Accolate Information
Accolate () Description
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-o-tolylsulfonylbenzamide. The molecular weight of zafirlukast is 575.7 and the structural formula is:
The empirical formula is: CHNOS
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.
Accolate () Clinical Pharmacology
Zafirlukast is a selective and competitive receptor antagonist of leukotriene D and E (LTD and LTE), 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. Patients with asthma were found in one study to be 25-100 times more sensitive to the bronchoconstricting activity of inhaled LTD than nonasthmatic subjects.
In vitro
In humans, zafirlukast inhibited bronchoconstriction caused by several kinds of inhalational challenges. Pretreatment with single oral doses of zafirlukast inhibited the bronchoconstriction caused by sulfur dioxide and cold air in patients with asthma. Pretreatment with single doses of zafirlukast attenuated the early- and late-phase reaction caused by inhalation of various antigens such as grass, cat dander, ragweed, and mixed antigens in patients with asthma. Zafirlukast also attenuated the increase in bronchial hyperresponsiveness to inhaled histamine that followed inhaled allergen challenge.
Three U.S. double-blind, randomized, placebo-controlled, 13-week clinical trials in 1380 adults and children 12 years of age and older with mild-to-moderate asthma demonstrated that Accolate () improved daytime asthma symptoms, nighttime awakenings, mornings with asthma symptoms, rescue beta-agonist use, FEV, and morning peak expiratory flow rate. In these studies, the patients had a mean baseline FEV of approximately 75% of predicted normal and a mean baseline beta-agonist requirement of approximately 4-5 puffs of albuterol per day. The results of the largest of the trials are shown in the table below.
In a second and smaller study, the effect of Accolate () on most efficacy parameters was comparable to the active control (inhaled cromolyn sodium 1600 mcg four times per day) and superior to placebo at end point for decreasing rescue beta-agonist use (figure below).
In these trials, improvement in asthma symptoms occurred within one week of initiating treatment with Accolate () . The role of Accolate () in the management of patients with more severe asthma, patients receiving antiasthma therapy other than as-needed, inhaled beta-agonists, or as an oral or inhaled corticosteroid-sparing agent remains to be fully characterized.
Accolate () Indications And Usage
Accolate () is indicated for the prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older.
Accolate () Contraindications
Accolate () is contraindicated in patients who are hypersensitive to zafirlukast or any of its inactive ingredients.
Accolate () is contraindicated in patients with hepatic impairment including hepatic cirrhosis.
Accolate () Warnings
Cases of life-threatening hepatic failure have been reported in patients treated with Accolate () . Cases of liver injury without other attributable cause have been reported from post-marketing adverse event surveillance of patients who have received the recommended dose of Accolate () (40 mg/day). In most, but not all post-marketing reports, the patient’s symptoms abated and the liver enzymes returned to normal or near normal after stopping Accolate () . In rare cases, patients have either presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death. In extremely rare post-marketing cases, no clinical symptoms or signs suggestive of liver dysfunction were reported to precede the latter observations.
Physicians may consider the value of liver function testing. Periodic serum transaminase testing has not proven to prevent serious injury but it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery.
Patients should be advised to be alert for signs and symptoms of liver dysfunction (eg, right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, and anorexia) and to contact their physician immediately if they occur. Ongoing clinical assessment of patients should govern physician interventions, including diagnostic evaluations and treatment.
If liver dysfunction is suspected based upon clinical signs or symptoms (eg, right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, anorexia, and enlarged liver), Accolate () should be discontinued.
Liver function tests, in particular serum ALT, should be measured immediately and the patient managed accordingly. If liver function tests are consistent with hepatic dysfunction, Accolate () therapy should not be resumed. Patients in whom Accolate () was withdrawn because of hepatic dysfunction where no other attributable cause is identified should not be re-exposed to Accolate () (see and ).
Accolate () Precautions
Patients should be told that a rare side effect of Accolate () is hepatic dysfunction, and to contact their physician immediately if they experience symptoms of hepatic dysfunction (eg. right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, and anorexia). Liver failure resulting in liver transplantation and death has occurred in patients taking zafirlukast (see and ).
Accolate () is indicated for the chronic treatment of asthma and should be taken regularly as prescribed, even during symptom-free periods. Accolate () is not a bronchodilator and should not be used to treat acute episodes of asthma. Patients receiving Accolate () should be instructed not to decrease the dose or stop taking any other antiasthma medications unless instructed by a physician. Patients should be instructed to notify their physician if neuropsychiatric events occur while using Accolate () (see ). Women who are breast-feeding should be instructed not to take Accolate () (see ). Alternative antiasthma medication should be considered in such patients.
The bioavailability of Accolate () may be decreased when taken with food. Patients should be instructed to take Accolate () at least 1 hour before or 2 hours after meals.
In a drug interaction study in 16 healthy male volunteers, coadministration of multiple doses of zafirlukast (160 mg/day) to steady-state with a single 25 mg dose of warfarin resulted in a significant increase in the mean AUC (+ 63%) and half-life (+36%) of S-warfarin. The mean prothrombin time (PT) increased by approximately 35%. This interaction is probably due to an inhibition by zafirlukast of the cytochrome P450 2C9 isoenzyme system. Patients on oral warfarin anticoagulant therapy and Accolate () should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly (see ). No formal drug-drug interaction studies with Accolate () and other drugs known to be metabolized by the cytochrome P450 2C9 isoenzyme (eg, tolbutamide, phenytoin, carbamazepine) have been conducted; however, care should be exercised when Accolate () is coadministered with these drugs.
In a drug interaction study in 11 asthmatic patients, coadministration of a single dose of zafirlukast (40 mg) with erythromycin (500 mg three times daily for 5 days) to steady-state resulted in decreased mean plasma levels of zafirlukast by approximately 40% due to a decrease in zafirlukast bioavailability.
Coadministration of zafirlukast (20 mg/day) or placebo at steady-state with a single dose of sustained release theophylline preparation (16 mg/kg) in 16 healthy boys and girls (6 through 11 years of age) resulted in no significant differences in the pharmacokinetic parameters of theophylline.
Coadministration of zafirlukast (80 mg/day) at steady-state with a single dose of a liquid theophylline preparation (6 mg/kg) in 13 asthmatic patients, 18 to 44 years of age, resulted in decreased mean plasma levels of zafirlukast by approximately 30%, but no effect on plasma theophylline levels was observed.
Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of theophylline toxicity after the addition of Accolate () to an existing theophylline regimen have been reported. The mechanism of the interaction between Accolate () and theophylline in these patients is unknown (see ).
Coadministration of zafirlukast (40 mg/day) with aspirin (650 mg four times daily) resulted in mean increased plasma levels of zafirlukast by approximately 45%.
In a single-blind, parallel-group, 3-week study in 39 healthy female subjects taking oral contraceptives, 40 mg twice daily of zafirlukast had no significant effect on ethinyl estradiol plasma concentrations or contraceptive efficacy.
No formal drug-drug interaction studies between Accolate () and marketed drugs known to be metabolized by the P450 3A4 (CYP3A4) isoenzyme (eg, dihydropyridine calcium-channel blockers, cyclosporin, cisapride) have been conducted. As Accolate () is known to be an inhibitor of CYP3A4 , it is reasonable to employ appropriate clinical monitoring when these drugs are coadministered with Accolate () .
In two-year carcinogenicity studies, zafirlukast was administered at dietary doses of 10, 100, and 300 mg/kg to mice and 40, 400, and 2000 mg/kg to rats. Male mice at an oral dose of 300 mg/kg/day (approximately 30 times the maximum recommended daily oral dose in adults and in children on a mg/m basis) showed an increased incidence of hepatocellular adenomas; female mice at this dose showed a greater incidence of whole body histocytic sarcomas. Male and female rats at an oral dose of 2000 mg/kg/day (resulting in approximately 160 times the exposure to drug plus metabolites from the maximum recommended daily oral dose in adults and in children based on a comparison of the plasma area-under the curve [AUC] values) of zafirlukast showed an increased incidence of urinary bladder transitional cell papillomas. Zafirlukast was not tumorigenic at oral doses up to 100 mg/kg (approximately 10 times the maximum recommended daily oral dose in adults and in children on a mg/m basis) in mice and at oral doses up to 400 mg/kg (resulting in approximately 140 times the exposure to drug plus metabolites from the maximum recommended daily oral dose in adults and in children based on a comparison of the plasma AUC values) in rats. The clinical significance of these findings for the long-term use of Accolate () is unknown.
Zafirlukast showed no evidence of mutagenic potential in the reverse microbial assay, in 2 forward point mutation (CHO-HGPRT and mouse lymphoma) assays or in two assays for chromosomal aberrations (the human peripheral blood lymphocyte clastogenic assay and the rat bone marrow micronucleus assay).
No evidence of impairment of fertility and reproduction was seen in male and female rats treated with zafirlukast at oral doses up to 2000 mg/kg (approximately 410 times the maximum recommended daily oral dose in adults on a mg/m basis).
Accolate () Adverse Reactions
The safety database for Accolate () consists of more than 4000 healthy volunteers and patients who received Accolate () , of which 1723 were asthmatics enrolled in trials of 13 weeks duration or longer. A total of 671 patients received Accolate () for 1 year or longer. The majority of the patients were 18 years of age or older; however, 222 patients between the age of 12 and 18 years received Accolate () .
A comparison of adverse events reported by ≥1% of zafirlukast-treated patients, and at rates numerically greater than in placebo-treated patients, is shown for all trials in the table below.
The frequency of less common adverse events was comparable between Accolate () and placebo.
Rarely, elevations of one or more liver enzymes have occurred in patients receiving Accolate () in controlled clinical trials. In clinical trials, most of these have been observed at doses four times higher than the recommended dose. The following hepatic events (which have occurred predominantly in females) have been reported from postmarketing adverse event surveillance of patients who have received the recommended dose of Accolate () (40 mg/day): cases of symptomatic hepatitis (with or without hyperbilirubinemia) without other attributable cause; and rarely, hyperbilirubinemia without other elevated liver function tests. In most, but not all postmarketing reports, the patient’s symptoms abated and the liver enzymes returned to normal or near normal after stopping Accolate () . In rare cases, patients have presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death (see and ).
In clinical trials, an increased proportion of zafirlukast patients over the age of 55 years reported infections as compared to placebo-treated patients. A similar finding was not observed in other age groups studied. 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. The clinical significance of this finding is unknown.
In rare cases, patients with asthma on Accolate () may present with systemic eosinophilia, eosinophilic pneumonia, or clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic steroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. These events have usually, but not always, been associated with reductions and/or withdrawal of steroid therapy. The possibility that Accolate () may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established (see ).
Neuropsychiatric adverse events, including insomnia and depression, have been reported in association with Accolate () therapy (see ). Hypersensitivity reactions, including urticaria, angioedema and rashes, with or without blistering, have also been reported in association with Accolate () therapy. Additionally, there have been reports of patients experiencing agranulocytosis, bleeding, bruising, or edema, arthralgia, myalgia, malaise, and pruritus in association with Accolate () therapy.
Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of theophylline toxicity after the addition of Accolate () to an existing theophylline regimen have been reported. The mechanism of the interaction between Accolate () and theophylline in these patients is unknown and not predicted by available metabolism data and the results of two clinical drug interaction studies (see and ).
Accolate () has been evaluated for safety in 788 pediatric patients 5 through 11 years of age. Cumulatively, 313 pediatric patients were treated with Accolate () 10 mg twice daily or higher for at least 6 months, and 113 of them were treated for one year or longer in clinical trials. The safety profile of Accolate () 10 mg twice daily-versus placebo in the 4- and 6-week double-blind trials was generally similar to that observed in the adult clinical trials with Accolate () 20 mg twice daily.
In pediatric patients receiving Accolate () in multi-dose clinical trials, the following events occurred with a frequency of ≥ 2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: headache (4.5 vs. 4.2%) and abdominal pain (2.8 vs. 2.3%).
The post-marketing experience in this age group is similar to that seen in adults, including hepatic dysfunction, which may lead to liver failure.
Accolate () Overdosage
No deaths occurred at oral zafirlukast doses of 2000 mg/kg in mice (approximately 210 times the maximum recommended daily oral dose in adults and children on a mg/m basis), 2000 mg/kg in rats (approximately 420 times the maximum recommended daily oral dose in adults and children on a mg/m basis), and 500 mg/kg in dogs (approximately 350 times the maximum recommended daily oral dose in adults and children on a mg/m basis).
Overdosage with Accolate () has been reported in four patients surviving reported doses as high as 200 mg. The predominant symptoms reported following Accolate () overdose were rash and upset stomach. There were no acute toxic effects in humans that could be consistently ascribed to the administration of Accolate () . It is reasonable to employ the usual supportive measures in the event of an overdose; eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.
Accolate () Dosage And Administration
Because food can reduce the bioavailability of zafirlukast, Accolate () should be taken at least 1 hour before or 2 hours after meals.
The recommended dose of Accolate () in children 5 through 11 years of age is 10 mg twice daily.
Elderly Patients:
max
Patients with Hepatic Impairment:
max
Patients with Renal Impairment:
Accolate () How Supplied
Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Protect from light and moisture. Dispense in the original air-tight container.
Accolate () is a trademark of the AstraZeneca group of companies.
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
6704–01
Rev. 02/2011
Read the Patient Information leaflet before you start taking Accolate () and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
Accolate () is a prescription medicine used to help prevent asthma attacks and for the long-term treatment of asthma symptoms in adults and children 5 years and older.
It is not known if Accolate () is safe and effective when used in children under 5 years old. The effect of Accolate () on growth in children has not been determined.
Do not take Accolate () if you need relief right away for a sudden asthma attack. If you get an asthma attack, you should follow the instructions your healthcare provider gave you for treating asthma attacks.
Do not take Accolate () if you;
· are allergic to zafirlukast or any of the ingredients in Accolate () . See the end of this leaflet for a complete list of ingredients in Accolate () .
· have problems with your liver.
Accolate () may affect the way other medicines work, and other medicines may affect how Accolate () works.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
The most common side effects of Accolate () in people 12 years and older include:
The most common side effects of Accolate () in children 5 to 11 years include:
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all of the possible side effects of Accolate () . For more information, ask your healthcare provider or pharmacist.
Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
You may also report side effects to AstraZeneca at 1-800-236-9933.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Accolate () for a condition for which it was not prescribed. Do not give Accolate () to other people, even if they have the same symptoms that you have. It may harm them.
This Patient Information leaflet summarizes the most important information about Accolate () . If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Accolate () that is written for healthcare professionals.
For more information, go to www.Accolate () .com or call AstraZeneca Information Center at 1-800-236-9933, Monday through Friday, 8 a.m. – 6 p.m. Eastern Standard Time, excluding holidays.
Accolate () is a trademark of the AstraZeneca group of companies.
©AstraZeneca 2011
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
6704–01
Rev. 02/2011
