Menstrual Pain Relief

Drug overview for MENSTRUAL PAIN RELIEF (acetaminophen/pyrilamine maleate/pamabrom):

Generic name: ACETAMINOPHEN/PYRILAMINE MALEATE/PAMABROM
Drug class: Diuretics
Therapeutic class: Analgesic, Anti-inflammatory or Antipyretic

Acetaminophen is a synthetic nonopiate derivative of p-aminophenol that produces analgesia and antipyresis.

Acetaminophen is used extensively in the treatment of mild to moderate pain and fever.

DRUG IMAGES

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The following indications for MENSTRUAL PAIN RELIEF (acetaminophen/pyrilamine maleate/pamabrom) have been approved by the FDA:

Indications:
None.

Professional Synonyms:
None.

The following dosing information is available for MENSTRUAL PAIN RELIEF (acetaminophen/pyrilamine maleate/pamabrom):

Dosing
Administration
Dosing Information
Generic

Acetaminophen is relatively safe when used at recommended dosages. However, acetaminophen overdosage has been the leading cause of acute liver failure in the US, United Kingdom, and most of Europe, with about 50% of US cases in recent years resulting from inadvertent overdosage (e.g., in patients not recognizing the presence of the drug in multiple over-the-counter (OTC) and/or prescription products that they may be taking). Therefore, patients should be warned about the importance of determining whether acetaminophen is present in their medications (e.g., by examining labels carefully, by consulting their clinician and pharmacist) and of not exceeding recommended dosages or combining acetaminophen-containing preparations.

Acetaminophen should not be used for self-medication of pain for longer than 10 days (in adults or children 12 years of age and older) or 5 days (in children 2-11 years of age), unless directed by a clinician because pain of such intensity and duration may indicate a pathologic condition requiring medical evaluation and supervised treatment.

Acetaminophen should not be used in adults or children for self-medication of marked fever (greater than 39.5degreesC), fever persisting longer than 3 days, or recurrent fever, unless directed by a clinician because such fevers may indicate serious illness requiring prompt medical evaluation.

Acetaminophen should not be used in adults or children for self-medication of sore throat pain (pharyngitis, laryngitis, tonsillitis) for longer than 2 days.

To minimize the risk of overdosage, recommended age-appropriate daily dosages of acetaminophen should not be exceeded. Because severe liver toxicity and death have occurred in children who received multiple excessive doses of acetaminophen as part of therapeutic administration, parents or caregivers should be instructed to use weight-based dosing for acetaminophen, to use only the calibrated measuring device provided with the particular acetaminophen formulation for measuring dosage, to ensure that the correct number of tablets required for the intended dose is removed from the package, and not to exceed the recommended daily dosage because serious adverse effects could result. In addition, patients should be warned that the risk of overdosage and severe liver damage is increased if more than one preparation containing acetaminophen are used concomitantly.

Pharmacists have an important role in preventing acetaminophen-induced hepatotoxicity by advising consumers about the risk of failing to recognize that a wide variety of OTC and prescription preparations contain acetaminophen. Failure to recognize acetaminophen as an ingredient may be particularly likely with prescription drugs because the label of the dispensed drug may not clearly state its presence. Educating consumers about the risk of exceeding recommended acetaminophen dosages also is important.

The US Food and Drug Administration (FDA) recommends that pharmacists receiving prescriptions for fixed-combination preparations containing more than 325 mg of acetaminophen per dosage unit contact the prescriber to discuss use of a preparation containing no more than 325 mg of the drug per dosage unit. (See Preparations.)

Clinicians should exercise caution when prescribing, preparing, and administering IV acetaminophen to avoid dosing errors that could result in accidental overdosage and death. In particular, clinicians should ensure that the dose (in mg) and the volume (in mL) are not confused, the dose for patients weighing less than 50 kg is based on body weight, the infusion pump is programmed correctly, and the total daily dosage of acetaminophen from all sources does not exceed the maximum recommended daily dosage.

In patients with hepatic impairment or active liver disease, reduction of the total daily dosage of acetaminophen may be warranted. In patients with severe renal impairment (creatinine clearance of 30 mL/minute or less), longer dosing intervals and a reduced total daily dosage of acetaminophen may be warranted. (See Cautions: Precautions and Contraindications.)

Acetaminophen is administered orally, rectally as suppositories, and by IV infusion over 15 minutes. Acetaminophen preparations for self-medication should not be used unless seals on the tamper-resistant packaging are intact.

No dosing information available.

No generic dosing information available.

The following drug interaction information is available for MENSTRUAL PAIN RELIEF (acetaminophen/pyrilamine maleate/pamabrom):

Contraindicated
Severe
Moderate

There are 0 contraindications.

There are 9 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
Solid Oral Potassium Tablets/Anticholinergics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concentrated potassium may damage the lining of the GI tract. Anticholinergics delay gastric emptying, resulting in the potassium product remaining in the gastrointestinal tract for a longer period of time.(1-16) CLINICAL EFFECTS: Use of solid oral dosage forms of potassium in patients treated with anticholinergics may result in gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16) PREDISPOSING FACTORS: Diseases or conditions which may increase risk for GI damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic gastroparesis, elderly status, or insufficient oral intake to allow dilution of potassium.(1-10,21) Other drugs which may add to risk for GI damage include: nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21) PATIENT MANAGEMENT: Regulatory agency and manufacturer recommendations regarding this interaction: - In the US, all solid oral dosage forms (including tablets and extended release capsules) of potassium are contraindicated in patients receiving anticholinergics at sufficient dosages to result in systemic effects.(2-8) Patients receiving such anticholinergic therapy should use a liquid form of potassium chloride.(2) - In Canada, solid oral potassium is contraindicated in any patient with a cause for arrest or delay in tablet/capsule passage through the gastrointestinal tract and the manufacturers recommend caution with concurrent anticholinergic medications.(1,9-10) Evaluate each patient for predisposing factors which may increase risk for GI damage. In patients with multiple risk factors for harm, consider use of liquid potassium supplements, if tolerated. For patients receiving concomitant therapy, assure any potassium dose form is taken after meals with a large glass of water or other fluid. To decrease potassium concentration in the GI tract, limit each dose to 20 meq; if more than 20 meq daily is required, give in divided doses.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Patients should be instructed to immediately report any difficulty swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In clinical trials, there was a higher incidence of gastric and duodenal lesions in patients receiving a high dose of a wax-matrix controlled-release formulation with a concurrent anticholinergic agent. Some lesions were asymptomatic and not accompanied by bleeding, as shown by a lack of positive Hemoccult tests.(1-17) Several studies suggest that the incidence of gastric and duodenal lesions may be less with the microencapsulated formulation of potassium chloride.(14-17)	KLOR-CON 10, KLOR-CON 8, KLOR-CON M10, KLOR-CON M15, KLOR-CON M20, POTASSIUM CHLORIDE, POTASSIUM CITRATE ER, UROCIT-K
Sodium Phosphate Bowel Cleanser/Diuretics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Bowel cleansing with sodium phosphate causes dehydration, decreased intravascular volume and hyperphosphatemia, which increases phosphate levels in the renal tubules. Abnormally high levels of calcium and phosphate in the renal tubules may precipitate out, resulting in renal injury.(1) CLINICAL EFFECTS: Use of sodium phosphate for bowel cleansing in patients maintained on diuretics may increase the risk of acute phosphate nephropathy, which is an acute kidney injury associated with deposits of calcium phosphate crystal in the renal tubules that may result in permanent renal function impairment. Acute phosphate nephropathy presents as acute kidney injury with minimal proteinuria and a bland urine sediment.(2) Use of oral sodium phosphate products at laxative doses has not been associated with acute kidney injury.(3) PREDISPOSING FACTORS: Patients who may be at an increased risk of acute phosphate nephropathy include those who are over age 55; are hypovolemic or have decreased intravascular volume; have baseline kidney disease, bowel obstruction, or active colitis; and who are using medications that affect renal perfusion or function (such as diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotension receptor blockers (ARBs) and possibly nonsteroidal anti-inflammatory drugs (NSAIDs).(2) PATIENT MANAGEMENT: If possible, use an alternative agent for bowel cleansing.(1) Use sodium phosphate products with caution in patients taking medications that affect kidney function or perfusion, such as diuretics. Obtain baseline and post-procedure labs (electrolytes, calcium, phosphate, BUN, creatinine, and [in smaller, frail individuals] glomerular filtration rate). Instruct patients to drink sufficient quantities of clear fluids before, during, and after bowel cleansing and to avoid other laxatives that contain sodium phosphate. Consider hospitalization and intravenous hydration during bowel cleansing to support frail patients who may be unable to drink an appropriate volume of fluid or who may be without assistance at home.(2) Use of an electrolyte solution for rehydration may decrease the risk of acute phosphate nephropathy.(4,5) DISCUSSION: Since May 2006, the FDA has received 20 reports of acute phosphate nephropathy associated with the use of Osmo Prep. Concomitant medications included ACE inhibitors or ARBs (11), diuretics (6), and NSAIDs (4).(2) In a retrospective review of colonoscopy patients, simultaneous use of ACE inhibitors or ARBs significantly increased the risk of acute kidney injury from oral sodium phosphate. Diuretic use was also a risk factor.(6) In a case series study of 21 cases of acute phosphate nephropathy in patients who had used oral sodium phosphate, 14 patients received an ACE inhibitor or ARB, 4 used a diuretic, and 3 used an NSAID.(7) Cases have also been reported with rectal products.(8)	MB CAPS, SODIUM PHOSPHATE DIBASIC, URIMAR-T, URNEVA
Solid Oral Potassium Capsules/Anticholinergics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concentrated potassium may damage the lining of the GI tract. Anticholinergics delay gastric emptying, resulting in the potassium product remaining in the gastrointestinal tract for a longer period of time.(1-16)) CLINICAL EFFECTS: Use of solid oral dosage forms of potassium in patients treated with anticholinergics may result in gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16) PREDISPOSING FACTORS: Diseases or conditions which may increase risk for GI damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic gastroparesis, elderly status, or insufficient oral intake to allow dilution of potassium.(1-10,21) Other drugs which may add to risk for GI damage include: nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21) PATIENT MANAGEMENT: Regulatory agency and manufacturer recommendations regarding this interaction: - In the US, all solid oral dosage forms (including tablets and extended release capsules) of potassium are contraindicated in patients receiving anticholinergics at sufficient dosages to result in systemic effects.(2-8) Patients receiving such anticholinergic therapy should use a liquid form of potassium chloride.(2) - In Canada, solid oral potassium is contraindicated in any patient with a cause for arrest or delay in tablet/capsule passage through the gastrointestinal tract and the manufacturers recommend caution with concurrent anticholinergic medications.(1,9-10) Evaluate each patient for predisposing factors which may increase risk for GI damage. In patients with multiple risk factors for harm, consider use of liquid potassium supplements, if tolerated. For patients receiving concomitant therapy, assure any potassium dose form is taken after meals with a large glass of water or other fluid. To decrease potassium concentration in the GI tract, limit each dose to 20 meq; if more than 20 meq daily is required, give in divided doses.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Patients should be instructed to immediately report any difficulty swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In clinical trials, there was a higher incidence of gastric and duodenal lesions in patients receiving a high dose of a wax-matrix controlled-release formulation with a concurrent anticholinergic agent. The lesions were asymptomatic and not accompanied by bleeding, as shown by a lack of positive Hemoccult tests.(1-17) Several studies suggest that the incidence of gastric and duodenal lesions may be less with the microencapsulated formulation of potassium chloride.(14-17)	POTASSIUM CHLORIDE
Radioactive Iodide/Agents that Affect Iodide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1) CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1) PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less. PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(2) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(3) DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1)	ADREVIEW, JEANATOPE, MEGATOPE, SODIUM IODIDE I-123
Clozapine/Anticholinergics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Clozapine has potent anticholinergic properties and inhibits serotonin receptors, including 5-HT3.(1-4) Both of these properties may cause inhibition of gastrointestinal (GI) smooth muscle contraction, resulting in decreased peristalsis.(3,4) These effects may be compounded by concurrent use of anticholinergic agents.(1-6) CLINICAL EFFECTS: Concurrent use of clozapine with other anticholinergic agents may increase the risk of constipation (common) and serious bowel complications (uncommon), including complete bowel obstruction, fecal impaction, paralytic ileus and intestinal ischemia or infarction.(1-6) PREDISPOSING FACTORS: The risk for serious bowel complications is higher with increasing age, higher frequency of constipation, and in patients on higher doses of clozapine or multiple anticholinergic agents.(1,5) PATIENT MANAGEMENT: Avoid the use of other anticholinergic agents with clozapine.(1-6) If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(2) Consider a prophylactic laxative in those with a history of constipation or bowel obstruction.(2) Review patient medication list for other anticholinergic agents. When possible, decrease the dosage or number of prescribed anticholinergic agents, particularly in the elderly. Counsel the patient about the importance of maintaining adequate hydration. Encourage regular exercise and eating a high-fiber diet.(2) DISCUSSION: In a prospective cohort study of 26,720 schizophrenic patients in the Danish Central Psychiatric Research Registry, the odds ratio (OR) for ileus was 1.99 with clozapine and 1.48 with anticholinergics. The OR for fatal ileus was 6.73 with clozapine and 5.88 with anticholinergics. Use of anticholinergics with 1st generation antipsychotics (FGA) increased the risk of ileus compare to FGA alone, but this analysis was not done with clozapine.(5) A retrospective cohort study of 24,970 schizophrenic patients from the Taiwanese National Health Insurance Research Database found that the hazard ratio (HR) for clozapine-induced constipation increased from 1.64 when clozapine is used alone, to 2.15 when used concomitantly with anticholinergics. However, there was no significant difference in the HR for ileus when clozapine is used with and without anticholinergics (1.95 and 2.02, respectively).(6) In the French Pharmacovigilance Database, 7 of 38 cases of antipsychotic-associated ischemic colitis or intestinal necrosis involved clozapine, and 5 of these cases involved use of concomitant anticholinergic agents. Three patients died, one of whom was on concomitant anticholinergics.(3) In a case series, 4 of 9 cases of fatal clozapine-associated GI dysfunction involved concurrent anticholinergic agents.(4)	CLOZAPINE, CLOZAPINE ODT, CLOZARIL, VERSACLOZ
Eluxadoline/Anticholinergics; Opioids SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Eluxadoline is a mixed mu-opioid and kappa-opioid agonist and delta-opioid antagonist and may alter or slow down gastrointestinal transit.(1) CLINICAL EFFECTS: Constipation related adverse events that sometimes required hospitalization have been reported, including the development of intestinal obstruction, intestinal perforation, and fecal impaction.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid use with other drugs that may cause constipation. If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(1) Instruct patients to stop eluxadoline and immediately contact their healthcare provider if they experience severe constipation. Loperamide may be used occasionally for acute management of severe diarrhea, but must be discontinued if constipation develops.(1) DISCUSSION: In phase 3 clinical trials, constipation was the most commonly reported adverse reaction (8%). Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving eluxadoline doses of 75 mg and 100 mg.(1)	VIBERZI
Alprostadil/Acetaminophen; NSAIDs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Alprostadil is a prostaglandin E1 product used to maintain patency of a patent ductus arteriosus (PDA).(1) Acetaminophen and nonsteroidal anti-inflammatory (NSAID) agents inhibit prostaglandins and may be used for PDA closure in addition to pain/fever management.(2-4) CLINICAL EFFECTS: Simultaneous administration of acetaminophen or NSAIDs may result in decreased clinical effects from alprostadil, including reduction in PDA.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concurrent administration of acetaminophen or NSAIDs in patients on alprostadil for maintaining patency of a patent ductus arteriosus (PDA).(1) DISCUSSION: NSAIDs and acetaminophen are used as management for patent ductus arteriosus (PDA) closure.(2-4) Alprostadil is used to maintain patency of a PDA.(1) In a case report, a 37-week gestational age neonate with cardiac defects required alprostadil therapy for PDA patency. After multiple doses of acetaminophen for pain, an echocardiogram showed reduction of the PDA requiring increased doses of alprostadil. Additional acetaminophen was discontinued. Follow up echocardiogram showed successful reversal of PDA reduction and alprostadil dose was reduced.(5)	ALPROSTADIL, PROSTAGLANDIN E1, PROSTIN VR PEDIATRIC
Glucagon (Diagnostic)/Anticholinergics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Glucagon and anticholinergic agents may have additive effects on inhibition of gastrointestinal motility.(1) CLINICAL EFFECTS: Concurrent use of glucagon with anticholinergic agents may increase the risk of gastrointestinal hypomotility, including constipation and bowel complications.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of glucagon as a diagnotic aid is not recommended with the use of anticholinergic agents.(1) If concurrent use is necessary, evaluate the patient's bowel function. Monitor for symptoms of constipation and gastrointestinal hypomotility. DISCUSSION: Both glucagon and anticholinergic agents may have additive effects on inhibition of gastrointestinal motility and increase the risk of gastrointestinal adverse effects.(1)	GLUCAGON HCL
Sodium Iodide I 131/Agents that Affect Iodide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1,2) CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1,2) PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less. PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1,2) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(3) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(4) DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1,2)	HICON, SODIUM IODIDE I-131

There are 6 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
Acetaminophen/Isoniazid SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Isoniazid may induce the metabolism of acetaminophen to its toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite by CYP2E1.(1) CLINICAL EFFECTS: Concurrent isoniazid and acetaminophen may result in hepatotoxicity.(1) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue. PREDISPOSING FACTORS: The interaction may be more severe in fast acetylators. PATIENT MANAGEMENT: Concurrent use of acetaminophen in patients treated with isoniazid should be approached with caution. Consider an alternative analgesic agent. If concurrent therapy is warranted, advise patients not to exceed the maximum recommended daily dose of acetaminophen and to immediately report any symptoms of hepatotoxicity. DISCUSSION: Isoniazid has been shown to induce, after initially inhibiting, the metabolism of acetaminophen to N-acetyl-p-benzoquinone imine (NAPQI), which is hepatotoxicity. Normally, NAPQI is rapidly converted to non-toxic metabolites by glutathione; however, high levels of NAPQI can overwhelm this system.(2-4) In a case report, a patient receiving isoniazid developed severe acetaminophen toxicity following a suicide attempt, despite only having ingested a maximum of 11.5 grams of acetaminophen and having a blood acetaminophen level of 15 mmol/L 13 hours later. Toxicity is usually seen with levels greater than 26 mmol/L.(5) In a retrospective review of 20 deaths in patients taking isoniazid alone or with ethambutol during a 13 year period, two deaths involved patients receiving concurrent isoniazid and acetaminophen.(6,7)	ISONIAZID
Selected Anticoagulants/Acetaminophen SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Acetaminophen may reduce levels of functional Factor VI, thereby increasing the International Normalized Ratio (INR).(1) In one trial factors II and VII levels were also reduced, thereby increasing the INR. (2) CLINICAL EFFECTS: Concurrent use of routine acetaminophen, especially at dosages greater than 2 grams/day, and coumarin anticoagulants may result in elevated anticoagulant effects. PREDISPOSING FACTORS: Routine use of acetaminophen at dosages greater than 2 grams/day may increase the risk of the interaction. PATIENT MANAGEMENT: Patients receiving routine acetaminophen at dosages greater than 2 grams/day with coumarin anticoagulants should be closely monitored for changes in anticoagulant effects. The dosage of the anticoagulant may need to be adjusted. Patients receiving coumarin anticoagulants should be counseled on the use of acetaminophen. DISCUSSION: A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 4 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and non-NSAID analgesics (OR=2.12; 95% CI 1.65-2.73). Increased bleeding risk was also seen in subgroup analyses with acetaminophen (OR=2.32; 95% CI 1.22-4.44).(3) In a study in 11 patients maintained on warfarin, use of acetaminophen (4 grams daily for 14 days) increased INR values by an average of 1.04.(4) In a study in 36 patients maintained on warfarin, the addition of acetaminophen (2 grams/day or 4 grams/day) increased INR values.(5) In a study in 20 patients maintained on warfarin, the addition of acetaminophen (4 grams/day for 14 days) increased average INR values by 1.20 (from 2.6 to 3.45).(6) In a study, 12 patients maintained on various anticoagulants (anisindione, dicoumarol, phenprocoumon, and warfarin) who received 4 weeks of acetaminophen (2.6 grams/day) were compared to 50 subjects maintained on various anticoagulants who did not receive acetaminophen. By the third week of concurrent acetaminophen, prothrombin times increased from 23 seconds to 28.4 seconds. The average warfarin-equivalent dose decreased by 5.8 mg to 4.4 mg. In another phase, 50 subjects maintained on various anticoagulants received acetaminophen (2.6 grams/day for 14 days). The mean prothrombin increase was 3.6 seconds.(7) There have been case reports of increased INRs following concurrent acetaminophen in patients maintained on warfarin(8-11) and acenocoumarol.(12) In contrast to the above reports, other studies have found no effects on acenocoumarol,(14) phenprocoumon,(13-15) or warfarin(16,17) by acetaminophen. In a study in 45 patients maintained on warfarin, the addition of acetaminophen (2 or 3 grams/day for 10 days) increased average INR by 0.7 and 0.67 with 2 grams/day and 3 grams/day, respectively. This increase was apparent by day 3, and a decrease in factor II and VII was observed.(2) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and acetaminophen resulted in a ratio of rate ratios (95% CI) of 1.28 (1.18-1.38).(18) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	DICUMAROL, JANTOVEN, WARFARIN SODIUM
Zoledronic Acid/Diuretics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of zoledronic acid and a diuretic may have adverse effects on the renal system.(1,2) CLINICAL EFFECTS: Concurrent use of zoledronic acid and a diuretic may result in renal dysfunction. Deterioration in renal function, acute renal failure requiring dialysis, and death have been reported.(1) PREDISPOSING FACTORS: The interaction may be more likely in elderly patients, patients who are taking other drugs that impact renal function, patients with pre-existing renal compromise, and patients who are dehydrated.(1) PATIENT MANAGEMENT: Patients should be adequately hydrated with 500 ml (2 glasses of water) before and after zoledronic acid administration.(1) Creatinine clearance should be monitored before and after therapy and zoledronic acid should not be administered in patients with a creatinine clearance less than 35 ml/min.(1,3) DISCUSSION: Zoledronic acid has been associated with renal dysfunction, including deterioration in renal function, acute renal failure requiring dialysis, and death. Risk factors include advanced age, concomitant nephrotoxic agents, and dehydration.(1) The FDA has received 16 reports of fatal acute renal failure and 9 reports of renal injury requiring dialysis following the administration of Reclast (zoledronic acid).(3)	RECLAST, ZOLEDRONIC ACID
Busulfan/Acetaminophen SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Busulfan is eliminated from the body via glutathione conjugation. Acetaminophen reduces glutathione levels in the blood and tissues and therefore could decrease the elimination rate of busulfan.(1,2) CLINICAL EFFECTS: Concurrent use of acetaminophen may result in elevated levels of, prolonged exposure to, and toxicity from busulfan, including myelosuppression, granulocytopenia, thrombocytopenia, anemia, seizures, hepatic veno-occlusive disease, cardiac tamponade, bronchopulmonary dysplasia, or cellular dysplasia.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Use acetaminophen concurrent with busulfan with caution.(1) Consider withholding acetaminophen for 72 hours before and during busulfan therapy. If concurrent use cannot be avoided, monitor patients for busulfan toxicity. DISCUSSION: Although a small population study in adult patients found no effect of acetaminophen on busulfan clearance,(3) caution is still warranted.(1)	BUSULFAN, BUSULFEX, MYLERAN
Zonisamide/Anticholinergics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Zonisamide can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2) CLINICAL EFFECTS: Concurrent use of zonisamide with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death. PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1) PATIENT MANAGEMENT: The UK and US manufacturers of zonisamide state that caution should be used in adults when zonisamide is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity.(1-2) Pediatric and adolescent patients must not take anticholinergic agents (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered. DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment and resulted in death.(1)	ZONEGRAN, ZONISADE, ZONISAMIDE
Topiramate/Anticholinergics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Topiramate can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2) CLINICAL EFFECTS: Concurrent use of topiramate with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death. PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1) PATIENT MANAGEMENT: The manufacturer of topiramate states that caution should be used when topiramate is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered. DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment.(1) A 64-year old woman developed non-exertional hyperthemia while taking multiple psychiatric medications with topiramate.(2)	EPRONTIA, PHENTERMINE-TOPIRAMATE ER, QSYMIA, TOPAMAX, TOPIRAMATE, TOPIRAMATE ER, TOPIRAMATE ER SPRINKLE, TROKENDI XR

The following contraindication information is available for MENSTRUAL PAIN RELIEF (acetaminophen/pyrilamine maleate/pamabrom):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

No enhanced Contraindications information available for this drug.

There are 3 contraindications. Absolute contraindication.

Contraindication List
Acetaminophen overdose
Acute hepatic failure
Acute hepatitis C

There are 9 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Angle-closure glaucoma
Benign prostatic hyperplasia
Bladder outflow obstruction
Chronic idiopathic constipation
Disease of liver
Protein-calorie malnutrition
Shock
Stenosing peptic ulcer
Urinary retention

There are 6 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Coronary artery disease
Hypertension
Hyperthyroidism
Ocular hypertension
Pyloroduodenal obstruction
Seizure disorder

The following adverse reaction information is available for MENSTRUAL PAIN RELIEF (acetaminophen/pyrilamine maleate/pamabrom):

Overview
Severe
Less Severe

Adverse reaction overview.

No enhanced Common Adverse Effects information available for this drug.

There are 15 severe adverse reactions.

More Frequent	Less Frequent
None.	Abnormal hepatic function tests

Rare/Very Rare
Acute generalized exanthematous pustulosis Acute hepatic failure Agranulocytosis Allergic dermatitis Angioedema Blood dyscrasias Drug-induced hepatitis Laryngeal edema Leukopenia Maculopapular rash Neutropenic disorder Stevens-johnson syndrome Thrombocytopenic disorder Toxic epidermal necrolysis

There are 24 less severe adverse reactions.

More Frequent	Less Frequent
Abdominal pain with cramps Drowsy Thick bronchial secretions	None.

Rare/Very Rare
Acute cognitive impairment Anorexia Anticholinergic toxicity Blurred vision Dizziness Dry nose Dry throat Dysuria Erythema Excitement Hyperhidrosis Medication overuse headache Nervousness Nightmares Skin photosensitivity Skin rash Tachycardia Tinnitus Urticaria Visual changes Xerostomia

The following precautions are available for MENSTRUAL PAIN RELIEF (acetaminophen/pyrilamine maleate/pamabrom):

Pediatric
Pregnant
Lactation
Geriatric

No enhanced Pediatric Use information available for this drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Epidemiologic data regarding oral acetaminophen use in pregnant women have shown no increased risk of major congenital malformations in infants exposed in utero to the drug. In a large population-based prospective cohort study involving more than 26,000 women with live-born singleton infants who were exposed to oral acetaminophen during the first trimester of pregnancy, no increase in the risk of congenital malformations was observed in exposed children compared with a control group of unexposed children; the rate of congenital malformations (4.3%) was similar to the rate in the general population. A population-based, case-control study from the National Birth Defects Prevention Study also found no increase in the risk of major birth defects in a group of 11,610 children who had been exposed to acetaminophen during the first trimester of pregnancy compared with a control group of 4500 children.

Animal reproduction studies in pregnant rats given oral acetaminophen during organogenesis at dosages up to 0.85 times the maximum recommended human daily dosage (4 g daily, based on body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes); the offspring showed no evidence of external, visceral, or skeletal malformations. When pregnant rats received oral acetaminophen throughout gestation at a dosage of 1.2

times the maximum recommended human daily dosage, areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses; these effects did not occur in animals given acetaminophen at dosages of 0.3 times the maximum recommended human dosage. In a continuous breeding study in which pregnant mice were given acetaminophen at dosages approximately equivalent to 0.43,

0.87, or 1.7 times the maximum recommended human daily dosage (based on body surface area comparison), a dose-related reduction in body weight of the fourth and fifth litter offspring of the treated mating pair occurred during lactation and following weaning at all dosages studied.

Animals receiving the highest dosage had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next-generation pups. Acetaminophen is commonly used during all stages of pregnancy for its analgesic and antipyretic effects. Although acetaminophen has been thought not to be associated with risk in offspring, some recent reports have questioned this assessment, especially with frequent maternal use or in cases involving genetic variability.

FDA reviewed data on a possible association between acetaminophen use during pregnancy and risk of attention deficit hyperactivity disorder (ADHD) in children and announced in January 2015 that the data were inconclusive. Some experts state that as with all drug use during pregnancy, routine use of acetaminophen should be avoided. The manufacturer states that there are no studies of IV acetaminophen in pregnant women and animal reproduction studies have not been conducted with this preparation.

Therefore, the manufacturer states that IV acetaminophen should be used during pregnancy only when clearly needed. Because there are no adequate and well-controlled studies of IV acetaminophen during labor and delivery, the manufacturer states that IV acetaminophen should be used in this setting only after careful assessment of potential benefits and risks.

Acetaminophen is distributed into human milk in small quantities after oral administration. Data from more than 15 nursing women suggest that approximately 1-2% of the maternal daily dosage would be ingested by a nursing infant. A case of maculopapular rash in a breast-fed infant has been reported; the rash resolved when the mother discontinued acetaminophen use and recurred when she resumed acetaminophen therapy.

The American Academy of Pediatrics and other experts state that acetaminophen is an acceptable choice for use in nursing women. The manufacturer states that IV acetaminophen should be used with caution in nursing women.

No enhanced Geriatric Use information available for this drug.