Zafirlukast

Zafirlukast belongs to the pharmacological class leukotriene receptor antagonist. Zafirlukast binds to the leukotrienes LTD4 and LTE4 as it has a greater affinity to this receptor.

Zafirlukast has been approved for relieving symptoms and also for the treatment and maintenance of episodes of asthma and urticaria.

Zafirlukast is completely and rapidly absorbed after oral absorption. Zafirlukast achieved a mean volume of distribution of 90L. The Zafirlukast is found to be metabolized by Hepatic metabolism. The hydroxylated metabolites are found to be excreted through fecal route.

The common side effects associated with Zafirlukast are hives, difficulty in breathing, loss of appetite, headache, fever, diarrhea, stomach ache, nausea, dry throat, etc.

Zafirlukast is available in the form of tablets, and Zafirlukast is available in the U.S., Canada, E.U., and India.

Zafirlukast belongs to the pharmacological class leukotriene receptor antagonist. Zafirlukast binds to the leukotrienes LTD4 and LTE4 as it has a greater affinity to this receptor.

Hence Zafirlukast inhibits the physiologic action of the LTD₄ and LTE4 in the CysLT₁ receptor without rendering any agonistic activity. This, in turn, reduces inflammations and relieves the symptoms associated with conditions such as urticaria and asthma.

Zafirlukast has an onset of action within 3hrs, and the duration of action lasts about 8-16 hrs.

The mean of Zafirlukast Cmax was found to be 0.30 ng/mL and Tmax to be 3hrs.

Zafirlukast is available in tablets and should be swallowed whole with water.

Zafirlukast can be used in the treatment of:

• Asthma
• Urticaria

Zafirlukast can help to relieve symptoms and also for the treatment and maintenance of episodes of asthma, and urticaria.

Zafirlukast is approved for use in the following clinical indications:

• Asthma
• Urticaria

Zafirlukast can be administered orally one to two hours before meals. The dosage and duration of treatment should be as per the clinical judgment of the treating physician.

In Adults

Asthma: 20mg two times a day

Urticaria: 20mg two times a day

In Children

Asthma

Aged 5-11 years: 10mg two times a day

Aged more than 12 years: 20mg twice a day

Tablet

• Dosage Adjustments in Hepatic Impairment Patients:

The use of Zafirlukast is said to be contraindicated in patients with Hepatic Impairment as there will be impairment of hepatic clearance and this might lead to 50-60% increase in maximum plasma concentration.

• Dosage Adjustments in Pediatric Patients:

In asthmatic condition:

Children aged 5-11 years: 10mg two times a day

For children aged more than 12 years: 20mg twice a day

Smoking cessation and maintaining health are a must.

Caffeine should be avoided or limited to use as it might lead to the risk of nausea, palpitations, nervousness, rapid heartbeat, etc.

Alcohol should be avoided in the patient, especially with an underlying liver disorder or liver dysfunction.

Diet containing food with a high glycemic index, saturated and trans fat food, red and processed meat, added sugar, salt, preservatives, refined and high energy-dense foods, low fiber, low antioxidants, and vitamins needs to be restricted.

The dietary restrictions are needed to be individualized as per the patient's requirements.

Zafirlukast may be contraindicated during the co-administration with the following :

• Hypersensitivity to the ingredients of the medication
• Patients with Hepatic impairment.

The treating physician should closely monitor the patients and keep pharmacovigilance as follows:

Neuropsychiatric Events

Neuropsychiatric events have been reported in adults, adolescents, and pediatric patients who use Zafirlukast. Post-marketing reports with Zafirlukast use include irritability, restlessness, somnambulism, suicidal thinking, disorientation, dream abnormalities, hallucinations, insomnia and behavior (including suicide), agitation, aggressive behavior or hostility, anxiousness, depression, and tremor. The clinical details of some post-marketing reports which involving Zafirlukast appears to be consistent with the drug-induced effect. Patients and physicians should be alert for neuropsychiatric events. Patients should be advised to tell their physicians if these changes occur. Prescribers must carefully evaluate the benefits and risks associated with continuing treatment with Zafirlukast if such events occur.

Eosinophilic Conditions

Patients suffering from asthma on therapy with Zafirlukast might present with systemic eosinophilia, which sometimes presents with clinical features of vasculitis consistent with a condition called Churg-Strauss syndrome. This is a condition which is often treated with a systemic corticosteroid therapy. These events have been usually associated with the reduction of oral corticosteroid therapy. Physicians should be alert to cardiac complications, eosinophilia, vasculitic rash, worsening pulmonary symptoms, and/or neuropathy presenting in their patients.

Hepatotoxicity

Life-threatening cases of hepatic failure had been reported in patients treated with Zafirlukast. Liver injury cases without other attributable causes have been reported from the post-marketing adverse event surveillance of patients who had received the recommended dose of Zafirlukast i.e.40 mg/day. In most of the post-marketing reports, the patient's symptoms abated, and also the liver enzymes had returned to normal or near normal after withdrawing from Zafurlukast administration. In some rare cases, patients had either presented with fulminant hepatitis or progressed to conditions like hepatic failure, liver transplantation, and even death conditions. In cases of extremely rare post-marketing cases, no clinical symptoms or signs suggestive of condition such as liver dysfunction had been reported to precede the latter observations.

Bronchospasm

Zafirlukast is not found to be indicated for use in the reversal of bronchospasm in the cases of acute asthma attacks, including status asthmaticus. Therapy with Zafirlukast can be considered to be continued during acute exacerbations of asthma.

Avoid alcohol usage while on Zafirlukast medication as alcohol can worsen the effects of any underlying disease condition, including conditions such as dizziness, blurred vision etc.

Zafirlukast is found to be excreted in breast milk. Following a repeated 40 mg two times a day dosing in healthy women, average steady-state concentrations of Zafirlukast in breast milk was found to be 50 ng/mL as compared to 255 ng/mL found in the plasma. As there potential for tumorigenicity shown for Zafirlukast in animal studies and the enhanced sensitivity of neonatal rats and dogs to the adverse effects related to Zafirlukast, hence it is advised that Zafirlukast should not be administered to patients who are in the breast-feeding stage, as it might effect the newborn.

Pregnancy Category B:

No teratogenicity was found to be observed at oral doses which was up to 1600 mg/kg/day of Zafirlukast in mice i.e.approximately 160 times the maximum recommended daily oral dose of Zafirlukast in adults, up to about 2000 mg/kg/day of Zafirlukast in rats i.e. approximately 410 times the maximum recommended daily oral dose of Zafirlukast in adults and also up to 2000 mg/kg/day of Zafirlukast in cynomolgus monkeys which resulted in about 20 times the exposure to drug plus metabolites compared to that from the maximum recommended daily oral dose of Zafirlukast in adults based on comparison of the AUC values. At oral dose of about 2000 mg/kg/day of Zafirlukast in rats, maternal toxicity and deaths were observed with increased incidence of early fetal resorption. Spontaneous abortions had been reported to have been occurred in cynomolgus monkeys at the maternally toxic oral dose of 2000 mg/kg/day of Zafirlukast. There were found to be no adequate and well-controlled clinical trials in pregnant women. Because the animal reproductive studies are not always predictive of human response therefore Zafirlukast should be used during pregnancy only when the potential benefits outweighs the potential risks associated.

No sufficient scientific evidence is traceable regarding the use and safety of Zafirlukast in concurrent use with any particular food. Zafirlukast can be taken without regard to food or meals. It is recommended to use Zafirlukast one or two hours before meals as the presence of food might delay absorption.

The adverse reactions related to Zafirlukast can be categorized as:

Less common

• Lower back or side pain
• Pain
• Painful or difficult urination
• Cough or hoarseness
• Fever or chills

Rare

• Loss of appetite
• Nausea
• Rash
• Unpleasant breath odor
• Unusual tiredness or weakness
• Vomiting of blood
• Yellow eyes or skin
• Abdominal or stomach pain
• Clay-colored stools
• Dark urine
• Diarrhea
• Dizziness
• Headache
• Itching

The clinically relevant drug interactions of Zafirlukast is briefly summarized here:

• Coadministration of multiple doses of Zafirlukast i.e. 160 mg/day to steady-state with a single dose of 25 mg warfarin which is a substrate of CYP2C9 resulted in a significant increase in the mean AUC i.e.+63% and half-life i.e.+36% of S-warfarin. The mean prothrombin time was found to be increased by approximately 35%. The pharmacokinetics of Zafirlukast were found to be unaffected by coadministration along with warfarin.

• Coadministration of Zafirlukast i.e. 80 mg/day at steady-state with a single dose of 6 mg/kg of liquid theophylline preparation, in 13 asthmatic patients, aged 18 to 44 years had resulted in a decreased mean plasma concentrations of Zafirlukast by approximately around 30%, but there was found to be no effect on plasma theophylline concentrations was observed.

• Coadministration of Zafirlukast i.e.20 mg/day or placebo at steady-state with a single dose of 16 mg/kg of sustained release theophylline preparation in 16 healthy boys and girls aged 6-11 years had resulted in no significant difference in the pharmacokinetic profile of theophylline.

• Coadministration of Zafirlukast which is dosed at 40 mg two times a day in a single-blind, parallel-group, which was a 3-week study in 39 healthy female subjects who were taking oral contraceptive s.There was found to be in no significant effect on ethinyl estradiol plasma concentrations or contraceptive efficacy.

• Coadministration of Zafirlukast i.e. 40 mg/day with aspirin about 650 mg four times a day resulted in a mean increase in plasma concentrations of Zafirlukast by approximately around 45%.

• Coadministration of a single dose of Zafirlukast i.e.40 mg with erythromycin which is 500 mg three times a day for 5 days to steady-state in 11 asthmatic patients had resulted in decreased mean plasma concentrations of Zafirlukast by approximately around 40% due to a decrease in zafirlukast bioavailability.

The common side effects of Zafirlukast include the following:

• Nausea
• Upper stomach pain
• Tired feeling
• Loss of appetite
• Dark urine
• Clay-colored stools
• Jaundice
• Skin rash
• Bruising
• Severe tingling
• Pain
• Muscle weakness
• New or worsening cough
• Fever
• Trouble breathing
• Hives
• Blisters
• Severe itching
• Difficulty breathing
• Swelling of face, lips, tongue, or throat,
• Depression
• Unusual thoughts or behavior
• Severe sinus pain
• Sinus congestion
• Numbness or tingly feeling in arms or legs
• Worsening or no improvement in asthma

Pregnancy

Pregnancy Category B: No teratogenicity was found to be observed at oral doses which was up to 1600 mg/kg/day of Zafirlukast in mice i.e.approximately 160 times the maximum recommended daily oral dose of Zafirlukast in adults, up to about 2000 mg/kg/day of Zafirlukast in rats i.e. approximately 410 times the maximum recommended daily oral dose of Zafirlukast in adults and also up to 2000 mg/kg/day of Zafirlukast in cynomolgus monkeys which resulted in about 20 times the exposure to drug plus metabolites when compared to that from the maximum recommended daily oral dose of Zafirlukast in adults based on comparison of the AUC values. At oral dose of about 2000 mg/kg/day of Zafirlukast in rats, maternal toxicity and deaths were observed with increased incidence of early fetal resorption. Spontaneous abortions have been reported to have occurred in cynomolgus monkeys at the maternally toxic oral dose of 2000 mg/kg/day of Zafirlukast. There were found to be no adequate and well-controlled clinical trials in pregnant women. Because the animal reproductive studies are not always predictive of human response therefore Zafirlukast should be used during pregnancy only when the potential benefits outweighs the potential risks associated.

Nursing Mothers

Zafirlukast is found to be excreted in breast milk. Following a repeated 40 mg two times a day dosing in healthy women, average steady-state concentrations of Zafirlukast in breast milk was found to be 50 ng/mL as compared to 255 ng/mL found in the plasma. As there potential for tumorigenicity shown for Zafirlukast in animal studies and the enhanced sensitivity of neonatal rats and dogs to the adverse effects related to Zafirlukast, hence it is advised that Zafirlukast should not be administered to patients who are in the breast-feeding stage, as it might effcet the newborn.

Pediatric Use

The safety data of Zafirlukast at doses of 10 mg two times a day has been demonstrated in around 205 pediatric patients aged 5 to 11 years in a placebo-controlled clinical trials lasting up to 6 weeks and with 179 patients in this age range participating in about 52 weeks of treatment with Zafirlukast in an open label extension. The effectiveness of the drug Zafirlukast for the chronic treatment and prophylaxis of asthma in pediatric patients aged 5 to 11 years is based on an extrapolation data of the demonstrated efficacy of Zafirlukast in adult patients suffering from asthma and the likelihood that the disease course, and also pathophysiology and the Zafirlukast's effect were found to be substantially similar between the two populations.The safety and effecacy of Zafirlukast for pediatric patients aged less than 5 years has not been established. The effect of Zafirlukast on growth of children has not been determined.

Geriatric Use

There was found to be no overall difference in adverse events in the elderly patients in the clinical study reports except for an increase infections frequency among zafirlukast-treated elderly patients as compared to placebo-treated elderly patients. The infections were not found to be severe, as they occurred mostly in the lower part of the respiratory tract, and did not need withdrawal of therapy. In the elderly patients,the adverse events occurring in population greater than 1% included headache , diarrhea and nausea , and pharyngitis. The elderly patients had reported the lowest percentage of infections as in comparison to all three age groups in this study.

Physician should be knowledgeable and vigilant about the treatment pertaining to the identification and treatment of overdosage of Zafirlukast.

Overdosage with Zafirlukast has been reported in 4 patients surviving reported doses of as 200 mg. The predominant symptoms that have been reported following Zafirlukast overdose were upset stomach and rashes. There were found to be no serious toxic effects in humans that could be consistently ascribed to the administration of Zafirlukast doses. It is reasonable to employ some of the usual supportive measures in case of an overdose i.e. removal of unabsorbed material from the gastrointestinal tract, employing clinical monitoring, and instituting supportive therapy, if required.

Pharmacodynamics

Zafirlukast is said to be a synthetic, selective peptide leukotriene receptor antagonist (LTRA) which was indicated for the chronic treatment and prophylaxis of asthma. Patients suffering from asthma were found in one study to be about 25-100 times more sensitive to the bronchoconstriction activity of inhaled LTD₄ than nonasthmatic subjects. The in-vitro studies had demonstrated that Zafirlukast had antagonized the contractile activity of three leukotrienes i.e. LTC₄, LTD₄ and LTE₄ in conducting airway smooth muscle from humans and also laboratory animals. Zafirlukast had prevented intradermal LTD₄-induced increase in cutaneous vascular permeability and inhibit inhaled LTD₄-induced influx of eosinophils into animal lung tissues.

Pharmacokinetics

• Absorption

Zafirlukast is said to be rapidly absorbed following oral administration. the peak plasma concentrations are generally achieved in about 3 hours after the oral administration. The absolute bioavailability of Zafirlukast is not known. In 2 separate studies, where one was using a high fat and the other was using a high protein meal, it was observed that the administration of Zafirlukast with food had reduced the mean bioavailability by about approximately 40%.

• Distribution

Zafirlukast is found to be more than 99% bound to plasma proteins, and it is predominantly bound to albumin. The degree of binding was found to be independent of concentration in the the clinically relevant range. The apparent steady-state volume of distribution was found to be approximately 70 L, suggesting a moderate distribution into tissues. Animal studies in rats using radiolabeled Zafirlukast indicated a minimal distribution across the blood-brain barrier.

• Metabolism

Zafirlukast was found to be extensively metabolized. The most common metabolic products were hydroxylated metabolites which were excreted in the feces. The metabolites of Zafirlukast which were identified in plasma were at least 90 times less potent as antagonists of LTD4 receptor as comapred to Zafirlukast in a standard in vitro test of activity. In-vitro studies using human liver microsomes show that the hydroxylated metabolites of Zafirlukast were excreted in the form of feces which were formed through the cytochrome P450 2C9 i.e. CYP2C9 pathway. The additional in vitro studies utilizing human liver microsomes showed that Zafirlukast inhibited the cytochrome P450 CYP3A4 and CYP2C9 isoenzymes at the concentrations which were close to the clinically achieved total plasma concentrations.

• Elimination

The apparent oral clearance of Zafirlukast was found to be approximately 20 L/h. Animal studies in the rat and dog suggests that biliary excretion is found to be the primary route of excretion. After oral administration of radiolabeled Zafirlukast to the volunteers, the urinary excretion accounts for about approximately 10% of the dose of Zafirlukat and the remainder was found to be excreted in feces. Zafirlukast was not found to be detected in urine. In the pivotal bioequivalence studies, the mean terminal half-life of Zafirlukast was found to be approximately 10 hours in both normal adult subjects and also patients suffering from asthma. In other clinical studies, the mean plasma half-life of Zafirlukast ranged between approximately around 8 to 16 hours in both normal subjects and also patients suffering from asthma. The pharmacokinetics of Zafirlukast was found to be approximately linear over the range between 5 mg to 80 mg. A steady-state plasma concentrations of Zafirlukast was found to be proportional to the dose and was predictable from single-dose pharmacokinetic data. Accumulation of Zafirlukast in the plasma following two times a day dosing was approximately 45%.

• Accolate [package insert]. Wilmington, DE: AstraZeneca; November 2013.cc
• Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf.
• Choi J,Azmat CE, Leukotriene Receptor Antagonists 2020 Jan
• Dempsey OJ, Leukotriene receptor antagonist
• therapy. Postgraduate medical journal. 2000 Dec
• Savidge RD,Bui KH,Birmingham BK,Morse JL,Spreen RC, Metabolism and excretion of zafirlukast in dogs, rats, and mice. Drug metabolism and disposition: the biological fate of chemicals. 1998 Nov.
• Piatti G,Ceriotti L,Cavallaro G,Ambrosetti U,Mantovani M,Pistone A,Centanni S, Effects of zafirlukast on bronchial asthma and allergic rhinitis. Pharmacological research. 2003 Jun.
• Dessanges JF,Préfaut C,Taytard A,Matran R,Naya I,Compagnon A,Dinh-Xuan AT, The effect of zafirlukast on repetitive exercise-induced bronchoconstriction: the possible role of leukotrienes in exercise-induced refractoriness. The Journal of allergy and clinical immunology. 1999 Dec.