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Zafirlukast

Pronunciation

Pronunciation

(za FIR loo kast)

Index Terms

  • ICI-204,219

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Accolate: 10 mg, 20 mg

Generic: 10 mg, 20 mg

Brand Names: U.S.

  • Accolate

Pharmacologic Category

  • Leukotriene-Receptor Antagonist

Pharmacology

Zafirlukast is a selectively and competitive leukotriene-receptor antagonist (LTRA) of leukotriene D4 and E4 (LTD4 and LTE4), components of slow-reacting substance of anaphylaxis (SRSA). Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma.

Absorption

Rapid

Distribution

Vdss: ~70 L

Metabolism

Extensively hepatic via CYP2C9

Excretion

Feces (~90%); Urine (~10%)

Clearance: Children 5 to 6 years: 9.2 L/hour; Children 7 to 11 years: 11.4 L/hour; Adults: 20 L/hour

Onset of Action

Asthma symptom improvement: Peak effect: 2 to 6 weeks

Time to Peak

Serum:

Children: 2 to 2.5 hours

Adults: 3 hours

Duration of Action

Asthma symptom improvement: 12 hours

Half-Life Elimination

~10 hours (range: 8 to 16 hours)

Protein Binding

>99%, primarily to albumin

Special Populations: Hepatic Function Impairment

Approximately 50% to 60% greater Cmax and AUC compared with healthy subjects.

Special Populations: Elderly

In patients older than 65 years of age, there are about 2- to 3-fold greater Cmax and AUC compared with young adults.

Use: Labeled Indications

Asthma: Prophylaxis and chronic treatment of asthma in adults and children 5 years and older.

Contraindications

Hypersensitivity to zafirlukast or any component of the formulation; hepatic impairment (including hepatic cirrhosis)

Canadian labeling: Additional contraindications (not in U.S. labeling): Patients in whom zafirlukast was discontinued due to treatment related hepatotoxicity

Dosing: Adult

Asthma: Oral: 20 mg twice daily

Chronic urticaria (off-label use): Oral: 20 mg twice daily (Bagenstose, 2004)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Asthma: Oral:

US labeling:

Children 5 to 11 years: 10 mg twice daily

Children ≥12 years: Refer to adult dosing.

Canadian labeling: Children ≥12 years: Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Use is contraindicated.

Administration

Oral: Administer at least 1 hour before or 2 hours after a meal.

Dietary Considerations

Should be taken on an empty stomach (1 hour before or 2 hours after meals).

Storage

Store tablets at controlled room temperature of 20°C to 25°C (68°F to 77°F). Protect from light and moisture; dispense in original airtight container.

Drug Interactions

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Bosentan: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

Ceritinib: May increase the serum concentration of CYP2C9 Substrates. Management: Concurrent use of ceritinib with a CYP2C9 substrate that has a narrow therapeutic index (e.g., warfarin, phenytoin) should be avoided when possible. Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

CYP2C9 Substrates: CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates. Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Erythromycin (Systemic): May decrease the serum concentration of Zafirlukast. Monitor therapy

Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Avoid combination

Lumacaftor: May decrease the serum concentration of CYP2C9 Substrates. Lumacaftor may increase the serum concentration of CYP2C9 Substrates. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2C9 Substrates. Management: Use CYP2C9 substrates at the lowest recommended dose, and monitor closely for adverse effects, during and in the 2 weeks following mifepristone treatment. Consider therapy modification

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Theophylline Derivatives: May decrease the serum concentration of Zafirlukast. Zafirlukast may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Zafirlukast may increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Adverse Reactions

Incidence reported in children ≥12 years and adults unless otherwise specified.

>10%: Central nervous system: Headache (13%; children 5-11 years: 5%)

1% to 10%:

Central nervous system: Dizziness (2%), pain (2%), fever (2%)

Gastrointestinal: Nausea (3%), diarrhea (3%), abdominal pain (2%; children 5-11 years: 3%), vomiting (2%), dyspepsia (1%)

Hepatic: ALT increased (2%)

Neuromuscular & skeletal: Back pain (2%), myalgia (2%), weakness (2%)

Miscellaneous: Infection (4%)

<1% (Limited to important or life-threatening): Agranulocytosis, angioedema, arthralgia, bleeding, bruising, depression, edema, eosinophilia (systemic), eosinophilic pneumonia, hepatic failure, hepatitis, hyperbilirubinemia, hypersensitivity reactions, insomnia, malaise, pruritus, rash, urticaria, vasculitis with clinical features of Churg-Strauss syndrome (rare)

Warnings/Precautions

Concerns related to adverse effects:

• Eosinophilia and vasculitis: In rare cases, patients may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. Healthcare providers should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between zafirlukast and these underlying conditions has not been established.

• Hepatotoxicity: Serious hepatic adverse events (including hepatitis, hyperbilirubinemia, and hepatic failure) have been reported with use; female patients may be at greater risk. Periodic testing of liver function may be considered (early detection coupled with therapy discontinuation is generally believed to improve the likelihood of recovery). Advise patients to be alert for and to immediately report symptoms (eg, anorexia, right upper quadrant abdominal pain, nausea). If hepatic dysfunction is suspected (due to clinical signs/symptoms), discontinue use immediately and measure liver function tests (particularly ALT); resolution observed in most but not all cases upon discontinuation of therapy. Do not resume or restart if hepatic function studies indicate dysfunction. Use in patients with hepatic impairment (including hepatic cirrhosis) is contraindicated.

• Infections: An increased proportion of patients >55 years of age reported infections as compared to placebo-treated patients. These infections were mostly mild or moderate in intensity and predominantly affected the respiratory tract. Infections occurred equally in both sexes, were dose-proportional to total milligrams of zafirlukast exposure, and were associated with coadministration of inhaled corticosteroids.

• Neuropsychiatric events: Postmarketing reports of behavioral changes (ie, depression, insomnia) have been noted. Instruct patients to report neuropsychiatric symptoms/events during therapy.

Concurrent drug therapy issues:

• Warfarin: Concomitant use with warfarin results in a clinically significant increase in INR; closely monitor INR with concurrent use.

Special populations:

• Elderly: Clearance is decreased in elderly patients; Cmax and AUC are increased approximately two- to threefold in adults ≥65 years compared to younger adults; however, no dosage adjustments are recommended in this age group.

Other warnings/precautions:

• Reversal of bronchospasm: Not approved for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus; therapy can be continued during acute exacerbations of asthma.

Monitoring Parameters

Monitor for improvements in air flow; monitor closely for sign/symptoms of hepatic injury; periodic monitoring of LFTs may be considered (not proved to prevent serious injury, but early detection may enhance recovery)

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies except with doses that were also maternally toxic. Based on limited data, an increased risk of teratogenic effects has not been observed with zafirlukast use in pregnancy (Bakhireva, 2007). Uncontrolled asthma is associated with adverse events on pregnancy (increased risk of perinatal mortality, pre-eclampsia, preterm birth, low birth weight infants). Zafirlukast may be considered for use in women who had a favorable response prior to becoming pregnant; however, initiating a leukotriene receptor antagonist during pregnancy is an alternative (but not preferred) treatment option for mild persistent asthma (NAEPP, 2005).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, abdominal pain, nausea, vomiting, or diarrhea. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), swelling of hands or feet, burning or numbness feeling, shortness of breath, behavioral changes, angina, or sinusitis (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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