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Zafirlukast

Medically reviewed by Drugs.com. Last updated on May 27, 2020.

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 of age. Note: The Global Initiative for Asthma recommends zafirlukast in patients with concomitant allergic rhinitis or those who cannot take inhaled corticosteroids (GINA 2020).

Off Label Uses

Chronic urticaria

Data from controlled, double-blind trials are conflicting regarding the use of zafirlukast as monotherapy or in combination with antihistamines for the management of chronic urticaria refractory to antihistamine monotherapy [Bagenstose 2004], [Reimers 2002]. Zafirlukast in combination with antihistamines may be more effective in patients with autoimmune (positive autologous serum skin test [ASST]) chronic urticaria [Bagenstose 2004].

Based on clinical practice guidelines from the American Academy of Allergy, Asthma and Immunology (AAAAI); the American College of Allergy, Asthma, and Immunology (ACAAI); the Joint Council of Allergy, Asthma and Immunology (JCAAI); and the World Allergy Organization for the diagnosis and management of acute and chronic urticaria, a leukotriene receptor antagonist may be added to antihistamine therapy in patients who do not respond to antihistamines [AAAAI [Bernstein 2014]], [WAO [Sánchez-Borges 2012]].

Contraindications

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

Canadian labeling: Additional contraindications (not in US 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; chronic: Oral:

Children 5 to 11 years: 10 mg twice daily

Children ≥12 years and Adolescents: 20 mg twice daily

Administration

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

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

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

Fosphenytoin-Phenytoin: CYP2C9 Inhibitors (Weak) may increase the serum concentration of Fosphenytoin-Phenytoin. 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

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

TOLBUTamide: CYP2C9 Inhibitors (Weak) may increase the serum concentration of TOLBUTamide. Monitor therapy

Vitamin K Antagonists (eg, warfarin): CYP2C9 Inhibitors (Weak) may increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Adverse Reactions

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

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

1% to 10%:

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

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

Hepatic: Increased serum ALT (2%)

Infection: Infection (4%)

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

Miscellaneous: Fever (2%)

<1%, postmarketing, and/or case reports: Agranulocytosis, angioedema, arthralgia, bruise, depression, edema, eosinophilia (systemic), eosinophilic pneumonitis, hemorrhage, hepatic failure, hepatitis, hyperbilirubinemia, hypersensitivity reaction, insomnia, malaise, pruritus, skin rash, urticaria, vasculitis (with clinical features of eosinophilic granulomatosis with polyangiitis [formerly known as Churg-Strauss]; 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 eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss), 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

Information related to the use of zafirlukast in pregnancy is limited (Bakhireva 2007).

Uncontrolled asthma is associated with adverse events in pregnancy (increased risk of perinatal mortality, preeclampsia, preterm birth, low birth weight infants, cesarean delivery, and the development of gestational diabetes). Poorly controlled asthma or asthma exacerbations may have a greater fetal/maternal risk than what is associated with appropriately used asthma medications. Maternal treatment improves pregnancy outcomes by reducing the risk of some adverse events (eg, preterm birth, gestational diabetes) (ERS/TSANZ [Middleton 2020]; GINA 2020).

Agents other than zafirlukast are preferred for the treatment of asthma in pregnancy (ERS/TSANZ [Middleton 2020]; GINA 2020).

Data collection to monitor pregnancy and infant outcomes associated with asthma and the medications used to treat asthma in pregnancy is ongoing. Health care providers are encouraged to enroll exposed pregnant females in the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (1-877-311-8972 or https://mothertobaby.org). Patients may also enroll themselves.

Patient Education

What is this drug used for?

• It is used to treat or prevent asthma.

• Do not use this drug to treat an asthma attack. Use a rescue inhaler. Talk with your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache

• Abdominal pain

• Nausea

• Diarrhea

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes

• Trouble sleeping

• Flu-like symptoms

• Chills

• Sore throat

• Burning or numbness feeling

• Shortness of breath

• Excessive weight gain

• Swelling of arms or legs

• Abnormal heartbeat

• Mood changes

• Depression

• Behavioral changes

• Chest pain

• Sinusitis

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.