatoid factor of right knee |
| M05.862 | Other rheumatoid arthritis with rheumatoid factor of left knee |
| M05.869 | Other rheumatoid arthritis with rheumatoid factor of unspecified knee |
| M05.87 | Other rheumatoid arthritis with rheumatoid factor of ankle and foot |
| M05.871 | Other rheumatoid arthritis with rheumatoid factor of right ankle and foot |
| M05.872 | Other rheumatoid arthritis with rheumatoid factor of left ankle and foot |
| M05.879 | Other rheumatoid arthritis with rheumatoid factor of unspecified ankle and foot |
| M05.89 | Other rheumatoid arthritis with rheumatoid factor of multiple sites |
| M05.8A | Other rheumatoid arthritis with rheumatoid factor of other specified site |
| M05.9 | Rheumatoid arthritis with rheumatoid factor, unspecified |
| M06 | Other rheumatoid arthritis |
| M06.0 | Rheumatoid arthritis without rheumatoid factor |
| M06.00 | Rheumatoid arthritis without rheumatoid factor, unspecified site |
| M06.01 | Rheumatoid arthritis without rheumatoid factor, shoulder |
| M06.011 | Rheumatoid arthritis without rheumatoid factor, right shoulder |
| M06.012 | Rheumatoid arthritis without rheumatoid factor, left shoulder |
| M06.019 | Rheumatoid arthritis without rheumatoid factor, unspecified shoulder |
| M06.02 | Rheumatoid arthritis without rheumatoid factor, elbow |
| M06.021 | Rheumatoid arthritis without rheumatoid factor, right elbow |
| M06.022 | Rheumatoid arthritis without rheumatoid factor, left elbow |
| M06.029 | Rheumatoid arthritis without rheumatoid factor, unspecified elbow |
| M06.03 | Rheumatoid arthritis without rheumatoid factor, wrist |
| M06.031 | Rheumatoid arthritis without rheumatoid factor, right wrist |
| M06.032 | Rheumatoid arthritis without rheumatoid factor, left wrist |
| M06.039 | Rheumatoid arthritis without rheumatoid factor, unspecified wrist |
| M06.04 | Rheumatoid arthritis without rheumatoid factor, hand |
| M06.041 | Rheumatoid arthritis without rheumatoid factor, right hand |
| M06.042 | Rheumatoid arthritis without rheumatoid factor, left hand |
| M06.049 | Rheumatoid arthritis without rheumatoid factor, unspecified hand |
| M06.05 | Rheumatoid arthritis without rheumatoid factor, hip |
| M06.051 | Rheumatoid arthritis without rheumatoid factor, right hip |
| M06.052 | Rheumatoid arthritis without rheumatoid factor, left hip |
| M06.059 | Rheumatoid arthritis without rheumatoid factor, unspecified hip |
| M06.06 | Rheumatoid arthritis without rheumatoid factor, knee |
| M06.061 | Rheumatoid arthritis without rheumatoid factor, right knee |
| M06.062 | Rheumatoid arthritis without rheumatoid factor, left knee |
| M06.069 | Rheumatoid arthritis without rheumatoid factor, unspecified knee |
| M06.07 | Rheumatoid arthritis without rheumatoid factor, ankle and foot |
| M06.071 | Rheumatoid arthritis without rheumatoid factor, right ankle and foot |
| M06.072 | Rheumatoid arthritis without rheumatoid factor, left ankle and foot |
| M06.079 | Rheumatoid arthritis without rheumatoid factor, unspecified ankle and foot |
| M06.08 | Rheumatoid arthritis without rheumatoid factor, vertebrae |
| M06.09 | Rheumatoid arthritis without rheumatoid factor, multiple sites |
| M06.0A | Rheumatoid arthritis without rheumatoid factor, other specified site |
| M06.8 | Other specified rheumatoid arthritis |
| M06.80 | Other specified rheumatoid arthritis, unspecified site |
| M06.81 | Other specified rheumatoid arthritis, shoulder |
| M06.811 | Other specified rheumatoid arthritis, right shoulder |
| M06.812 | Other specified rheumatoid arthritis, left shoulder |
| M06.819 | Other specified rheumatoid arthritis, unspecified shoulder |
| M06.82 | Other specified rheumatoid arthritis, elbow |
| M06.821 | Other specified rheumatoid arthritis, right elbow |
| M06.822 | Other specified rheumatoid arthritis, left elbow |
| M06.829 | Other specified rheumatoid arthritis, unspecified elbow |
| M06.83 | Other specified rheumatoid arthritis, wrist |
| M06.831 | Other specified rheumatoid arthritis, right wrist |
| M06.832 | Other specified rheumatoid arthritis, left wrist |
| M06.839 | Other specified rheumatoid arthritis, unspecified wrist |
| M06.84 | Other specified rheumatoid arthritis, hand |
| M06.841 | Other specified rheumatoid arthritis, right hand |
| M06.842 | Other specified rheumatoid arthritis, left hand |
| M06.849 | Other specified rheumatoid arthritis, unspecified hand |
| M06.85 | Other specified rheumatoid arthritis, hip |
| M06.851 | Other specified rheumatoid arthritis, right hip |
| M06.852 | Other specified rheumatoid arthritis, left hip |
| M06.859 | Other specified rheumatoid arthritis, unspecified hip |
| M06.86 | Other specified rheumatoid arthritis, knee |
| M06.861 | Other specified rheumatoid arthritis, right knee |
| M06.862 | Other specified rheumatoid arthritis, left knee |
| M06.869 | Other specified rheumatoid arthritis, unspecified knee |
| M06.87 | Other specified rheumatoid arthritis, ankle and foot |
| M06.871 | Other specified rheumatoid arthritis, right ankle and foot |
| M06.872 | Other specified rheumatoid arthritis, left ankle and foot |
| M06.879 | Other specified rheumatoid arthritis, unspecified ankle and foot |
| M06.88 | Other specified rheumatoid arthritis, vertebrae |
| M06.89 | Other specified rheumatoid arthritis, multiple sites |
| M06.8A | Other specified rheumatoid arthritis, other specified site |
| M06.9 | Rheumatoid arthritis, unspecified |
Formulary Reference Tool