Zafirlukast

• Accolate is an FDA approved prescription drug used for the medical treatment of chronic asthma.
• It also is effective in preventing exercise-induced asthma and in relieving the symptoms of allergic rhinitis.
• For the treatment of asthma, it starts working only after 3 to 14 days of therapy. Therefore, it should not be used for the treatment an acute asthma attack because immediate relief is needed.

Zafirlukast comes as a tablet to take by mouth. It is usually taken two times a day, 1 hour before or 2 hours after meals. Try to take zafirlukast at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take zafirlukast exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Do not use zafirlukast to treat a sudden attack of asthma symptoms. Your doctor will prescribe a short-acting inhaler to use during attacks. Talk to your doctor about how to treat symptoms of a sudden asthma attack.

Continue to take or use all other medications that your doctor has prescribed to treat your asthma. Do not stop taking any of your medications or change the doses of any of your medications unless your doctor tells you that you should.

Zafirlukast may help control asthma symptoms, but it does not cure asthma. Continue to take zafirlukast even if you feel well. Do not stop taking zafirlukast without talking to your doctor.

Zafirlukast is a synthetic, selective peptide leukotriene receptor antagonist (LTRA), with the chemical name 4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-3-ylmethyl)-3-methoxy-N-otolylsulfonylbenzamide. The molecular weight of zafirlukast is 575.7 and the structural formula is:

The empirical formula is: C31H33N3O6S

Zafirlukast, a fine white to pale yellow amorphous powder, is practically insoluble in water. It is slightly soluble in methanol and freely soluble in tetrahydrofuran, dimethylsulfoxide, and acetone.

ACCOLATE is supplied as 10 and 20 mg tablets for oral administration.

Film-coated tablets containing croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, povidone, hypromellose, and titanium dioxide.

Zafirlukast is a prescription medication used to prevent asthma attacks in adults and children 5 years of age and older with chronic asthma.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Zafirlukast may be found in some form under the following brand names:

• Accolate

Zafirlukast is a leukotriene (loo-koe-TRY-een) inhibitor. Leukotrienes are chemicals your body releases when you breathe in an allergen (such as pollen). These chemicals cause swelling in your lungs and tightening of the muscles around your airways, which can result in asthma symptoms.

Zafirlukast is used for chronic treatment of asthma, and to prevent asthma attacks in adults and children as young as 5 years old.

Do not give this medicine to a child younger than 5 years without a doctor's advice.

Zafirlukast may also be used for purposes not listed in this medication guide.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Zafirlukast will not work fast enough to treat an asthma attack. Use only a fast acting inhalation medicine for an asthma attack. Tell your doctor if it seems like your asthma medications don't work as well.

Take zafirlukast on an empty stomach, at least 1 hour before or 2 hours after a meal.

Your dose needs may change if you have surgery, are ill, are under stress, or have recently had an asthma attack. Do not change your medication dose or schedule without your doctor's advice.

Keep using this medicine as directed, even if you have no asthma symptoms.

Asthma is sometimes treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Every person with asthma should remain under the care of a doctor.

If you also use a steroid medication, do not stop using it suddenly or you may have unpleasant withdrawal symptoms. Talk with your doctor about tapering your steroid dose before stopping completely.

Store at room temperature away from moisture, heat, and light. Keep the bottle tightly closed when not in use.

Contraindications

Known hypersensitivity to zafirlukast or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Hepatic dysfunction, including increases in liver enzyme concentrations, hepatitis, and/or hyperbilirubinemia, reported.1 52 Zafirlukast-induced hepatotoxicity usually is reversible following discontinuance of the drug.1 52

Serious and potentially fatal hepatotoxicity, including fulminant hepatitis and liver failure, reported rarely.1 52

Monitor closely for signs and symptoms of hepatic impairment; consider performing liver function tests (e.g., serum AST and ALT) periodically.1 Advise patients to immediately contact their clinician if they notice signs and symptoms of liver dysfunction.1

Discontinue therapy if signs and/or symptoms suggestive of liver dysfunction occur; immediately perform liver function tests (i.e., serum ALT) and manage patient accordingly.52

Do not reinitiate therapy if results of liver function tests are consistent with hepatic dysfunction or if zafirlukast was discontinued because of hepatic dysfunction when no other attributable cause could be identified.1

Do not use for relief of acute bronchospasm (including status asthmaticus); zafirlukast can be continued during acute exacerbations of asthma, but it will not provide immediate symptomatic relief.1 45 52 Patients who experience exacerbations of asthma should continue their usual regimen of inhaled β2–adrenergic agonists for prophylaxis and have a short-acting orally inhaled β2-adrenergic agonist available for rescue.1 11 45 52

Concomitant use with warfarin results in a clinically important increase in PT.1 45 (See Specific Drugs under Interactions.)

Sensitivity Reactions

Systemic eosinophilia, eosinophilic pneumonia, or clinical features of vasculitis consistent with Churg-Strauss syndrome reported rarely in patients receiving leukotriene modifiers; these events usually associated with reduction (tapered dosage) or withdrawal of oral or high-dose inhaled corticosteroid therapy.1 57 58 59 60 61 62 63 64

Be alert to the development of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy; causal relationship not established.1 57 58 59 60 61 62 63 64

General Precautions

Do not abruptly substitute zafirlukast for oral or inhaled corticosteroids. Orally inhaled corticosteroid requirements may be reduced during zafirlukast therapy; undertake only gradual (e.g., at 2-week intervals) reduction of corticosteroid dosage.1 45 52 53

Neuropsychiatric events reported with zafirlukast during postmarketing experience.75 80 81 Data from placebo-controlled trials with leukotriene modifiers indicate that suicidal ideation occurred in 0.01% of 9929 patients treated with montelukast and in none of those receiving other leukotriene modifiers; no completed suicide occurred during therapy with any leukotriene modifier.80 FDA concluded that some neuropsychiatric events reported with zafirlukast (e.g., depression, insomnia) appear consistent with a drug-induced effect.1 81

Be alert to the potential for neuropsychiatric events in patients receiving the drug.1 81 Instruct patients to contact their clinician if behavior or mood changes occur.1 81 Carefully evaluate the risks and benefits of continuing zafirlukast therapy in patients who develop neuropsychiatric symptoms.1 81

Specific Populations

Category B.1

ACOG generally recommends use of leukotriene receptor antagonists (i.e., zafirlukast, montelukast) as alternatives to a long-acting β2-agonist in pregnant women with moderate persistent asthma who are inadequately controlled with low to medium dosages of an inhaled corticosteroid.66 (See Asthma under Uses.)

Distributed into milk.1 45 52 Discontinue nursing or the drug.1 45

Safety demonstrated in children 5–11 years of age; efficacy extrapolated from demonstrated efficacy in adults with asthma and the likelihood that the disease course, pathophysiology, and drug’s effect are similar between the two populations.1

Safety and efficacy not established in children <5 years of age.1

Increased systemic exposure and AUC, reflecting decreased clearance in children relative to adults.1

Effect on growth in pediatric patients not evaluated in clinical studies to date.1

Possible increased incidence of infection (e.g., pharyngitis, rhinitis) compared with younger adults.1 12 16 22 23 45

Decreased clearance; dosage reduction may be necessary.1 45 53 (See Special Populations under Absorption and under Elimination in Pharmacokinetics.)

Common Adverse Effects

Headache, infection, nausea, diarrhea.1 45

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Cough or hoarseness
• fever or chills
• lower back or side pain
• pain
• painful or difficult urination

• Abdominal or stomach pain
• clay-colored stools
• dark urine
• diarrhea
• dizziness
• headache
• itching
• loss of appetite
• nausea
• rash
• unpleasant breath odor
• unusual tiredness or weakness
• vomiting of blood
• yellow eyes or skin

• Attack, assault, or force
• attempts at killing oneself
• discouragement
• dry mouth
• fear or nervousness
• feeling sad or empty
• fever with or without chills
• general feeling of tiredness or weakness
• hyperventilation
• irregular heartbeats
• irritability
• lack of appetite
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of interest or pleasure
• restlessness
• seeing, hearing, or feeling things that are not there
• shakiness in the legs, arms, hands, or feet
• shortness of breath
• sleeplessness
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• tiredness
• trembling or shaking of the hands or feet
• trouble with concentrating
• trouble with sleeping
• unable to sleep
• unusual bleeding or bruising

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• back pain
• belching
• difficulty with moving
• heartburn
• indigestion
• joint pain
• lack or loss of strength
• muscle aching or cramping
• muscle pains or stiffness
• stomach discomfort or upset
• swollen joints
• vomiting

• Hives or welts
• redness of the skin

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• It is used to treat or prevent asthma.
• Do not use zafirlukast to treat an asthma attack. Use a rescue inhaler. Talk with your doctor.

• Store in the original container at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

(za FIR loo kast)

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

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

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

Less than 5 years: The safety and effectiveness has not been established.

5 to 11 years:
-10 mg orally twice a day, 1 hour before or 2 hours after meals

12 years or older:
-20 mg orally twice a day, 1 hour before or 2 hours after meals

Use: Prophylaxis and chronic treatment of asthma

No adjustment recommended.