Accolate

Name: Accolate

What should I know about storage and disposal of this medication?

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from light, excess heat, and moisture (not in the bathroom) . Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

What other information should I know?

Keep all appointments with your doctor and the laboratory. Your doctor may order certain lab tests to check your response to zafirlukast.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Interactions for Accolate

Metabolized by CYP2C9.1

Inhibits CYP3A4 and CYP2C9.1

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2C9 and CYP3A4 substrates: Potential pharmacokinetic interaction (increased plasma substrate concentrations).1

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants (e.g., carbamazepine, phenytoin)

Possible increased plasma anticonvulsant concentrationsa

Monitor for adverse effects1

Aspirin

Increased plasma zafirlukast concentrations1 45 52

Monitor for alterations in clinical response and/or adverse effects1

Astemizole (no longer commercially available in the US)

Possible increased plasma astemizole concentrations1 45

Calcium-channel blocking agents, dihydropyridine (nicardipine, nifedipine)

Possible increased plasma concentrations of dihydropyridine calcium-channel blocking agents1 45

Monitor for alterations in clinical response and/or adverse effects1 45 52 53

Cisapride (commercially available in US only under limited-access protocol)

Possible increased cisapride concentrations 1 45

Monitor for alterations in clinical response and/or adverse effects45 a

Contraceptives, oral (fixed dose estrogen-progestin combination)

Pharmacokinetic interactions unlikely1 45

Contraceptive efficacy not affected by concomitant administration 1 45

Cyclosporine

Possible increased plasma cyclosporine concentrations1 45

Monitor for alterations in clinical response and/or adverse effects1 45 52 53

Erythromycin

Decreased plasma zafirlukast concentrations1 45

Monitor for alterations in clinical response and/or adverse effects1

Terfenadine (no longer commercially available in US)

Decreased plasma concentrations of zafirlukast1 45

No alteration in terfenadine pharmacokinetics; no effect on QTc interval45

Theophylline

Rarely, increased theophylline concentrations when zafirlukast is added to existing theophylline regimen1 65

Decreased plasma zafirlukast concentrations when administered with liquid theophylline preparation1 45

No alterations in pharmacokinetics of theophylline administered orally in pediatric patients1 45

Monitor for alterations in clinical response and/or adverse effects1

Tolbutamide

Possible increased plasma tolbutamide concentrationsa

Monitor for adverse effects1

Warfarin

Increased AUC and half-life of S-warfarin; possible increased PT1 45

Monitor PT frequently and adjust warfarin dose accordingly1 45 52 53 56

Stability

Storage

Oral

Tablets

20–25°C; protect from light and moisture.1

Actions

  • Selective, competitive leukotriene-receptor antagonist. 1 2 3 4 5 10 11 12 21 22 23 24 25 26 45 46

  • Binds selectively and with high affinity to a group of cysteinyl leukotriene receptors (CysLT1) in airway smooth muscle and competitively inhibits the action of LTD4 and LTE4 (cysteinyl leukotrienes) at these receptors. 1 2 3 4 5 6 11 12 13 18 19 20 21 23 24 45 53

  • Modification of leukotriene activity may be used to reduce symptoms of asthma since cysteinyl leukotrienes are especially important in the pathogenesis of asthma, causing increased mucous secretion and vascular permeability, airway edema, bronchoconstriction, and altered cellular activity associated with the inflammatory process.1 5 6 7 9 12 13 20 21 22 23 24 26 28 45 53

  • Inhibits bronchoconstriction induced by exposure to known precipitating factors (e.g., allergens, environmental pollutants, cold and/or dry air, exercise);1 2 6 7 9 12 13 20 22 23 44 45 48 49 50 51 53 55 inhibits both the acute bronchoconstrictor response and the delayed inflammatory response to inhaled antigens.1 2 6 7 10 12 21 22 44 45 55

  • Has essentially no affinity for α- or β-adrenergic, histamine, type-2 serotonergic, muscarinic, thromboxane, prostaglandin, and calcium-channel receptors.3 45

Accolate Side Effects

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:

Less common
  • Cough or hoarseness
  • fever or chills
  • lower back or side pain
  • pain
  • painful or difficult urination
Rare
  • 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
Incidence not known
  • 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:

Less common
  • 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
Incidence not known
  • 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.

What do I need to tell my doctor BEFORE I take Accolate?

  • If you have an allergy to zafirlukast or any other part of this medicine.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have liver disease.
  • If you are breast-feeding. Do not breast-feed while you take Accolate.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Accolate with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

How do I store and/or throw out Accolate?

  • 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.

Clinical pharmacology

Mechanism of Action:

Zafirlukast is a selective and competitive receptor antagonist 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. Patients with asthma were found in one study to be 25-100 times more sensitive to the bronchoconstricting activity of inhaled LTD4 than nonasthmatic subjects.

In vitro studies demonstrated that zafirlukast antagonized the contractile activity of three leukotrienes (LTC4, LTD4 and LTE4) in conducting airway smooth muscle from laboratory animals and humans. Zafirlukast prevented intradermal LTD4-induced increases in cutaneous vascular permeability and inhibited inhaled LTD4-induced influx of eosinophils into animal lungs. Inhalational challenge studies in sensitized sheep showed that zafirlukast suppressed the airway responses to antigen; this included both the early- and late-phase response and the nonspecific hyperresponsiveness.

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.

Clinical Pharmacokinetics and Bioavailability:

Absorption

Zafirlukast is rapidly absorbed following oral administration. Peak plasma concentrations are generally achieved 3 hours after oral administration. The absolute bioavailability of zafirlukast is unknown. In two separate studies, one using a high fat and the other a high protein meal, administration of zafirlukast with food reduced the mean bioavailability by approximately 40%.

Distribution

Zafirlukast is more than 99% bound to plasma proteins, predominantly albumin. The degree of binding was independent of concentration in the clinically relevant range. The apparent steady-state volume of distribution (Vss/F) is approximately 70 L, suggesting moderate distribution into tissues. Studies in rats using radiolabeled zafirlukast indicate minimal distribution across the blood-brain barrier.

Metabolism

Zafirlukast is extensively metabolized. The most common metabolic products are hydroxylated metabolites which are excreted in the feces. The metabolites of zafirlukast identified in plasma are at least 90 times less potent as LTD4 receptor antagonists than zafirlukast in a standard in vitro test of activity. In vitro studies using human liver microsomes showed that the hydroxylated metabolites of zafirlukast excreted in the feces are formed through the cytochrome P450 2C9 (CYP2C9) pathway. Additional in vitro studies utilizing human liver microsomes show that zafirlukast inhibits the cytochrome P450 CYP3A4 and CYP2C9 isoenzymes at concentrations close to the clinically achieved total plasma concentrations (see Drug Interactions).

Excretion

The apparent oral clearance (CL/f) of zafirlukast is approximately 20 L/h. Studies in the rat and dog suggest that biliary excretion is the primary route of excretion. Following oral administration of radiolabeled zafirlukast to volunteers, urinary excretion accounts for approximately 10% of the dose and the remainder is excreted in feces. Zafirlukast is not detected in urine.

In the pivotal bioequivalence study, the mean terminal half-life of zafirlukast is approximately 10 hours in both normal adult subjects and patients with asthma. In other studies, the mean plasma half-life of zafirlukast ranged from approximately 8 to 16 hours in both normal subjects and patients with asthma. The pharmacokinetics of zafirlukast are approximately linear over the range from 5 mg to 80 mg. Steady-state plasma concentrations of zafirlukast are proportional to the dose and predictable from single-dose pharmacokinetic data. Accumulation of zafirlukast in the plasma following twice-daily dosing is approximately 45%.

The pharmacokinetic parameters of zafirlukast 20 mg administered as a single dose to 36 male volunteers are shown with the table below.

Mean (% Coefficient of Variation) pharmacokinetic parameters of zafirlukast following single 20 mg oral dose administration to male volunteers (n=36)
* Median and range

Cmax

ng/ml

tmax*

h

AUC

ng•h/mL

t1/2

h

CL/f

L/h

326 (31.0)

2 (0.5 - 5.0)

1137 (34)

13.3 (75.6)

19.4 (32)

Special Populations

Gender: The pharmacokinetics of zafirlukast are similar in males and females. Weight-adjusted apparent oral clearance does not differ due to gender.

Race: No differences in the pharmacokinetics of zafirlukast due to race have been observed.

Elderly: The apparent oral clearance of zafirlukast decreases with age. In patients above 65 years of age, there is an approximately 2-3 fold greater Cmax and AUC compared to young adult patients.

Children: Following administration of a single 20 mg dose of zafirlukast to 20 boys and girls between 7 and 11 years of age, and in a second study, to 29 boys and girls between 5 and 6 years of age, the following pharmacokinetic parameters were obtained:

Parameter

Children age 5-6 years Mean (% Coefficient of Variation)

Children age 7-11 years Mean

(% Coefficient of Variation)

Cmax (ng/mL)

756 (39%)

601 (45%)

AUC (ng•h/mL)

2458 (34%)

2027 (38%)

tmax (h)

2.1 (61%)

2.5 (55%)

CL/f (L/h)

9.2 (37%)

11.4 (42%)

Weight unadjusted apparent clearance was 11.4 L/h (42%) in the 7-11 year old children and 9.2 L/h (37%) in the 5-6 year old children, which resulted in greater systemic drug exposures than that obtained in adults for an identical dose. To maintain similar exposure levels in children compared to adults, a dose of 10 mg twice daily is recommended in children 5-11 years of age (see DOSAGE AND ADMINISTRATION).

Zafirlukast disposition was unchanged after multiple dosing (20 mg twice daily) in children and the degree of accumulation in plasma was similar to that observed in adults.

Hepatic Insufficiency: In a study of patients with hepatic impairment (biopsy-proven cirrhosis), there was a reduced clearance of zafirlukast resulting in a 50-60% greater Cmax and AUC compared to normal subjects.

Renal Insufficiency: Based on a cross-study comparison, there are no apparent differences in the pharmacokinetics of zafirlukast between renally-impaired patients and normal subjects.

Drug-Drug Interactions: The following drug interaction studies have been conducted with zafirlukast (see PRECAUTIONS, Drug Interactions).

• Coadministration of multiple doses of zafirlukast (160 mg/day) to steady-state with a single 25 mg dose of warfarin (a substrate of CYP2C9) resulted in a significant increase in the mean AUC (+63%) and half-life (+36%) of S-warfarin. The mean prothrombin time increased by approximately 35%. The pharmacokinetics of zafirlukast were unaffected by coadministration with warfarin. • 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 concentrations of zafirlukast by approximately 30%, but no effect on plasma theophylline concentrations was observed. • 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 dosed at 40 mg twice daily in a single-blind, parallel-group, 3-week study in 39 healthy female subjects taking oral contraceptives, resulted in no significant effect on ethinyl estradiol plasma concentrations or contraceptive efficacy. • Coadministration of zafirlukast (40 mg/day) with aspirin (650 mg four times daily) resulted in mean increased plasma concentrations of zafirlukast by approximately 45%. • Coadministration of a single dose of zafirlukast (40 mg) with erythromycin (500 mg three times daily for 5 days) to steady-state in 11 asthmatic patients resulted in decreased mean plasma concentrations of zafirlukast by approximately 40% due to a decrease in zafirlukast bioavailability. • Coadministration of zafirlukast with fluconazole, a moderate CYP2C9 inhibitor, resulted in increased plasma levels of zafirlukast, by approximately 58% (90% CI:28, 95). The clinical significance of this interaction is unknown. Zafirlukast exposure is likely to be increased by other moderate and strong CYP2C9 inhibitors. Coadministration of zafirlukast with itraconazole, a strong CYP3A4 inhibitor, caused no change in plasma levels of zafirlukast. Clinical Studies

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 beta2-agonist use, FEV1, and morning peak expiratory flow rate. In these studies, the patients had a mean baseline FEV1 of approximately 75% of predicted normal and a mean baseline beta2-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.

Mean Change from Baseline at Study End Point
* p<0.05, compared to placebo

Accolate

20 mg twice daily

N=514

Placebo

N=248

Daytime Asthma symptom score

(0-3 scale)

-0.44*

-0.25

Nightime Awakenings

(number per week)

-1.27*

-0.43

Mornings with Asthma Symptoms

(days per week)

-1.32*

-0.75

Rescue β2-agonist use

(puffs per day)

-1.15*

-0.24

FEV1 (L)

+0.15*

+0.05

Morning PEFR (L/min)

+22.06*

+7.63

Evening PEFR (L/min)

+13.12

+10.14

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 beta2-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 beta2-agonists, or as an oral or inhaled corticosteroid-sparing agent remains to be fully characterized.

Package/label principal display panel

PRINCIPAL DISPLAY PANEL – 10 mg

Package/Label Display Panel

PRINCIPAL DISPLAY PANEL – 20 mg

Accolate 
zafirlukast tablet, coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:49884-589
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ZAFIRLUKAST (ZAFIRLUKAST) ZAFIRLUKAST 10 mg
Inactive Ingredients
Ingredient Name Strength
CROSCARMELLOSE SODIUM  
LACTOSE, UNSPECIFIED FORM  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
POVIDONES  
HYPROMELLOSES  
TITANIUM DIOXIDE  
Product Characteristics
Color WHITE Score no score
Shape ROUND Size 6mm
Flavor Imprint Code
Contains     
Packaging
# Item Code Package Description
1 NDC:49884-589-02 60 TABLET, COATED in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA020547 11/01/2015
Accolate 
zafirlukast tablet, coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:49884-590
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ZAFIRLUKAST (ZAFIRLUKAST) ZAFIRLUKAST 20 mg
Inactive Ingredients
Ingredient Name Strength
CROSCARMELLOSE SODIUM  
LACTOSE, UNSPECIFIED FORM  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
POVIDONES  
HYPROMELLOSES  
TITANIUM DIOXIDE  
Product Characteristics
Color WHITE Score no score
Shape ROUND Size 8mm
Flavor Imprint Code
Contains     
Packaging
# Item Code Package Description
1 NDC:49884-590-02 60 TABLET, COATED in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA020547 11/01/2015
Labeler - Par Pharmaceutical Inc. (092733690)
Registrant - Par Pharmaceutical Inc. (092733690)
Establishment
Name Address ID/FEI Operations
Par Pharmaceutical Inc. 092733690 MANUFACTURE(49884-589, 49884-590)
Revised: 12/2015   Par Pharmaceutical Inc.

Side Effects of Accolate

Serious side effects have been reported with Accolate. See the "Accolate Precautions" section.

Common side effects of Accolate include:

  • headache
  • infection
  • nausea
  • diarrhea
  • stomach pain
  • dizziness
  • fever
  • back pain
  • vomiting
  • acid indigestion

This is not a complete list of Accolate side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effects that bother you or do not go away.

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

Accolate Food Interactions

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. 

In the case of Accolate, there are no specific foods that you must exclude from your diet, but because food can reduce the amount of Accolate that gets absorbed into your body, Accolate should be taken at least 1 hour before or 2 hours after meals.

Accolate and Pregnancy

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Accolate falls into category B. There are no well-done studies that have been done in humans with Accolate. But in animal studies, pregnant animals were given this medication, and the babies did not show any medical issues related to this medication. Accolate should be used during pregnancy only if clearly needed.

Adverse Effects

>10%

headache (12.9% in age >12 yr)

1-10%

Abdominal pain (1.8%)

Infection (3.5%)

Nausea (3.1%)

Diarrhea (2.8%)

Generalized pain (1.8%)

Vomiting (1.5%)

Dyspepsia/gastritits (1.3%)

Increased ALT (1.5%)

Infection (4%)

Back pain (2%)

Weakness (2%)

Myalgia (2%)

Frequency Not Defined

Eosinophilia

Eosinophilic pneumonia

Vasculitis

Malaise

Bleeding

Bruising

Zafirlukast Breastfeeding Warnings

Use should be avoided. Excreted into human milk: Yes Comments: The effects in the nursing infant are unknown.

Following repeated 40 mg twice-a-day dosing in healthy women, average steady-state concentrations in breast milk were 50 ng/mL compared to 255 ng/mL in plasma. Studies in mouse and rats showed a potential for tumorigenicity and enhanced sensitivity of neonatal rats and dogs to the adverse effects of this drug.

Zafirlukast Identification

Substance Name

Zafirlukast

CAS Registry Number

107753-78-6

Drug Class

Anti-Asthmatic Agents

Leukotriene Antagonists

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