Zafirlukast (zafirlukast)

For the prevention and long-term symptomatic control of asthma, the usual dosage of zafirlukast for adults and children 12 years of age or older is 20 mg twice daily.

For the prevention and long-term symptomatic control of asthma, the usual dosage of zafirlukast for children 5-11 years of age is 10 mg twice daily.

Patients should be advised that zafirlukast must be taken at regular intervals to be therapeutically effective. In addition, patients should be advised that the drug will not provide immediate symptomatic relief and should not be used for the relief of acute bronchospasm; however, zafirlukast therapy generally should be continued during acute exacerbations of asthma. Patients should not discontinue or reduce the dosage of other antiasthmatic agents, even if they feel better as a result of initiation of zafirlukast therapy, unless instructed to do so by their clinician.

Although clearance of zafirlukast is reduced in geriatric patients 65 years of age or older (See Pharmacokinetics: Elimination), the overall incidence of adverse effects or study withdrawal because of adverse effects in clinical trials was comparable in geriatric or younger patients receiving zafirlukast 20 mg twice daily, and the manufacturer makes no specific recommendations regarding alteration of zafirlukast dosage solely on the basis of age.

Limited evidence in patients with stable alcoholic cirrhosis indicates that the peak plasma concentration and area under the plasma concentration-time curve (AUC) of zafirlukast are 50-60% higher in these patients relative to these pharmacokinetic values in patients with normal hepatic function. While the manufacturer currently makes no specific recommendations for adjustment of zafirlukast dosage in patients with hepatic impairment, the possibility that dosage reduction may be necessary should be considered. Zafirlukast has not been evaluated systematically in patients with hepatitis or in long-term studies in patients with cirrhosis.

Limited data suggest that renal impairment does not affect the pharmacokinetics of zafirlukast, and the manufacturer currently states that dosage adjustment in patients with renal impairment (e.g., creatinine clearance 10-30 mL/minute) is not necessary.

Zafirlukast is administered orally, usually in 2 equally divided doses daily. Because food generally decreases oral bioavailability of the drug, the manufacturer recommends that zafirlukast be taken on an empty stomach (i.e., at least 1 hour before or 2 hours after meals).

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Selected Cyp2c9 Inhibitors/Selected Nsaids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The major metabolic pathway for many non-steroidal anti-inflammatory agents (NSAIDs) is CYP2C9. Inhibitors of CYP2C9 include: amiodarone, asciminib, diosmin, fluconazole, ketoconazole, miconazole, nitisinone, oxandrolone, piperine, voriconazole, and zafirlukast.(1,2)

CLINICAL EFFECTS: Concurrent use of NSAIDs with inhibitors of CYP2C9 may result in increased levels of and adverse effects from NSAIDs, including increased risk for bleeding. NSAIDs linked to this monograph are celecoxib, diclofenac, flurbiprofen, ibuprofen, meloxicam, naproxen, parecoxib, piroxicam and valdecoxib.

PREDISPOSING FACTORS: Higher doses of either agent would be expected to increase the risk for serious adverse effects such as gastrointestinal bleeding (GIB) or renal failure. Patients who smoke, are elderly, debilitated, dehydrated, have renal impairment, or who have a history of GIB due to NSAIDs are also at increased risk for serious adverse events.(3-7) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients on routine NSAID therapy when an inhibitor of CYP2C9 is started should be evaluated for patient-specific risk factors for NSAID toxicity. Based upon this risk assessment, consider dose reduction of the NSAID or close monitoring for adverse effects. For a patient already receiving a CYP2C9 inhibitor when an NSAID is started, consider initiating the NSAID at a lower than usual dose, particularly when predisposing risk factors for harm are present. The manufacturer of celecoxib recommends that celecoxib be introduced at the lowest recommended dose in patients receiving fluconazole therapy.(3) The manufacturer of fluconazole states that half the dose of celecoxib may be necessary when fluconazole is added.(4) It would be prudent to follow this recommendation with other CYP2C9 inhibitors and to decrease the dose of celecoxib in patients in whom CYP2C9 inhibitors are added to celecoxib therapy. The manufacturer of diclofenac-misoprostol states that the total daily dose of diclofenac should not exceed the lowest recommended dose of 50 mg twice daily in patients taking CYP2C9 inhibitors.(5) It would be prudent to use the lowest recommended dose of other diclofenac formulations in patients taking CYP2C9 inhibitors. The manufacturer of parecoxib states that the dose of parecoxib should be reduced in those patients who are receiving fluconazole therapy.(6) It would be prudent to follow this recommendation with other CYP2C9 inhibitors. The manufacturer of nitisinone recommends reducing the dosage of a CYP2C9 substrate by one-half.(7) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: The concomitant administration of celecoxib and fluconazole (200 mg daily) resulted in a 2-fold increase in celecoxib plasma concentration.(3) In vitro studies in human hepatocytes found that amiodarone inhibited diclofenac metabolism.(8) In two separate studies, single doses of diclofenac (50 mg) or ibuprofen (400 mg) were coadministered with the last dose of voriconazole (400 mg q12h on Day 1, followed by 200 mg q12h on Day 2). Voriconazole increased the mean AUC of diclofenac by 78% and increased the AUC of the active isomer of ibuprofen by 100%.(9-11) Coadministration of diosmin increased diclofenac levels by 63%.(2) Coadministration of flurbiprofen or ibuprofen with fluconazole increased the AUC of flurbiprofen by 81% and of the active ibuprofen by 82% compared with either agent alone.(4) Concurrent voriconazole increased meloxicam AUC by 47%.(12,13) The concurrent administration of fluconazole and parecoxib resulted in increases in the area-under-curve (AUC) and maximum concentration (Cmax) of valdecoxib (the active metabolite of parecoxib) by 62% and 19%, respectively.(6) In a study, single dose diclofenac (50mg) given concurrently with the last dose of voriconazole (400 mg every 12 hours on Day 1, 200 mg every 12 hours on Day 2) increased Cmax and AUC by 2.1-fold and 1.8-fold, respectively. (5) Inhibitors of CYP2C9 include: amiodarone, asciminib, camizestrant, diosmin, fluconazole, ketoconazole, miconazole, nitisinone, oxandrolone, piperine, voriconazole, and zafirlukast.(1,2)

Zafirlukast/Selected Anticoagulants (Vit K Antagonists)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Zafirlukast may inhibit the CYP2C9 mediated metabolism of warfarin.(1,2)

CLINICAL EFFECTS: Concurrent use of select anticoagulants and zafirlukast may increase the risk for bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with warfarin and zafirlukast should have their prothrombin or INR values monitored closely and their warfarin dosage adjusted accordingly.(1) The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a study reported in the manufacturer's prescribing information, the administration of a single dose of warfarin (25 mg) during concurrent administration of steady-state zafirlukast resulted in significant increases in the area-under-curve (AUC) and half-life (63% and 36%, respectively) of warfarin. Prothrombin times increased 35% during concurrent administration.(1) In contrast, concurrent administration of the recommended dose of montelukast with warfarin did not result in clinically significant effects on warfarin. (4)

There is no enhanced messaging for this drug.

• Disease of liver
• Hepatic cirrhosis

There are no severe contraindications for this drug.

• Anxiety disorder
• Depression
• Dream disorder
• Hallucinations
• Insomnia
• Mood changes
• Nervousness
• Suicidal ideation
• Tremor

There is no enhanced messaging for this drug.

Rare or Very Rare

• Abnormal hepatic function tests
• Acute hepatic failure
• Agranulocytosis
• Angioedema
• Bruising
• Drug-induced hepatitis
• Eosinophilic pneumonia
• Hemorrhage
• Hepatitis
• Hyperbilirubinemia
• Hypersensitivity angiitis
• Suicidal
• Suicidal ideation
• Urticaria

Less Frequent

• Headache disorder
• Nausea

Rare or Very Rare

• Abdominal pain with cramps
• Aggressive behavior
• Agitation
• Arthralgia
• Depression
• Diarrhea
• Dream disorder
• Dyspepsia
• Edema
• Eosinophilia
• Fever
• Hallucinations
• Insomnia
• Irritability
• Malaise
• Myalgia
• Nervousness
• Pruritus of skin
• Symptoms of anxiety
• Tremor
• Vomiting

No enhanced messaging available.

No enhanced messaging available.

There are no adequate and well-controlled studies of zafirlukast in pregnant women. No evidence of teratogenicity was seen in reproductive studies in mice using oral dosages up to 1600 mg/kg daily (about 160 times the maximum recommended adult daily dosage on a mg/m2 basis), in rats using oral dosages up to 2000 mg/kg daily (about 410 times the maximum recommended adult daily dosage on a mg/m2 basis), and in cynomolgus monkeys using oral dosages up to 2000 mg/kg daily (about 20 times the maximum recommended adult daily dose based on AUC). In rats, administration of oral zafirlukast dosages of 2000 mg/kg daily resulted in maternal toxicity and deaths and an increased incidence of early fetal resorption. In cynomolgus monkeys, zafirlukast dosages of 2000 mg/kg daily resulted in maternal toxicity and spontaneous abortions.

The manufacturer states that zafirlukast should be used during pregnancy only when clearly needed. The American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma, and Immunology (ACAAI) state that while leukotriene modifiers generally would not be used during pregnancy, use of zafirlukast or montelukast could be considered in patients with recalcitrant asthma who have shown a uniquely favorable response to the drugs prior to pregnancy.

Zafirlukast is distributed into milk. Following multiple-dose administration of zafirlukast 40 mg every 12 hours in healthy women, concurrent steady-state drug concentrations in breast milk or plasma averaged 50 or 255 ng/mL, respectively. Because of the potential for tumorigenicity associated with administration of zafirlukast in rodent studies and enhanced sensitivity of neonatal rats and dogs to adverse effects of the drug, zafirlukast should not be administered to women who are breast feeding.

No enhanced messaging available.