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Drug overview for XATMEP (methotrexate):
Generic name: METHOTREXATE (METH-oh-TREX-ate)
Drug class: Antipsoriatics
Therapeutic class: Antineoplastics
Methotrexate, a folic acid antagonist, is an antineoplastic agent and immunosuppressant.
No enhanced Uses information available for this drug.
Generic name: METHOTREXATE (METH-oh-TREX-ate)
Drug class: Antipsoriatics
Therapeutic class: Antineoplastics
Methotrexate, a folic acid antagonist, is an antineoplastic agent and immunosuppressant.
No enhanced Uses information available for this drug.
DRUG IMAGES
XATMEP 2.5 MG/ML ORAL SOLUTION
The following indications for XATMEP (methotrexate) have been approved by the FDA:
Indications:
Acute lymphoid leukemia
Polyarticular juvenile idiopathic arthritis
Professional Synonyms:
Acute lymphatic leukemia
Acute lymphocytic leukemia
Acute lymphogenous leukemia
Lymphoblastic leukemia
Polyarticular JIA
Polyarticular JRA
Polyarticular juvenile chronic arthritis
Polyarticular juvenile rheumatoid arthritis
Indications:
Acute lymphoid leukemia
Polyarticular juvenile idiopathic arthritis
Professional Synonyms:
Acute lymphatic leukemia
Acute lymphocytic leukemia
Acute lymphogenous leukemia
Lymphoblastic leukemia
Polyarticular JIA
Polyarticular JRA
Polyarticular juvenile chronic arthritis
Polyarticular juvenile rheumatoid arthritis
The following dosing information is available for XATMEP (methotrexate):
Dosage of methotrexate sodium is expressed in terms of methotrexate.
Methotrexate is administered orally as tablets or an oral solution. Methotrexate sodium is administered by IM, IV, sub-Q, or intrathecal injection; methotrexate powder for injection may also be administered intraarterially. Some injectable preparations of methotrexate sodium (Rasuvo(R) and Otrexup(R)) are only administered sub-Q.
Rasuvo(R) is only available in doses between 7.5-30 mg in 2.5 mg increments; use a different formulation of methotrexate for alternative dosing via the oral, IM, IV, intraarterial, or intrathecal routes, for dosages <7.5
mg per week, dosages >30 mg per week, high-dose regimens, or dosage adjustments in increments that are <2.5 mg. Otrexup(R) is only available in doses between 10-25 mg in 2.5
mg increments; use a different formulation of methotrexate for alternative dosing via the oral, IM, IV, intraarterial, or intrathecal routes, for dosages <10 mg per week, dosages >25 mg per week, high-dose regimens, or dosage adjustments between the available doses. Methotrexate sodium powder for injection should be reconstituted according to the manufacturers' directions. Methotrexate sodium injection is available as a single-dose vial that is ready for use. Rasuvo(R) and Otrexup(R) (methotrexate sodium injection for sub-Q use) are commercially available in single-use, prefilled auto-injectors.
Rasuvo(R) is only available in doses between 7.5-30 mg in 2.5 mg increments; use a different formulation of methotrexate for alternative dosing via the oral, IM, IV, intraarterial, or intrathecal routes, for dosages <7.5
mg per week, dosages >30 mg per week, high-dose regimens, or dosage adjustments in increments that are <2.5 mg. Otrexup(R) is only available in doses between 10-25 mg in 2.5
mg increments; use a different formulation of methotrexate for alternative dosing via the oral, IM, IV, intraarterial, or intrathecal routes, for dosages <10 mg per week, dosages >25 mg per week, high-dose regimens, or dosage adjustments between the available doses. Methotrexate sodium powder for injection should be reconstituted according to the manufacturers' directions. Methotrexate sodium injection is available as a single-dose vial that is ready for use. Rasuvo(R) and Otrexup(R) (methotrexate sodium injection for sub-Q use) are commercially available in single-use, prefilled auto-injectors.
No dosing information available.
No generic dosing information available.
The following drug interaction information is available for XATMEP (methotrexate):
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 |
|---|---|
| Acitretin/Methotrexate 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: Additive hepatic toxicity.(1-3) CLINICAL EFFECTS: Methotrexate has a risk of causing hepatic fibrosis and cirrhosis.(1) Concurrent use with another hepatotoxic agent like acitretin increases the risk of hepatotoxicity.(2,3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of acitretin states that the concurrent use of acitretin and methotrexate is contraindicated.(2) DISCUSSION: Because of the risk of increased hepatotoxicity during concurrent administration of methotrexate and etretinate, the manufacturer of acitretin states that concurrent administration of methotrexate and acitretin is contraindicated.(2) |
ACITRETIN |
| Efalizumab; Natalizumab/Immunosuppressives; Immunomodulators 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: Natalizumab,(1-3) efalizumab,(4) immunosuppressives, and immunomodulators all suppress the immune system. CLINICAL EFFECTS: Concurrent use of natalizumab(1-3) or efalizumab(4) with immunosuppressives or immunomodulators may result in an increased risk of infections, including progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV). PREDISPOSING FACTORS: Previous JCV infection, longer duration of natalizumab treatment - especially if greater than 2 years, and prior or concomitant treatment with immunosuppressant medication are all independent risk factors which increase the risk for PML.(1,5) The FDA has estimated PML incidence stratified by risk factors: If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment less than 25 months, incidence <1/1,000. If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment less than 25 months, incidence 2/1,000 If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 4/1,000 If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 11/1,000. PATIENT MANAGEMENT: The US manufacturer of natalizumab states patients with Crohn's disease should not receive concurrent immunosuppressants, with the exception of limited overlap of corticosteroids, due to the increased risk for PML. For new natalizumab patients currently receiving chronic oral corticosteroids for Crohn's Disease, begin corticosteroid taper when therapeutic response to natalizumab has occurred. If corticosteroids cannot be discontinued within six months of starting natalizumab, discontinue natalizumab.(3) The US manufacturer of natalizumab states that natalizumab should not ordinarily be used in multiple sclerosis patients receiving immunosuppressants or immunomodulators due to the increased risk for PML. Immunosuppressives include, but are not limited to azathioprine, cyclophosphamide, cyclosporine, mercaptopurine, methotrexate, mitoxantrone, mycophenolate, and corticosteroids.(3,6) The UK manufacturer of natalizumab states that concurrent use with immunosuppressives or antineoplastic agents is contraindicated.(1) The Canadian manufacturer of natalizumab states that natalizumab should not be used with immunosuppressive or immunomodulatory agents.(2) The US manufacturer of certolizumab states that concurrent therapy with natalizumab is not recommended.(7) DISCUSSION: Progressive multifocal leukoencephalopathy has been reported in patients receiving concurrent natalizumab were recently or concomitantly taking immunomodulators or immunosuppressants.(1-5,8,9) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(10) |
TYSABRI |
| Talimogene laherparepvec/Selected Immunosuppressants 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: Talimogene laherparepvec is a live, attenuated herpes simplex virus.(1) CLINICAL EFFECTS: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Talimogene laherparepvec is contraindicated in immunosuppressed patients.(1) The magnitude of immunocompromise and associated risks due to immunosuppressant drugs should be determined by a physician. DISCUSSION: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1) |
IMLYGIC |
| Nadofaragene Firadenovec/Selected Immunosuppressants 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: Nadofaragene firadenovec may contain low levels of replication-competent adenovirus.(1) CLINICAL EFFECTS: Concurrent use of nadofaragene firadenovec in patients receiving immunosuppressive therapy may cause disseminated adenovirus infection.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Individuals who are immunosuppressed or immune-deficient should not receive nadofaragene firadenovec.(1) DISCUSSION: Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy but may contain low levels of replication-competent adenovirus. Immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection.(1) |
ADSTILADRIN |
There are 29 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 (low strength injection, oral)/Select Salicylates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Salicylates may inhibit the renal tubular excretion of methotrexate. CLINICAL EFFECTS: The concurrent use of methotrexate and salicylates may result in an increase in the therapeutic and toxic effects of methotrexate, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia. PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Anti-inflammatory doses of aspirin/salicylates - impaired renal function, ascites, or pleural effusions PATIENT MANAGEMENT: US manufacturer prescribing information for methotrexate states nonsteroidal anti-inflammatory drugs, including salicylates should not be administered prior to or concomitantly with high doses of methotrexate. If concurrent therapy is warranted, methotrexate plasma levels should be monitored and patients should be observed for methotrexate toxicity. The dosage of methotrexate may need to be adjusted. Use caution when administering salicylates and low dose methotrexate. Salicylate doses > or = 2 grams per day have been associated with hepatic impairment or impaired renal elimination of methotrexate. It would be prudent to avoid high-dose aspirin, especially in patients with renal impairment or near the time of methotrexate dosage (in patients receiving weekly therapy). DISCUSSION: Several studies and case reports have reported increased and prolonged methotrexate levels in patients receiving concurrent aspirin. One study noted an effect with average weekly doses of methotrexate of 16.6 mg, but not weekly doses of 7.5 mg. Decreased renal function has also been reported with the combination. Single ingredient aspirin or buffered aspirin products with strengths < or = to 325 mg or formulations which are associated with once daily use for cardiovascular protection are not linked to this interaction. Other lower-strength aspirin formulations (e.g. headache, cough & cold, opioid combinations) which could be consumed multiple times a day remain linked to this interaction. |
ACETYL SALICYLIC ACID, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, ASPIRIN, BALSALAZIDE DISODIUM, BISMUTH SUBSALICYLATE, BUTALBITAL-ASPIRIN-CAFFEINE, CARISOPRODOL-ASPIRIN, CARISOPRODOL-ASPIRIN-CODEINE, CHOLINE MAGNESIUM TRISALICYLAT, COLAZAL, DIFLUNISAL, DISALCID, DOLOBID, MB CAPS, NORGESIC, NORGESIC FORTE, ORPHENADRINE-ASPIRIN-CAFFEINE, ORPHENGESIC FORTE, PHENYL SALICYLATE, SALSALATE, SODIUM SALICYLATE, URETRON D-S, URIBEL TABS, URIMAR-T, URNEVA, URO-MP, URO-SP |
| 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. |
ANAPROX DS, ANJESO, ARTHROTEC 50, ARTHROTEC 75, BROMFENAC SODIUM, BUPIVACAINE-KETOROLAC-KETAMINE, CALDOLOR, CAMBIA, CELEBREX, CELECOXIB, COMBOGESIC, COMBOGESIC IV, CONSENSI, COXANTO, DAYPRO, DICLOFENAC, DICLOFENAC POTASSIUM, DICLOFENAC SODIUM, DICLOFENAC SODIUM ER, DICLOFENAC SODIUM MICRONIZED, DICLOFENAC SODIUM-MISOPROSTOL, EC-NAPROSYN, ELYXYB, ETODOLAC, ETODOLAC ER, FELDENE, FENOPROFEN CALCIUM, FENOPRON, FLURBIPROFEN, HYDROCODONE-IBUPROFEN, IBU, IBUPAK, IBUPROFEN, IBUPROFEN LYSINE, IBUPROFEN-FAMOTIDINE, INDOCIN, INDOMETHACIN, INDOMETHACIN ER, INFLAMMACIN, INFLATHERM(DICLOFENAC-MENTHOL), KETOPROFEN, KETOPROFEN MICRONIZED, KETOROLAC TROMETHAMINE, KIPROFEN, LODINE, LOFENA, LURBIPR, MECLOFENAMATE SODIUM, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NABUMETONE MICRONIZED, NALFON, NAPRELAN, NAPROSYN, NAPROTIN, NAPROXEN, NAPROXEN SODIUM, NAPROXEN SODIUM CR, NAPROXEN SODIUM ER, NAPROXEN-ESOMEPRAZOLE MAG, NEOPROFEN, OXAPROZIN, PHENYLBUTAZONE, PIROXICAM, R.E.C.K.(ROPIV-EPI-CLON-KETOR), RELAFEN DS, ROPIVACAINE-CLONIDINE-KETOROLC, ROPIVACAINE-KETOROLAC-KETAMINE, SPRIX, SULINDAC, SUMATRIPTAN SUCC-NAPROXEN SOD, SYMBRAVO, TOLECTIN 600, TOLMETIN SODIUM, TORONOVA II SUIK, TORONOVA SUIK, TOXICOLOGY SALIVA COLLECTION, TRESNI, TREXIMET, VIMOVO, VIVLODEX, ZIPSOR, ZORVOLEX |
| Methotrexate; Pralatrexate/Sulfonamide Antibacterials; Trimethoprim SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Sulfonamide antibacterials and/or trimethoprim may decrease the renal clearance of methotrexate and pralatrexate or produce a synergistically-induced folate deficiency. Sulfonamide antibacterials and/or trimethoprim may decrease protein binding of methotrexate. CLINICAL EFFECTS: Concurrent use of sulfonamide antibacterials and/or trimethoprim may increase levels of and toxicity from methotrexate and pralatrexate, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia. PREDISPOSING FACTORS: Risk factors for methotrexate or pralatrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions PATIENT MANAGEMENT: Concurrent use of sulfonamide antibiotics or trimethoprim with methotrexate or pralatrexate should be avoided. If coadministration cannot be avoided, closely monitor patients who are receiving concurrent therapy or patients who have recently finished methotrexate or pralatrexate therapy and who are beginning sulfonamide therapy for signs of toxicity, including bone marrow suppression, pancytopenia, thrombocytopenia, and stomatitis. DISCUSSION: In one study in pediatric leukemia patients, concurrent administration of methotrexate and trimethoprim-sulfamethoxazole resulted in an increase in free methotrexate and a decrease in free methotrexate clearance. These changes resulted in a 66% increase in systemic exposure to methotrexate, although there were no significant changes in total methotrexate clearance or methotrexate half-life. In another study in pediatric leukemia patients, concurrent therapy with methotrexate and trimethoprim-sulfamethoxazole did not alter the intestinal absorption, degree of plasma protein binding, or average concentration of methotrexate. Case reports have documented methotrexate toxicities such as bone marrow hypoplasia, pancytopenia, thrombocytopenia, and stomatitis during concurrent therapy and during therapy with trimethoprim-sulfamethoxazole following the conclusion of methotrexate therapy. Some of these reports involved patients receiving low-dose methotrexate for rheumatoid arthritis. Methotrexate plasma protein binding and renal clearance have been shown to be decreased by the concurrent administration of sulfisoxazole. In a retrospective cohort study of 3204 adults taking low-dose methotrexate, the risk of all-cause hospitalization (Risk Ratio (RR) 1.49 (95% Confidence Interval (CI) 1.13-1.97) and infection (RR 2.78 (95% CI 1.30 - 5.95)) was higher in adults treated with trimethoprim-sulfamethoxazole (n=1602) than those treated with cephalosporins (n=1602). This interaction has also been reported in patients receiving concurrent methotrexate and trimethoprim without concurrent sulfamethoxazole. |
BACTRIM, BACTRIM DS, PRIMSOL, SULFADIAZINE, SULFADIAZINE SODIUM, SULFAMERAZINE, SULFAMETHOXAZOLE, SULFAMETHOXAZOLE-TRIMETHOPRIM, SULFAPYRIDINE, SULFATRIM, SULFISOXAZOLE, TRIMETHOPRIM, TRIMETHOPRIM MICRONIZED |
| Cytarabine; Methotrexate/Asparaginase SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism of the interaction is unknown and may be a combination of mechanisms. Asparaginase has been shown to decrease the cellular uptake of methotrexate. This effect is maximal 24 hours after asparaginase administration and returns to baseline 96 hours later. Asparaginase inhibits DNA synthesis and asparaginase-induced amino acid depletion may cause cells to enter a stationary phase of growth. Since methotrexate is most toxic against cells that are actively synthesizing DNA, its transport and cytocidal effects may be decreased.(1) CLINICAL EFFECTS: When asparaginase is administered prior to or with cytarabine or methotrexate, asparaginase may diminish the effect of cytarabine or methotrexate on malignant cells (1-3). PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Cytarabine and methotrexate should not be administered with or during the period following asparaginase therapy when asparagine levels are below normal.(2-3) A synergistic effect was observed when cytarabine was given before asparaginase therapy and was most prominent with a treatment interval of about 120 hours.(4) The optimal time interval between asparaginase and a subsequent dose of methotrexate has been shown to be 9-10 days. A 24-hour interval between methotrexate and a subsequent dose of asparaginase allows for the return of methotrexate's effects on malignant cells.(1) DISCUSSION: The effects of asparaginase with cytarabine or methotrexate in combination are schedule-dependent. When asparaginase is given concurrently with or prior to cytarabine or methotrexate, asparaginase inhibits the cytocidal effects of cytarabine and methotrexate. However, when given 24 hours after larger doses of cytarabine or methotrexate, asparaginase may decrease some of the toxic effects of cytarabine or methotrexate, allowing the host to tolerate larger doses of chemotherapy. The sequential administration of cytarabine or methotrexate followed by asparaginase may result in synergistic effects and decreased toxicity (1). |
ASPARLAS, ERWINASE, ONCASPAR, RYLAZE |
| Methotrexate/Penicillins SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Penicillins may compete with the renal tubular secretion of methotrexate. CLINICAL EFFECTS: The concurrent use of methotrexate and penicillins may result in elevated levels of methotrexate and methotrexate toxicity, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression. PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions PATIENT MANAGEMENT: Patients receiving concurrent therapy with methotrexate and penicillins should be monitored closely for elevated methotrexate levels and methotrexate toxicity. The dose and duration of leucovorin rescue therapy may need to be increased. DISCUSSION: Elevated methotrexate levels, signs of methotrexate toxicity, and death have been reported following the concurrent use of methotrexate (both low dose and high dose) and penicillin derivatives. In a patient being treated with high-dose methotrexate (8 G/m2), the concurrent use of amoxicillin resulted in a 56% decrease in the clearance of methotrexate and signs of methotrexate toxicity.(1) There are two cases of methotrexate toxicity following the addition of amoxicillin to low-dose methotrexate therapy (7.5 mg-10 mg weekly) for psoriasis. In another case, a patient was found to have a toxic methotrexate level 12 days after her last dose of weekly methotrexate (7.5 mg). The patient had been treated with amoxicillin followed by flucloxacillin.(2) In a case report, dicloxacillin decreased methotrexate clearance 93%.(4) Flucloxacillin was shown to increase the area-under-curve (AUC) of methotrexate by 7.3% in a study in 10 subjects.(5) In a case report, a patient on low-dose methotrexate (5 mg) developed methotrexate pneumonia following the addition of flucloxacillin to his regimen.(5) In a patient being treated with high-dose methotrexate (12 G/m2), the concurrent use of mezlocillin increased the half-life of methotrexate from 10.1 to 27.2 hours.(6) In a case report, a patient developed methotrexate toxicity following the addition of penicillin V potassium to his methotrexate (50 mg weekly).(7) In a case report, penicillin decreased methotrexate clearance 36%.(4) In one report, leucovorin rescue therapy had to be continued for 192 hours following the concurrent use of methotrexate (3 G/m2) and piperacillin. During cycles without concurrent piperacillin, leucovorin rescue therapy was only required for 72 hours.(8) There are two reports of neutropenia and death following the concurrent use of piperacillin and low-dose methotrexate (2.5 mg three times weekly in one patient, 5 mg weekly in another) for psoriasis. One of these patients also received flucloxacillin. (3) In another case report, the concurrent use of piperacillin decreased methotrexate clearance by 67%.(4) In a case report, ticarcillin decreased methotrexate clearance by 60%.(4) |
AMOXICILLIN, AMOXICILLIN TRIHYDRATE, AMOXICILLIN-CLAVULANATE POT ER, AMOXICILLIN-CLAVULANATE POTASS, AMPICILLIN SODIUM, AMPICILLIN TRIHYDRATE, AMPICILLIN-SULBACTAM, AUGMENTIN, AUGMENTIN ES-600, AUGMENTIN XR, BICILLIN C-R, BICILLIN L-A, DICLOXACILLIN SODIUM, EXTENCILLINE, LANSOPRAZOL-AMOXICIL-CLARITHRO, LENTOCILIN S, MOXATAG, NAFCILLIN, NAFCILLIN SODIUM, OMECLAMOX-PAK, OXACILLIN, OXACILLIN SODIUM, PENICILLIN G POTASSIUM, PENICILLIN G SODIUM, PENICILLIN GK-ISO-OSM DEXTROSE, PENICILLIN V POTASSIUM, PFIZERPEN, PIPERACILLIN-TAZOBACTAM, PIVYA, TALICIA, UNASYN, VOQUEZNA DUAL PAK, VOQUEZNA TRIPLE PAK, ZOSYN |
| Cyclosporine/Methotrexate SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Cyclosporine may inhibit the metabolism of methotrexate to its inactive metabolite, increasing its toxicity.(1) Concurrent use may result in excessive immunosuppression.(2) CLINICAL EFFECTS: Concurrent use of cyclosporine and methotrexate may increase the levels of and toxicity from methotrexate, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia. Concurrent use may also increase the risk of malignancy.(2) PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions PATIENT MANAGEMENT: The US manufacturer of cyclosporine states that concurrent use of cyclosporine and methotrexate in contraindicated in psoriasis patients because of the possibility of excessive immunosuppression and the subsequent risk of malignancies.(2) Cyclosporine and methotrexate can be used concurrently in the treatment of rheumatoid arthritis. CBC and liver function tests should be performed monthly in patients receiving concurrent therapy.(2) DISCUSSION: In a study in 30 subjects with rheumatoid arthritis, concurrent cyclosporine increased methotrexate maximum concentration (Cmax) and area-under-curve (AUC) by 26% and 18%, respectively. The plasma AUC of the inactive 7-hydroxymethotrexate metabolite decreased by 80%. In 13 subjects who received a 10 mg dose of methotrexate, the urinary excretion of 7-hydroxymethotrexate decreased by 87%. There were no effects on the pharmacokinetics of cyclosporine or its metabolites.(1) A study that compared 30 rheumatoid arthritis patients who received concurrent cyclosporine and methotrexate to 30 rheumatoid arthritis patients who received cyclosporine alone found no effects by methotrexate on cyclosporine pharmacokinetics.(3) Tumors have been reported in 32 (2.2%) of 1439 psoriasis patients treated with cyclosporine in clinical trials. Tumors have been reported in an additional 7 patients in post-marketing reports. Sixteen of these reports involved skin malignancies. Methotrexate was used by 7 of the patients.(2) |
CYCLOSPORINE, CYCLOSPORINE MODIFIED, GENGRAF, NEORAL, SANDIMMUNE |
| Deferiprone/Selected Myelosuppressive Agents SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1) CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal. PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2) PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1) DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3) |
DEFERIPRONE, DEFERIPRONE (3 TIMES A DAY), FERRIPROX, FERRIPROX (2 TIMES A DAY), FERRIPROX (3 TIMES A DAY) |
| Tofacitinib/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of tofacitinib and azathioprine, other biologic disease-modifying antirheumatic drugs (DMARDs), or potent immunosuppressants may result in additive or synergistic effects on the immune system.(1) CLINICAL EFFECTS: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants use may increase the risk of serious infections.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Tofacitinib should not be used concurrently with azathioprine, other biologic DMARDs, or cyclosporine.(1) Patient should be monitored for decreases in lymphocytes and neutrophils. Therapy should be adjusted based on the indication. - For all indications: If absolute neutrophil count (ANC) or lymphocyte count is less than 500 cells/mm3, discontinue tofacitinib. - For rheumatoid arthritis or psoriatic arthritis and absolute neutrophil count (ANC) 500 to 1000 cells/mm3: interrupt dosing. When ANC is greater than 1000 cells/mm3, resume Xeljanz 5 mg twice daily or Xeljanz XR 11 mg once daily. - For ulcerative colitis and ANC 500 to 1000 cells/mm3: -If taking Xeljanz 10 mg twice daily, decrease to 5 mg twice daily. When ANC is greater than 1000 cells/mm3, increase to 10 mg twice daily based on clinical response. -If taking Xeljanz 5 mg twice daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 5 mg twice daily. -If taking Xeljanz XR 22 mg once daily, decrease to 11 mg once daily. When ANC is greater than 1000 cells/mm3, increase to 22 mg once daily based on clinical response. -If taking Xeljanz XR 11 mg once daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 11 mg once daily. - For polyarticular course juvenile idiopathic arthritis (pcJIA) and ANC 500 to 1000 cells/mm3: interrupt dosing until ANC is greater than 1000 cells/mm3.(1) DISCUSSION: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants may increase the risk of infection.(1) |
TOFACITINIB CITRATE, XELJANZ, XELJANZ XR |
| Live Vaccines/Methotrexate (low strength injection, oral) SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: A variety of disease modifying agents such as methotrexate suppress the immune system. Immunocompromised patients may be at increased risk for uninhibited replication after administration of live, attenuated vaccines. Immune response to vaccines may be decreased during periods of immunocompromise.(1) CLINICAL EFFECTS: The expected serum antibody response may not be obtained and/or the vaccine may result in illness.(1) PREDISPOSING FACTORS: Immunosuppressive diseases (e.g. hematologic malignancies, HIV disease), treatments (e.g. radiation) and drugs may all increase the magnitude of immunodeficiency. PATIENT MANAGEMENT: The Centers for Disease Control(CDC) Advisory Committee on Immunization Practices (ACIP) states that live-virus and live, attenuated vaccines should not be administered to patients who are immunocompromised. The magnitude of immunocompromise and associated risks should be determined by a physician.(1) CDC recommendations for zoster vaccine state it may be administered to patients receiving methotrexate if the dose is < or = to 0.4 mg/kg/week for treatment of rheumatoid arthritis, psoriasis, inflammatory bowel disease or other conditions.(1) For patients scheduled to receive chemotherapy, vaccination should ideally precede the initiation of chemotherapy by 14 days. Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy.(1) DISCUSSION: Killed or inactivated vaccines do not pose a danger to immunocompromised patients.(1) Patients with a history of leukemia who are in remission and have not received chemotherapy for at least 3 months are not considered to be immunocompromised.(1) |
ACAM2000 (NATIONAL STOCKPILE), ADENOVIRUS TYPE 4, ADENOVIRUS TYPE 4 AND TYPE 7, ADENOVIRUS TYPE 7, BCG VACCINE (TICE STRAIN), DENGVAXIA, ERVEBO (NATIONAL STOCKPILE), FLUMIST TRIVALENT 2024-2025, IXCHIQ, M-M-R II VACCINE, PRIORIX, PROQUAD, ROTARIX, ROTATEQ, STAMARIL, VARIVAX VACCINE, VAXCHORA ACTIVE COMPONENT, VAXCHORA VACCINE, VIVOTIF, YF-VAX |
| Clozapine/Selected Myelosuppressive Agents SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2) CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal. PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia. PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent ANC monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. Clozapine is only available through a restricted distribution system which requires documentation of the absolute neutrophil count (ANC) prior to dispensing.(1-2) For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2) DISCUSSION: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing.(1) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26) |
CLOZAPINE, CLOZAPINE ODT, CLOZARIL, VERSACLOZ |
| Azathioprine; Mercaptopurine/Methotrexate SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The mechanism of this interaction has not been fully characterized. It has been suggested that methotrexate may inhibit the metabolism of mercaptopurine by xanthine oxidase.(1-3) CLINICAL EFFECTS: Concurrent use of methotrexate with azathioprine or mercaptopurine may increase the risk for elevated levels of and toxicity from mercaptopurine, including bone marrow suppression, neutropenia and hepatotoxicity.(1-3) PREDISPOSING FACTORS: Larger doses of methotrexate may produce larger increases in mercaptopurine levels.(1-3) Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are at higher risk of accumulating thiopurine metabolites and severe myelosuppression. Approximately 0.3 % of patients of European, Latino, or African descent have mutations of the TPMT gene resulting in little to no TPMT activity (homozygous deficiency), and approximately 10 % have intermediate TPMT activity (heterozygous deficiency). NUDT15 deficiency is not seen in patients of African descent and is seen in less than 1 % of patients of European descent. Approximately 1 % of patients of East Asian descent, 0.5 % of patients of central/south Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15 deficiency. About 17 % of patients of East Asian descent, 13 % of patients of central/south Asian descent, and 8 % of patients of Latino descent have heterozygous NUDT15 deficiency.(5) PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy closely for myelosuppression and hepatotoxicity. The dose of azathioprine or mercaptopurine may need to be adjusted when administered concomitantly with high-dose methotrexate.(1-4) DISCUSSION: In a study in 14 pediatric patients with leukemia, methotrexate (20 mg/m2) increased the maximum concentration (Cmax) and area-under-curve (AUC) of mercaptopurine by 26% and 31%, respectively.(1,3) In a study in 10 pediatric patients with acute lymphoblastic leukemia, 2 g/m2 of methotrexate increased the Cmax and AUC of mercaptopurine (25 mg/m2) by 108% and 69%, respectively. Administration of 5 g/m2 of methotrexate increased the Cmax and AUC of mercaptopurine (25 mg/m2) by 121% and 93%, respectively.(2-3) |
AZASAN, AZATHIOPRINE, AZATHIOPRINE SODIUM, IMURAN, MERCAPTOPURINE, PURIXAN |
| Selected Oral BCRP Substrates/Oral Rolapitant SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Oral rolapitant may inhibit transport of irinotecan, methotrexate, and topotecan by BCRP, leading to increased levels of these agents.(1) CLINICAL EFFECTS: Concurrent use of oral rolapitant may result in elevated levels of and toxicity from irinotecan, methotrexate, and topotecan.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concurrent use if possible. If concurrent use cannot be avoided, monitor patients for increased effects of irinotecan, methotrexate, and topotecan.(1) DISCUSSION: A single dose of oral rolapitant (180 mg on day 1) was found to increase the maximum concentration (Cmax) and area-under-curve (AUC) of sulfasalazine (500 mg single dose), a substrate of BCRP, by 140% and 130%, respectively.(1) A single dose of intravenous rolapitant (166.5 mg on day 1) was found to have no effect on Cmax and AUC of sulfasalazine (500 mg single dose).(1) |
VARUBI |
| Selected Multiple Sclerosis Agents/Immunosuppressants; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ocrelizumab or ofatumumab in combination with immunosuppressives and immune-modulators all suppress the immune system.(1,2) CLINICAL EFFECTS: Concurrent use of ocrelizumab or ofatumumab with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1,2) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications. PATIENT MANAGEMENT: The ocrelizumab US prescribing information states: - Ocrelizumab and other immune-modulating or immunosuppressive therapies, (including immunosuppressant doses of corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with ocrelizumab. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating ocrelizumab.(1) The ofatumumab US prescribing information states: - Ofatumumab and other immunosuppressive therapies (including systemic corticosteroids) may have the potential for increased immunosuppressive effects and increase the risk of infection. When switching between therapies, the duration and mechanism of action of each therapy should be considered due to the potential for additive immunosuppressive effects. Ofatumumab for MS therapy has not been studied in combination with other MS agents that suppress the immune system.(2) DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1,2) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(3) |
KESIMPTA PEN, OCREVUS, OCREVUS ZUNOVO |
| Selected Oral BCRP Substrates/Oral Tedizolid SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Oral tedizolid may may inhibit Breast Cancer Resistance Protein (BCRP) in the intestine, which may result in increased absorption of orally administered BCRP substrates.(1-3) CLINICAL EFFECTS: Concurrent use of oral tedizolid may result in elevated levels of and toxicity from orally administered BCRP substrates.(1-3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: If possible, consider interrupting therapy with orally administered BCRP substrates during therapy with oral tedizolid. If concurrent therapy is warranted, monitor patients for toxicity.(1-3) DISCUSSION: Orally administered tedizolid (200 mg) increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin (10 mg) by 70% and 55%, respectively.(1-3) BCRP substrates include: imatinib, lapatinib, methotrexate, rosuvastatin, sulfasalazine, and topotecan.(1-3) |
SIVEXTRO |
| Selected BCRP Substrates/Darolutamide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Darolutamide inhibits BCRP, which may result in increased absorption of BCRP substrates.(1) CLINICAL EFFECTS: Administration of darolutamide with BCRP substrates may result in elevated levels of and toxicity from these agents.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer recommends avoiding concurrent use of darolutamide with BCRP substrates when possible. DISCUSSION: Concurrent administration of darolutamide with rosuvastatin increased the mean area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin approximately 5-fold.(1) BCRP substrates linked to this monograph include: ciprofloxacin, diclofenac, glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, and topotecan.(1-3) |
NUBEQA |
| Upadacitinib/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Upadacitinib, immunosuppressives, and immunomodulators all suppress the immune system. CLINICAL EFFECTS: Concurrent use of upadacitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of upadacitinib states that concurrent use of upadacitinib with immunosuppressives or immunomodulators is not recommended. DISCUSSION: Serious infections have been reported in patients receiving upadacitinib. Reported infections included pneumonia, cellulitis, tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, cryptococcosis. Reports of viral reactivation, including herpes virus reactivation and hepatitis B reactivation, were reported in clinical studies with upadacitinib.(1) |
RINVOQ, RINVOQ LQ |
| Selected BCRP Substrates/Capmatinib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Capmatinib inhibits BCRP, which may result in increased absorption of BCRP substrates.(1) CLINICAL EFFECTS: Administration of capmatinib with BCRP substrates may result in elevated levels of and toxicity from these agents.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of capmatinib states that the concurrent use of narrow therapeutic index BCRP substrates should be avoided. If concurrent therapy cannot be avoided, the dosage of the narrow therapeutic index BCRP substrate should be decreased according to the substrate prescribing information.(1) DISCUSSION: In a study, capmatinib increased rosuvastatin (a BCRP substrate) area-under-curve (AUC) by 108% and maximum concentration (Cmax) by 204%.(1) BCRP substrates linked to this monograph include: ciprofloxacin, glyburide, imatinib, irinotecan, lapatinib, methotrexate, and mitoxantrone.(1-2) |
TABRECTA |
| Inebilizumab/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inebilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of inebilizumab with immunosuppressive or immunomodulating agents may result in myelosuppression including neutropenia resulting in an increased risk for serious infections.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of inebilizumab states that the concurrent use of inebilizumab with immunosuppressive agents, including systemic corticosteroids, may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1) DISCUSSION: Inebilizumab has not been studied in combination with other immunosuppressants. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents. The most common infections reported by inebilizumab treated patients in the randomized and open-label clinical trial periods included urinary tract infections (20%), nasopharyngitis (13%), upper respiratory tract infections (8%), and influenza (7%). Although there been no cases of Hepatitis B virus reactivation or progressive multifocal leukoencephalopathy reported in patients taking inebilizumab, these infections have been observed in patients taking other B-cell-depleting antibodies.(1) |
UPLIZNA |
| Baricitinib/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of baricitinib with other biologic disease-modifying antirheumatic drugs (DMARDs) or potent immunosuppressants such as azathioprine or cyclosporine may result in additive or synergistic effects on the immune system. CLINICAL EFFECTS: Concurrent use of baricitinib with other biologic DMARDs or potent immunosuppressants such as azathioprine or cyclosporine may increase the risk of serious infections.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of baricitinib states that concurrent use of baricitinib with biologic DMARDs or potent immunosuppressants is not recommended.(1) DISCUSSION: Most patients who developed serious infections while being treated with baricitinib were on concomitant immunosuppressants like methotrexate and corticosteroids. The combination of baricitinib with other biologic DMARDs has not been studied.(1) |
OLUMIANT |
| Ponesimod/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ponesimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of ponesimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications. PATIENT MANAGEMENT: The ponesimod US prescribing information states ponesimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ponesimod after alemtuzumab is not recommended. However, ponesimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1) DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1) |
PONVORY |
| Sodium Iodide I 131/Myelosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1) DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1) |
HICON, SODIUM IODIDE I-131 |
| Fingolimod/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Fingolimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-3) CLINICAL EFFECTS: Concurrent use of fingolimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-3) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications. PATIENT MANAGEMENT: Recommendations for fingolimod regarding this interaction differ between regulatory approving agencies. The fingolimod US prescribing information states: - Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with fingolimod. When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating fingolimod.(1) The fingolimod Canadian prescribing information states: - Concurrent use with immunosuppressive or immunomodulatory agents is contraindicated due to the risk of additive immune system effects. However, co-administration of a short course of corticosteroids (up to 5 days) did not increase the overall rate of infection in patients participating Phase III clinical trials.(2) The fingolimod UK specific product characteristics states: - Fingolimod is contraindicated in patients currently receiving immunosuppressive therapies or those immunocompromised by prior therapies. When switching patients from another disease modifying therapy to Gilenya, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimizing the risk of disease activation.(3) DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-3) |
FINGOLIMOD, GILENYA, TASCENSO ODT |
| Ozanimod/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ozanimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of ozanimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications. PATIENT MANAGEMENT: The ozanimod US prescribing information state this information regarding this interaction: -Ozanimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ozanimod after alemtuzumab is not recommended. However, ozanimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1) DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1) |
ZEPOSIA |
| Siponimod/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Siponimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of siponimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications. PATIENT MANAGEMENT: The siponimod US prescribing information state this information regarding this interaction: -Siponimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with siponimod after alemtuzumab is not recommended. However, siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1) DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1) |
MAYZENT |
| Cladribine/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2) CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-2) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications. PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US prescribing information states: -Concomitant use with myelosuppressive or other immunosuppressive drugs is not recommended. Acute short-term therapy with corticosteroids can be administered. In patients who have previously been treated with immunomodulatory or immunosuppressive drugs, consider potential additive effect, the mode of action, and duration of effect of the other drugs prior to initiation of cladribine.(1) The cladribine Canadian prescribing information states: -Use of cladribine in immunocompromised patients is contraindicated because of a risk of additive effects on the immune system. Acute short-term therapy with corticosteroids can be administered during cladribine treatment.(2) DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-2) |
CLADRIBINE, MAVENCLAD |
| Selected BCRP Substrates/Oteseconazole SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Oteseconazole is an inhibitor of the BCRP transporter, which may result in increased absorption of BCRP substrates.(1) CLINICAL EFFECTS: Administration of oteseconazole with BCRP substrates may result in elevated levels of and toxicity of the BCRP substrates.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of oteseconazole states that the lowest possible starting dose of the BCRP substrate should be used and to consider reducing the dose of the substrate drug according to the product labeling and monitor for adverse reactions.(1) DISCUSSION: Oteseconazole increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin, a BCRP substrate, by 118% and 114%, respectively.(1) BCRP substrates linked to this monograph include: ciprofloxacin, diclofenac, glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, and sulfasalazine.(1-2) |
VIVJOA |
| Ritlecitinib/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ritlecitinib, immunosuppressives, and immunomodulators all suppress the immune system. CLINICAL EFFECTS: Concurrent use of ritlecitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of ritlecitinib states that concurrent use of ritlecitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1) DISCUSSION: Serious infections have been reported in patients receiving ritlecitinib. Reported infections included appendicitis, COVID-19 infection (including pneumonia), and sepsis. Reports of viral reactivation, including herpes virus reactivation was reported in clinical studies with ritlecitinib.(1) |
LITFULO |
| Etrasimod/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Etrasimod causes reversible sequestration of lymphocytes in lymphoid tissues, resulting in a mean 55% decrease in peripheral blood lymphocyte count at 52 weeks.(1) Other immunosuppressives and immune-modulators also suppress the immune system. CLINICAL EFFECTS: Concurrent use of etrasimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious and fatal infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML).(1) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications increases the risk of adverse effects. PATIENT MANAGEMENT: The etrasimod US prescribing information states etrasimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Concomitant administration of these therapies with etrasimod should be avoided because of the risk of additive immune effects during therapy and in the weeks following administration. Etrasimod's effect on peripheral lymphocytes may persist for up to 5 weeks after discontinuation.(1) When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects.(1) DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with other sphingosine-1 phosphate receptor modulators.(1) |
VELSIPITY |
| Ropeginterferon alfa-2b/Slt Immunosuppress; Immunomodulator SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ropeginterferon alfa-2b and immunosuppressives both suppress the immune system. CLINICAL EFFECTS: Concurrent use of ropeginterferon alfa-2b with immunosuppressives may result in an increased risk of serious infections. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concurrent use of myelosuppressive agents.(1-2) If concurrent use cannot be avoided, monitor for effects of excessive immunosuppression. DISCUSSION: In clinical trials, 20% of patients experienced leukopenia. Interferon alfa products may cause fatal or life-threatening infections.(1-2) |
BESREMI |
There are 13 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 |
|---|---|
| Methotrexate (low strength inj, oral)/OAT3 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of organic anion transporter 3 (OAT3) may inhibit the renal elimination of methotrexate. CLINICAL EFFECTS: Concurrent use of organic anion transporter 3 (OAT3) inhibitors may result in an increase in both the therapeutic and toxic effects of methotrexate, 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: If concurrent use cannot be avoided, monitor methotrexate blood levels closely and adjust the dose accordingly. DISCUSSION: Concomitant administration of methotrexate and probenecid has been shown to increase methotrexate plasma levels two to four times higher than when methotrexate is administered alone. OAT3 inhibitors linked to this monograph include: probenecid and vadadustat.(7) |
PROBENECID, PROBENECID-COLCHICINE, VAFSEO |
| Leflunomide; Teriflunomide/Methotrexate (low strength inj, oral) SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Teriflunomide inhibits organic anion transporter 3 (OAT3). The combination may also result in additive or synergistic effects on the liver or lung tissue. CLINICAL EFFECTS: The concurrent administration of leflunomide and methotrexate may result in increased levels and toxicity from methotrexate, including hepatotoxicity, pancytopenia, agranulocytosis, or thrombocytopenia.(1) Both agents can cause interstitial lung disease (ILD).(2) Teriflunomide is the active metabolite of leflunomide and recommended doses of both agents produce similar concentrations of teriflunomide.(3) PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions This interaction should also be considered if leflunomide(1) or teriflunomide is followed by methotrexate if no drug elimination procedure is performed. PATIENT MANAGEMENT: In patients receiving concurrent methotrexate and leflunomide or teriflunomide, platelets, white blood cells, hemoglobin or hematocrit, and ALT (SGPT) should be performed at baseline and at monthly intervals. American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly. Patients should be monitored for signs and symptoms of hepatotoxicity and bone marrow suppression. If evidence of bone marrow suppression occurs, treatment with leflunomide or teriflunomide should be discontinued and cholestyramine or charcoal should be used to rapidly decrease plasma concentrations of the active metabolite of leflunomide. Pulmonary status should be evaluated in patients who have recently received methotrexate and these patients should be closely monitored during therapy. Patients should be instructed to contact their doctor if any symptoms of ILD occur. Symptoms include cough and dyspnea, with or without associated fever.(2) New or worsening pulmonary symptoms may warrant therapy discontinuation. If leflunomide or teriflunomide therapy is discontinued, consider initiating washout procedures. DISCUSSION: The combined use of leflunomide and methotrexate has not been adequately studied.(1) In clinical trials, the administration of leflunomide alone has resulted in abnormal liver enzymes in 5% of subjects. ALT (SGPT) values were greater than 3-fold of normal in 1.5-4.4% of subjects.(1) In a small trial in 30 subjects, the concurrent administration of leflunomide and methotrexate resulted in a greater than 3-fold increase in liver enzymes in five subjects and a 2- to 3-fold increase in another five subjects. Three patients met ACR criteria for liver biopsy. There was no evidence of a pharmacokinetic interaction.(1) In a 6 month study, an increase in ALT greater than or equal to 3 times the upper limit of normal was observed in 3.8% of patients (n=133) receiving concurrent leflunomide and methotrexate. In comparison, such increases were only seen in 0.8% of patients (n=130) who received methotrexate with placebo.(1) There have been rare reports of pancytopenia, agranulocytosis, and thrombocytopenia during leflunomide therapy. In most of these reports, patients were receiving concurrent therapy with methotrexate and/or another immunosuppressive agent.(1) ILD has been rarely reported with leflunomide and has been associated with fatal outcomes.(1) Many of these reports are confounded by preexisting pulmonary disease and/or previous or concomitant use of other agents that cause ILD, including methotrexate.(2) Teriflunomide is the active metabolite of leflunomide and recommended doses of both agents produce similar concentrations of teriflunomide.(3) |
ARAVA, AUBAGIO, LEFLUNICLO, LEFLUNOMIDE, TERIFLUNOMIDE |
| Hydantoins/Selected Antineoplastics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Antineoplastic agents may decrease the absorption and increase the metabolism of phenytoin. CLINICAL EFFECTS: The pharmacological effects of phenytoin may be decreased. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor serum phenytoin concentrations when starting or discontinuing cancer chemotherapy. Adjust the dose of phenytoin as needed. DISCUSSION: Decreased plasma phenytoin concentrations and loss of seizure control have been reported after starting chemotherapy in patients receiving phenytoin. In order to maintain adequate levels of phenytoin during chemotherapy, it may be necessary to increase the dose of phenytoin. |
CEREBYX, DILANTIN, DILANTIN-125, FOSPHENYTOIN SODIUM, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED |
| Digoxin, Oral/Antineoplastics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Decreased gastrointestinal digoxin absorption. CLINICAL EFFECTS: The pharmacologic effects of digoxin may be decreased. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor serum digoxin concentrations and observe the patient for a decrease in pharmacologic activity. Adjust the dose of digoxin accordingly. Substituting digitoxin or digoxin capsules for digoxin tablets may circumvent this interaction. DISCUSSION: There are a number of factors affecting the outcome of this interaction. The effects of antineoplastic therapy on the gastrointestinal absorption of digoxin have only been studied with certain chemotherapeutic agents or regimens (e.g., bleomycin, carmustine, cyclophosphamide, cytarabine, doxorubicin, methotrexate, procarbazine, vincristine). The interaction appears to occur with the administration of oral digoxin tablets as opposed to digoxin capsules. The gastrointestinal absorption of digitoxin does not seem to be altered by antineoplastic therapy. |
DIGITEK, DIGOXIN, LANOXIN |
| Methotrexate(low strength inj, oral)/Proton Pump Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Proton pump inhibitors(PPIs) may inhibit the active secretion of methotrexate from the kidney via inhibition of the hydrogen-potassium ATPase(1) and may reduce uptake of methotrexate into breast cancer resistance protein via competitive inhibition.(2,3) CLINICAL EFFECTS: The concurrent use of methotrexate and proton pump inhibitors may result in elevated levels of methotrexate and increased methotrexate-related adverse effects and toxicities, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.(1-7,9) PREDISPOSING FACTORS: High dose methotrexate therapy appears to increase the risk for and severity of this interaction.(4,9) PATIENT MANAGEMENT: Patients receiving concurrent use of methotrexate and proton pump inhibitors should be monitored closely for elevated methotrexate levels and methotrexate toxicity. The US manufacturer of omeprazole states that secretory ability returns gradually over three to five days following discontinuation.(4) This interaction has best described in patients receiving high dose methotrexate for cancer treatment. Therefore, it would seem prudent to discontinue proton pump inhibitors several days prior to high dose methotrexate therapy. The magnitude and frequency of this interaction in patients receiving less than or equal to 15 mg weekly is less clear. While a small study suggested lansoprazole was safe in rheumatoid arthritis patients taking 7.5 - 15 mg weekly(8), at least one case report of PPI associated methotrexate toxicity at a low dose (15 mg IM weekly) has been described.(7) DISCUSSION: In a clinical trial in 74 patients on high dose (1-5 G/m2) methotrexate therapy, data was examined to determine if proton pump inhibitor (omeprazole, pantoprazole, rabeprazole) use affects methotrexate elimination. Delayed elimination was found to be more frequent in those with co-administration of a proton pump inhibitor (31.7% vs. 13.8%), resulting in higher plasma methotrexate concentrations at 24, 48, and 74 hours. The effect was seen with lansoprazole, omeprazole, pantoprazole, and rabeprazole.(2) There are three case reports(1,5,6) of elevated methotrexate levels or delayed methotrexate elimination resulting from concurrent administration of high dose methotrexate and omeprazole, including one patient(6) that developed severe mucositis. In each case, omeprazole was discontinued and normal methotrexate kinetics were observed on subsequent cycles with no further adverse effects noted. In a case report of a 59 year-old male on low dose (15 mg weekly) methotrexate, administration of pantoprazole (20 mg daily) was found to increase the AUC of the metabolite 7-hydroxymethotrexate by 70%.(7) In a manufacturer sponsored clinical trial, 28 adults with rheumatoid arthritis on low dose (7.5-15 mg weekly) methotrexate were assigned to receive lansoprazole (30 mg daily) and naproxen (500 mg twice daily) on Days 1-7 of therapy. The half life of the metabolite 7-hydroxymethotrexate was prolonged with concurrent administration, but no other statistically significant differences were found in regards to the plasma concentration profiles of methotrexate or 7-hydroxymethotrexate.(8) |
ACIPHEX, ACIPHEX SPRINKLE, DEXILANT, DEXLANSOPRAZOLE DR, ESOMEPRAZOLE MAGNESIUM, ESOMEPRAZOLE SODIUM, KONVOMEP, LANSOPRAZOL-AMOXICIL-CLARITHRO, LANSOPRAZOLE, NAPROXEN-ESOMEPRAZOLE MAG, NEXIUM, OMECLAMOX-PAK, OMEPRAZOLE, OMEPRAZOLE-SODIUM BICARBONATE, PANTOPRAZOLE SODIUM, PANTOPRAZOLE SODIUM-0.9% NACL, PREVACID, PRILOSEC, PROTONIX, PROTONIX IV, RABEPRAZOLE SODIUM, TALICIA, VIMOVO, VOQUEZNA, VOQUEZNA DUAL PAK, VOQUEZNA TRIPLE PAK, YOSPRALA |
| Selected BCRP Substrates/Safinamide SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Safinamide transiently inhibits BCRP in the small intestine, which may result in increased absorption of BCRP substrates.(1) CLINICAL EFFECTS: Administration of safinamide with BCRP substrates may result in elevated levels of and toxicity from these agents.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The EMA and UK manufacturer of safinamide recommend monitoring patients who are on concomitant drugs that are substrates of BCRP, including ciprofloxacin, diclofenac, methotrexate, rosuvastatin, and topotecan. Dose adjustment of the BCRP substrate should be performed according to the prescribing information for the BCRP substrate.(1) On the other hand, the US manufacturer of safinamide states that rosuvastatin did not have a clinically significant effect on the pharmacokinetics of safinamide.(2) DISCUSSION: Safinamide transiently inhibits BCRP in the small intestine, which may result in increased absorption of BCRP substrates.(1) In a clinical study, safinamide increased the AUC of rosuvastatin by 1.25- to 2-fold.(1,3) BCRP substrates linked to this monograph include: ciprofloxacin, diclofenac, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, and topotecan.(1,3) |
XADAGO |
| Methotrexate (low strength injection, oral)/Iodinated Contrast Media SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: One possible mechanism is renal dysfunction caused by the nephrotoxicity of both agents. CLINICAL EFFECTS: Concurrent use of iodinated contrast media may result in methotrexate toxicity, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia. PREDISPOSING FACTORS: Renal impairment PATIENT MANAGEMENT: It is recommended that the use of iodinated contrast media in patients receiving high dose methotrexate therapy be avoided until the serum methotrexate level is 0.1 mcmol/L or lower. With lower dose methotrexate therapy, iodinated contrast media should be used with caution and preventative measures should be considered.(1) DISCUSSION: There are three case reports of patients receiving concurrent iodinated contrast agents and methotrexate therapy developing methotrexate toxicity. One patient received iodinated contrast media the day after receiving a methotrexate infusion while the other two patients received contrast media 30 hours and 4.5 hours after methotrexate therapy.(1,2) |
IODIXANOL, IOHEXOL, IOMERON 350, IOPAMIDOL, IOPANOIC ACID, ISOVUE-200, ISOVUE-250, ISOVUE-300, ISOVUE-370, ISOVUE-M 200, ISOVUE-M 300, LIPIODOL, OMNIPAQUE, OPTIRAY 240, OPTIRAY 300, OPTIRAY 320, OPTIRAY 350, SINOGRAFIN, ULTRAVIST, VISIPAQUE |
| Ustekinumab/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ustekinumab, immunosuppressives, and immunomodulators all suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of ustekinumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of ustekinumab recommends caution because the concurrent use of ustekinumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1) DISCUSSION: Ustekinumab has not been studied in combination with other immunosuppressants in psoriasis studies. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by ustekinumab treated patients in the clinical trial periods included nasopharyngitis(8%) and upper respiratory tract infection(5%). Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab. Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia resulting in respiratory failure or prolonged hospitalization have been reported in patients receiving ustekinumab.(1) |
OTULFI, PYZCHIVA, SELARSDI, STELARA, STEQEYMA, USTEKINUMAB, USTEKINUMAB-AEKN, USTEKINUMAB-TTWE, WEZLANA, YESINTEK |
| Methotrexate (low strength injections, oral)/Ciprofloxacin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ciprofloxacin inhibits renal tubular elimination of methotrexate.(1,2) CLINICAL EFFECTS: The concurrent use of methotrexate and ciprofloxacin may result in elevated levels of methotrexate and increased methotrexate-related adverse effects and toxicities, 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: For patients receiving high dose methotrexate, consider an alternative antibiotic or discontinuation of ciprofloxacin for the duration of therapy.(3) Manufacturers recommend patients receiving concomitant ciprofloxacin and methotrexate therapy should be closely monitored for elevated methotrexate levels and methotrexate toxicity.(1,2) DISCUSSION: A 90-year-old woman with severe plaque psoriasis vulgaris treated with methotrexate 12.5 mg weekly developed nausea, vomiting, and oral ulcerations after completing a 2-week course of ciprofloxacin 500 mg twice daily for foot ulcers. She had previously tolerated methotrexate for 4 years. Her past medical history is significant for type 2 diabetes mellitus, hypertension, hyperlipidemia, arthritis and nephrolithiasis. The serum methotrexate level was 0.05 micromol/L, under the level of toxicity, but the patient's last dose of methotrexate was 5 days prior. Methotrexate levels typically become undetectable after 18 to 24 hours.(3) |
CIPRO, CIPROFLOXACIN, CIPROFLOXACIN HCL, CIPROFLOXACIN-D5W |
| BCRP or OATP1B1 Substrates/Eltrombopag SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Eltrombopag has been shown to inhibit BCRP and OATP1B1.(1-3) Inhibition of BCRP may increase absorption and/or decrease biliary excretion of substrates, while inhibition of OATP1B1 may decrease hepatic uptake of substrates. CLINICAL EFFECTS: Simultaneous use of eltrombopag with BCRP or OATP1B1 substrates may result in increased levels and side effects from the substrates.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of eltrombopag states that concomitant BCRP or OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects, and dose reduction of the substrate should be considered.(1) DISCUSSION: In a clinical trial in 39 healthy subjects, administration of eltrombopag (75 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of rosuvastatin (10 mg, a BCRP and OATP1B1 substrate) by 55% and 103%, respectively.(1,4) In a physiologically-based pharmacokinetic (PBPK) model, eltrombopag 75 mg was predicted to increase the AUC and Cmax of pitavastatin 1 mg by approximately 2-fold.(5) BCRP substrates linked to this monograph include: ciprofloxacin, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, and topotecan.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, and simvastatin.(1) |
ALVAIZ, PROMACTA |
| COVID-19 Vaccines/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Immunosuppressants and immunomodulators may prevent the immune system from properly responding to the COVID-19 vaccine.(1,2) CLINICAL EFFECTS: Administration of a COVID-19 vaccine with immunosuppressants or immunomodulators may interfere with vaccine-induced immune response and impair the efficacy of the vaccine. However, patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: In an effort to optimize COVID-19 vaccine response, the American College of Rheumatology (ACR) published conditional recommendations for administration of COVID-19 vaccines with immunosuppressants and immunomodulators.(1) The CDC also provides clinical considerations for COVID-19 vaccination in patients on immunosuppressants.(2) The CDC states that all immunocompromised patients over 6 months of age should receive at least 1 dose of COVID-19 vaccine if eligible. See the CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines for specific recommendations based on age, vaccination history, and vaccine manufacturer.(2) The ACR states that in general, immunosuppressants and immunomodulators should be held for 1-2 weeks after each vaccine dose. See below for specific recommendations for certain agents.(1) The CDC advises planning for vaccination at least 2 weeks before starting or resuming immunosuppressive therapy.(2) Patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1,2) B-cell depleting agents, including rituximab: The ACR recommends consulting with the rheumatologist to determine optimal timing of COVID-19 vaccination. Measuring CD19 B cells may be considered to determine need for a booster vaccine dose. If B cell levels are not measured, a supplemental vaccine dose 2-4 weeks before the next scheduled dose of rituximab is recommended.(1) The CDC states that the utility of B-cell quantification to guide clinical care is not known and is not recommended. Patients who receive B-cell depleting therapy should receive COVID-19 vaccines about 4 weeks before the next scheduled dose. For patients who received 1 or more doses of COVID-19 vaccine during treatment with B-cell-depleting therapies that were administered over a limited period (e.g., as part of a treatment regimen for certain malignancies), revaccination may be considered. The suggested interval to start revaccination is about 6 months after completion of the B-cell-depleting therapy.(2) Abatacept: - Subcutaneous abatacept should be withheld for 1-2 weeks after each vaccine dose, as disease activity allows. - For intravenous abatacept, time administration so that vaccination will occur 1 week before the next abatacept infusion.(1) Cyclophosphamide: When feasible, administer cyclophosphamide one week after each COVID-19 vaccine dose.(1) Recipients of hematopoietic cell transplant or CAR-T-cell therapy who received one or more doses of COVID-19 vaccine prior to or during treatment should undergo revaccination following the current CDC recommendations for unvaccinated patients. Revaccination should start at least 3 months (12 weeks) after transplant or CAR-T-cell therapy.(2) TNF-alpha inhibitors and cytokine inhibitors: The ACR was not able to reach consensus on whether to modify dosing or timing of these agents with COVID-19 vaccination.(1) The CDC includes these agents in their general recommendation to hold therapy for at least 2 weeks following vaccination.(2) DISCUSSION: The ACR convened a COVID-19 Vaccine Guidance Task Force to provide guidance on optimal use of COVID-19 vaccines in rheumatology patients. These recommendations are based on limited clinical evidence of COVID-19 vaccines in patients without rheumatic and musculoskeletal disorders and evidence of other vaccines in this patient population.(1) The ACR recommendation for rituximab is based on studies of humoral immunity following receipt of other vaccines. These studies have uncertain generalizability to vaccination against COVID-19, as it is unknown if efficacy is attributable to induction of host T cells versus B cell (antibody-based) immunity.(1) The ACR recommendation for mycophenolate is based on preexisting data of mycophenolate on non-COVID-19 vaccine immunogenicity. Emerging data suggests that mycophenolate may impair SARS-CoV-2 vaccine response in rheumatic and musculoskeletal disease and transplant patients.(1) The ACR recommendation for methotrexate is based on data from influenza vaccines and pneumococcal vaccines with methotrexate.(1) The ACR recommendation for JAK inhibitors is based on concerns related to the effects of JAK inhibitors on interferon signaling that may result in a diminished vaccine response.(1) The ACR recommendation for subcutaneous abatacept is based on several studies suggesting a negative effect of abatacept on vaccine immunogenicity. The first vaccine dose primes naive T cells, naive T cell priming is inhibited by CTLA-4, and abatacept is a CTLA-4Ig construct. CTLA-4 should not inhibit boosts of already primed T cells at the time of the second vaccine dose.(1) |
COMIRNATY 2024-2025, MODERNA COVID 24-25(6M-11Y)EUA, NOVAVAX COVID 2024-2025 (EUA), PFIZER COVID 2024-25(5-11Y)EUA, PFIZER COVID 2024-25(6M-4Y)EUA, SPIKEVAX 2024-2025 |
| Valproate/Methotrexate SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. Methotrexate may compete with valproate for binding to albumin and displace valproate. Unbound valproate may be rapidly metabolized.(1-3) CLINICAL EFFECTS: Concurrent use of methotrexate with valproate may decrease the levels and effectiveness of valproate.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor valproate levels and clinical response when starting or stopping methotrexate therapy. Valproate dosage adjustments may be necessary.(1) DISCUSSION: A 6-year-old male with acute lymphoblastic leukemia who developed epileptic symptoms during chemotherapy was maintained on valproate 30 mg/kg/day. Upon receipt of methotrexate-containing chemotherapy (5 gram/m2), the patient developed a focal epileptic attack that became generalized. Serum valproate levels were found to have dropped from 800 mmol/L before methotrexate to 196 mmol/L after methotrexate. Before the next dose of methotrexate, valproate dosage was increased and clonazepam was added. Valproate levels again dropped from 660 mmol/L to 172 mmol/L, but no seizures developed.(2) In another case report, a 21-year-old male who was seizure-free for 5 years on valproic acid 600 mg/day for juvenile Absence Epilepsy started methotrexate 15 mg/week for psoriasis. His absence seizures relapsed and serum valproate levels was found to have dropped from 92 mcg/mL before methotrexate administration to 18 mcg/mL after methotrexate.(3) |
DEPAKOTE, DEPAKOTE ER, DEPAKOTE SPRINKLE, DIVALPROEX SODIUM, DIVALPROEX SODIUM ER, SODIUM VALPROATE, VALPROATE SODIUM, VALPROIC ACID |
| Selected BCRP Substrates/Momelotinib SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Momelotinib is an inhibitor of the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of BCRP substrates.(1) CLINICAL EFFECTS: Administration of momelotinib with BCRP substrates may result in elevated levels of and toxicity of the BCRP substrates.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of momelotinib states concurrent use with BCRP substrates should be approached with caution. If concurrent use is warranted, consider reducing the dose of the substrate drug according to the product labeling and monitor for adverse reactions.(1) DISCUSSION: Momelotinib increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin, a BCRP substrate, by 220% and 170%, respectively.(1) BCRP substrates linked to this monograph include: ciprofloxacin, glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, and topotecan.(1-2) |
OJJAARA |
The following contraindication information is available for XATMEP (methotrexate):
Drug contraindication overview.
*History of hypersensitivity to methotrexate. *Pregnancy (in patients with non-neoplastic diseases). *Lactation (powder for injection formulation only).
*Alcoholism, alcoholic liver disease, or other chronic liver disease in patients with psoriasis or rheumatoid arthritis. *Overt laboratory evidence of immunodeficiency syndromes in patients with psoriasis or rheumatoid arthritis. *Preexisting blood dyscrasias (i.e., bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia) in patients with psoriasis or rheumatoid arthritis.
*History of hypersensitivity to methotrexate. *Pregnancy (in patients with non-neoplastic diseases). *Lactation (powder for injection formulation only).
*Alcoholism, alcoholic liver disease, or other chronic liver disease in patients with psoriasis or rheumatoid arthritis. *Overt laboratory evidence of immunodeficiency syndromes in patients with psoriasis or rheumatoid arthritis. *Preexisting blood dyscrasias (i.e., bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia) in patients with psoriasis or rheumatoid arthritis.
There are 4 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Alcohol use disorder |
| Alcoholic liver damage |
| Lactation |
| Pregnancy |
There are 14 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Anemia |
| Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min |
| Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min |
| Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min |
| Chronic kidney disease stage 5 (failure) GFr<15 ml/min |
| Hepatic cirrhosis |
| Hepatic fibrosis |
| Leukopenia |
| Neutropenic disorder |
| Peptic ulcer |
| Pleural effusions |
| Severe hepatic disease |
| Thrombocytopenic disorder |
| Ulcerative colitis |
There are 5 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Ascites |
| Dehydration |
| Kidney disease with likely reduction in glomerular filtration rate (GFr) |
| Radiation therapy of cranium |
| Radiation therapy of vertebral column |
The following adverse reaction information is available for XATMEP (methotrexate):
Adverse reaction overview.
The most common adverse effects reported in patients receiving methotrexate injection, powder for injection, oral solution, and tablets include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Elevated liver function tests are also commonly reported in patients receiving Xatmep(R) oral solution. The most common adverse effects reported in patients receiving methotrexate injection for sub-Q use include nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leukopenia, pancytopenia, dizziness, photosensitivity, and "burning of skin lesions."
The most common adverse effects reported in patients receiving methotrexate injection, powder for injection, oral solution, and tablets include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Elevated liver function tests are also commonly reported in patients receiving Xatmep(R) oral solution. The most common adverse effects reported in patients receiving methotrexate injection for sub-Q use include nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leukopenia, pancytopenia, dizziness, photosensitivity, and "burning of skin lesions."
There are 69 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abnormal hepatic function tests Aphthous stomatitis Azotemia Bacterial infection Bacterial sepsis Gastrointestinal hemorrhage Gastrointestinal ulcer Leukopenia Thrombocytopenic disorder |
Anemia Drug-induced hepatitis Hepatic cirrhosis Hepatic necrosis Leukoencephalopathy Pulmonary fibrosis |
| Rare/Very Rare |
|---|
|
Acute hepatic failure Acute respiratory failure Agranulocytosis Alveolitis Anaphylaxis Aplastic anemia Arterial thrombosis Avascular necrosis of bone Cerebral thrombosis Chemical arachnoiditis Cutaneous vasculitis Cytomegalovirus disease Deep venous thrombosis Dermal necrosis Diabetes mellitus Encephalopathy Eosinophilia Erythema multiforme Exfoliative dermatitis Fracture Gastrointestinal perforation Hemiplegia Hemorrhagic enteritis Hepatic fibrosis Hypogammaglobulinemia Hypotension Increased cerebrospinal fluid pressure Interstitial pneumonitis Intestinal perforation Kidney disease with reduction in glomerular filtration rate (GFr) Neutropenic disorder Opportunistic fungal infection Optic neuropathy Pancreatitis Pancytopenia Pericardial effusion Pericarditis Pneumocystis jirovecii pneumonia Progressive multifocal leukoencephalopathy Proteinuria Pulmonary hemorrhage Pulmonary thromboembolism Renal failure Seizure disorder Sepsis Skin photosensitivity Stevens-johnson syndrome Subacute necrotizing encephalomyelopathy Thromboembolic disorder Thrombophlebitis Thrombosis of retinal vein Toxic epidermal necrolysis Transient blindness Tumor lysis syndrome |
There are 47 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Acute abdominal pain Alopecia Anorexia Bronchitis Dizziness Fatigue Gingivostomatitis Headache disorder Malaise Nausea Stinging of skin |
Chills Diarrhea Fever Furunculosis Pharyngitis Pruritus of skin Skin rash Vomiting |
| Rare/Very Rare |
|---|
|
Acne vulgaris Acute cognitive impairment Anticholinergic toxicity Aphasia Arthralgia Black tarry stools Blurred vision Conjunctivitis Cystitis Drowsy Dry eye Dysarthria Erectile dysfunction Gynecomastia Hematuria Hypoalbuminemia Infection Injection site necrosis Injection site sequelae Libido changes Lymphadenopathy Menstrual disorder Myalgia Oligospermia Stomatitis Telangiectasia Tinnitus Vasculitis |
The following precautions are available for XATMEP (methotrexate):
The safety and efficacy of methotrexate (all formulations) have been established in pediatric patients for the treatment of polyarticular juvenile idiopathic arthritis. The safety and efficacy of methotrexate injection and powder for injection have been established in pediatric patients for the treatment of acute lymphoblastic leukemia (ALL), meningeal leukemia prophylaxis and treatment, non-Hodgkin lymphoma, and osteosarcoma. Severe neurotoxic effects, manifested mainly by focal or generalized seizures, have been reported with increased frequency in pediatric patients with ALL who were receiving intermediate-dose IV methotrexate (1 g/m2).
The safety and efficacy of methotrexate injection and powder for injection have not been established in pediatric patients for the treatment of other types of cancer, including breast cancer, squamous cell carcinoma of the head and neck, and gestational trophoblastic diseases. The safety and efficacy of methotrexate oral solution and tablets have also been established in pediatric patients for the treatment of ALL, but have not been established for the treatment of other neoplastic diseases. The safety and efficacy of Rasuvo(R) and Otrexup(R) (methotrexate injection for sub-Q use) have not been established in pediatric patients for the treatment of any neoplastic diseases. The safety and efficacy of methotrexate (all formulations) have not been established in pediatric patients for the treatment of rheumatoid arthritis or psoriasis.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
The safety and efficacy of methotrexate injection and powder for injection have not been established in pediatric patients for the treatment of other types of cancer, including breast cancer, squamous cell carcinoma of the head and neck, and gestational trophoblastic diseases. The safety and efficacy of methotrexate oral solution and tablets have also been established in pediatric patients for the treatment of ALL, but have not been established for the treatment of other neoplastic diseases. The safety and efficacy of Rasuvo(R) and Otrexup(R) (methotrexate injection for sub-Q use) have not been established in pediatric patients for the treatment of any neoplastic diseases. The safety and efficacy of methotrexate (all formulations) have not been established in pediatric patients for the treatment of rheumatoid arthritis or psoriasis.
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Abortion, fetal death, and/or congenital anomalies have occurred in pregnant women receiving methotrexate, especially during the first trimester of pregnancy. Methotrexate is contraindicated in the management of all non-neoplastic disorders (i.e., psoriasis or rheumatoid arthritis (including polyarticular juvenile idiopathic arthritis)) in pregnant women. Verify pregnancy status in female patients of reproductive potential prior to initiating treatment with methotrexate.
Advise female patients of reproductive potential to use effective contraception during treatment with methotrexate and for 6 months following the final dose; advise male patients with such female partners to use effective contraception during treatment with methotrexate and for 3 months following the final dose. Women of childbearing potential should be fully informed of the potential hazard to the fetus should they become pregnant during methotrexate therapy. Benzyl alcohol is present in certain formulations of methotrexate injection and powder for injection and can cross the placenta. If methotrexate injection is administered to treat a neoplastic disease in a pregnant patient, use a preservative-free formulation when possible.
Advise female patients of reproductive potential to use effective contraception during treatment with methotrexate and for 6 months following the final dose; advise male patients with such female partners to use effective contraception during treatment with methotrexate and for 3 months following the final dose. Women of childbearing potential should be fully informed of the potential hazard to the fetus should they become pregnant during methotrexate therapy. Benzyl alcohol is present in certain formulations of methotrexate injection and powder for injection and can cross the placenta. If methotrexate injection is administered to treat a neoplastic disease in a pregnant patient, use a preservative-free formulation when possible.
Methotrexate is distributed into breast milk, with a reported breast milk to plasma concentration ratio as high as 0.08:1. The potential effects of methotrexate on the breast-fed infant or on milk production are not known.
Methotrexate powder for injection is contraindicated in nursing mothers due to the potential for serious adverse reactions in breast-fed infants exposed to methotrexate. Advise patients taking all other formulations of methotrexate not to breast-feed during treatment and for 1 week after the final dose.
Methotrexate powder for injection is contraindicated in nursing mothers due to the potential for serious adverse reactions in breast-fed infants exposed to methotrexate. Advise patients taking all other formulations of methotrexate not to breast-feed during treatment and for 1 week after the final dose.
Clinical studies of methotrexate did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently from younger patients. Post-marketing reports have suggested that the risk of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age. Due to the reduced hepatic and renal function, decreased folate stores, and possibility of concomitant diseases or drug therapies in this population, consider relatively low doses and closely monitor for early signs of renal, hepatic, and bone marrow toxicity.
The following prioritized warning is available for XATMEP (methotrexate):
WARNING: Methotrexate has rarely caused serious (sometimes fatal) side effects. This medication should be used only to treat cancer or severe diseases caused by an overactive immune system (such as psoriasis, rheumatoid arthritis). Methotrexate has caused birth defects and death in unborn babies.
Women must avoid becoming pregnant while taking this medication. Pregnant women who have psoriasis or rheumatoid arthritis must not use methotrexate. (See also Precautions section.) If you have kidney problems or excess body water (ascites, pleural effusion), you must be closely monitored and your dose may be adjusted or stopped by your doctor.
Methotrexate (usually at high dosages) has rarely caused severe (sometimes fatal) blood/bone marrow problems (decreasing your body's ability to fight infections) and stomach/intestinal disease (such as bleeding) when used at the same time as non-steroidal anti-inflammatory drugs (NSAIDs such as indomethacin, ketoprofen). NSAIDs should not be used with high-dose methotrexate. Caution is advised if you also take aspirin.
NSAIDs/aspirin may be used with low-dose methotrexate such as for the treatment of rheumatoid arthritis if directed by your doctor. If your doctor has told you to take low-dose aspirin to prevent heart attack or stroke (usually 81-162 milligrams a day), you should keep taking the aspirin unless your doctor tells you not to. Ask your doctor or pharmacist for more details on the safe use of these drugs (such as close monitoring by your doctor, keeping the same doses of NSAIDs).
In rare instances, this drug may also cause liver problems when it is used for long periods of time. If you are using methotrexate long term, a liver biopsy is usually recommended. Methotrexate use has rarely caused serious (sometimes fatal) side effects, such as lung problems, lung infections (Pneumocystis jiroveci pneumonia), skin reactions, diarrhea, and mouth sores (ulcerative stomatitis).
(See also Side Effects section.) Lumps (tumors/abnormal growths) may very rarely appear during methotrexate use. The drug must be stopped and treatment may be needed. Tell your doctor right away if new lumps/growths occur.
When used to treat tumors, methotrexate sometimes causes side effects due to the rapid destruction of cancer cells (tumor lysis syndrome). To lower your risk, drink plenty of fluids unless your doctor directs you otherwise. Also, your doctor may prescribe an additional medication.
Tell your doctor right away if you have symptoms such as irregular heartbeat, low back/side pain, signs of kidney problems (such as pink/bloody urine, change in the amount of urine, painful urination), or muscle spasms/weakness. When this medication is used with radiation treatment, it may rarely increase the risk of tissue and bone damage. Discuss the risks and benefits of your treatment with your doctor.
WARNING: Methotrexate has rarely caused serious (sometimes fatal) side effects. This medication should be used only to treat cancer or severe diseases caused by an overactive immune system (such as psoriasis, rheumatoid arthritis). Methotrexate has caused birth defects and death in unborn babies.
Women must avoid becoming pregnant while taking this medication. Pregnant women who have psoriasis or rheumatoid arthritis must not use methotrexate. (See also Precautions section.) If you have kidney problems or excess body water (ascites, pleural effusion), you must be closely monitored and your dose may be adjusted or stopped by your doctor.
Methotrexate (usually at high dosages) has rarely caused severe (sometimes fatal) blood/bone marrow problems (decreasing your body's ability to fight infections) and stomach/intestinal disease (such as bleeding) when used at the same time as non-steroidal anti-inflammatory drugs (NSAIDs such as indomethacin, ketoprofen). NSAIDs should not be used with high-dose methotrexate. Caution is advised if you also take aspirin.
NSAIDs/aspirin may be used with low-dose methotrexate such as for the treatment of rheumatoid arthritis if directed by your doctor. If your doctor has told you to take low-dose aspirin to prevent heart attack or stroke (usually 81-162 milligrams a day), you should keep taking the aspirin unless your doctor tells you not to. Ask your doctor or pharmacist for more details on the safe use of these drugs (such as close monitoring by your doctor, keeping the same doses of NSAIDs).
In rare instances, this drug may also cause liver problems when it is used for long periods of time. If you are using methotrexate long term, a liver biopsy is usually recommended. Methotrexate use has rarely caused serious (sometimes fatal) side effects, such as lung problems, lung infections (Pneumocystis jiroveci pneumonia), skin reactions, diarrhea, and mouth sores (ulcerative stomatitis).
(See also Side Effects section.) Lumps (tumors/abnormal growths) may very rarely appear during methotrexate use. The drug must be stopped and treatment may be needed. Tell your doctor right away if new lumps/growths occur.
When used to treat tumors, methotrexate sometimes causes side effects due to the rapid destruction of cancer cells (tumor lysis syndrome). To lower your risk, drink plenty of fluids unless your doctor directs you otherwise. Also, your doctor may prescribe an additional medication.
Tell your doctor right away if you have symptoms such as irregular heartbeat, low back/side pain, signs of kidney problems (such as pink/bloody urine, change in the amount of urine, painful urination), or muscle spasms/weakness. When this medication is used with radiation treatment, it may rarely increase the risk of tissue and bone damage. Discuss the risks and benefits of your treatment with your doctor.
The following icd codes are available for XATMEP (methotrexate)'s list of indications:
| Acute lymphoid leukemia | |
| C91.0 | Acute lymphoblastic leukemia [ALl] |
| C91.00 | Acute lymphoblastic leukemia not having achieved remission |
| C91.02 | Acute lymphoblastic leukemia, in relapse |
| Polyarticular 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 |
Formulary Reference Tool