Resma

Resma is an oral leukotriene receptor antagonist (LTRA) for the maintenance treatment of asthma, often used in conjunction with an inhaled steroid and/or long-acting bronchodilator. It is available as a tablet and is usually dosed twice daily. Another leukotriene receptor antagonist is montelukast (Singulair), which is usually taken just once daily. Resma blocks the action of the cysteinyl leukotrienes on the CysLT1 receptors, thus reducing constriction of the airways, build-up of mucus in the lungs and inflammation of the breathing passages.

Resma is indicated for the prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older.

Resma 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.

Resma 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.

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

Because food can reduce the bioavailability of Resma, Resma should be taken at least 1 hour before or 2 hours after meals.

Adults and Children 12 years of age and older

The recommended dose of Resma in adults and children 12 years and older is 20 mg twice daily.

Pediatric Patients 5 through 11 years of age

The recommended dose of Resma in children 5 through 11 years of age is 10 mg twice daily.

Elderly Patients

Based on cross-study comparisons, the clearance of Resma is reduced in elderly patients (65 years of age and older), such that Cmax and AUC are approximately twice those of younger adults. In clinical trials, a dose of 20 mg twice daily was not associated with an increase in the overall incidence of adverse events or withdrawals because of adverse events in elderly patients.

Patients with Hepatic Impairment

Resma is contraindicated in patients with hepatic impairment including hepatic cirrhosis. The clearance of Resma is reduced in patients with stable alcoholic cirrhosis such that the Cmax and AUC are approximately 50 - 60% greater than those of normal adults. Resma has not been evaluated in patients with hepatitis or in long-term studies of patients with cirrhosis.

Patients with Renal Impairment

Dosage adjustment is not required for patients with renal impairment.

How supplied

Resma 10 mg Tablets, (NDC 0310-0401) white, unflavored, round, biconvex, film-coated, minitablets identified with “Resma 10” debossed on one side are supplied in opaque HDPE bottles of 60 tablets.

Resma 20 mg Tablets, (NDC 0310-0402) white, round, biconvex, coated tablets identified with “Resma 20” debossed on one side are supplied in opaque HDPE bottles of 60 tablets.

Store at controlled room temperature, 20-25°C (68-77°F). Protect from light and moisture. Dispense in the original air-tight container.

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. Revised: Nov 2013

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What is the most important information I should know about Resma?

Resma will not work fast enough to treat an asthma attack that has already begun. Use only a fast-acting inhalation medicine to treat an asthma attack. Talk with your doctor if any of your asthma medications do not seem to work as well in treating or preventing attacks.

It may take up to several weeks before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not improve after several weeks of treatment.

Call your doctor right away if you feel that this medicine is not working as well as usual, or if it makes your condition worse. If it seems like you need to use more of any of your medications in a 24-hour period, talk with your doctor.

Use Resma as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Resma. Talk to you pharmacist if you have questions about this information.
• Take Resma by mouth on an empty stomach at least 1 hour before or 2 hours after eating.
• Taking Resma at the same time each day will help you remember to take it.
• Take Resma on a regular schedule to get the most benefit from it.
• Continue to take Resma even if you feel well. Do not miss any doses.
• If you miss a dose of Resma, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Resma.

Resma is used to control and prevent symptoms (such as wheezing and shortness of breath) caused by asthma. Controlling symptoms of asthma helps you maintain your normal activities and cuts down on time lost from work or school.

This medication must be used regularly to be effective. It does not work right away and should not be used to relieve sudden asthma attacks. If an asthma attack occurs, use your quick-relief inhaler (such as albuterol, salbutamol) as prescribed.

How to use Resma

Read the Patient Information Leaflet if available from your pharmacist before you start taking Resma and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth without food as directed by your doctor, usually 2 times daily. Take Resma on an empty stomach at least 1 hour before or 2 hours after meals. The dosage is based on your age.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day. Keep taking this medication even if you feel well. Do not increase your dose, use this drug more often, or stop using it without first consulting your doctor.

Get medical help right away if your asthma symptoms worsen or if you are using your quick-relief inhaler more than usual or more often than prescribed.

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What other drugs will affect Resma?

In a drug interaction study in 16 healthy male volunteers, coadministration of multiple doses of Resma (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 Resma of the cytochrome P450 2C9 isoenzyme system. Patients on oral warfarin anticoagulant therapy and Resma should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly. No formal drug-drug interaction studies with Resma 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 Resma is coadministered with these drugs.

In a drug interaction study in 11 asthmatic patients, coadministration of a single dose of Resma (40 mg) with erythromycin (500 mg three times daily for 5 days) to steady-state resulted in decreased mean plasma levels of Resma by approximately 40% due to a decrease in Resma bioavailability.

Coadministration of Resma (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 Resma (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 Resma 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 Resma to an existing theophylline regimen have been reported. The mechanism of the interaction between Resma and theophylline in these patients is unknown.

Coadministration of Resma (40 mg/day) with aspirin (650 mg four times daily) resulted in mean increased plasma levels of Resma 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 Resma had no significant effect on ethinyl estradiol plasma concentrations or contraceptive efficacy.

Coadministration of Resma with fluconazole, a moderate CYP2C9 inhibitor, resulted in increased plasma levels of Resma, by approximately 58% (90% CI:28, 95). The clinical significance of this interaction is unknown. Resma exposure is likely to be increased by other moderate and strong CYP2C9 inhibitors. Coadministration of Resma with itraconazole, a strong CYP3A4 inhibitor, caused no change in plasma levels of Resma.

No other formal drug-drug interaction studies between Resma and marketed drugs known to be metabolized by the P450 3A4 (CYP3A4) isoenzyme (eg, dihydropyridine calcium-channel blockers, cyclosporin, cisapride) have been conducted. As Resma is known to be an inhibitor of CYP3A4 in vitro, it is reasonable to employ appropriate clinical monitoring when these drugs are coadministered with Resma.

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What are the possible side effects of Resma?

Adults and Children 12 years of age and older

The safety database for Resma consists of more than 4000 healthy volunteers and patients who received Resma, of which 1723 were asthmatics enrolled in trials of 13 weeks duration or longer. A total of 671 patients received Resma 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 Resma.

A comparison of adverse events reported by ≥ 1% of Resma-treated patients, and at rates numerically greater than in placebo-treated patients, is shown for all trials in the table below.

Resma Placebo

Headache 12.9% 11.7%

Infection 3.5% 3.4%

Nausea 3.1% 2.0%

Diarrhea 2.8% 2.1%

Pain (generalized) 1.9% 1.7%

Asthenia 1.8% 1.6%

Abdominal Pain 1.8% 1.1%

Accidental Injury 1.6% 1.5%

Dizziness 1.6% 1.5%

Myalgia 1.6% 1.5%

Fever 1.6% 1.1%

Back Pain 1.5% 1.2%

Vomiting 1.5% 1.1%

SGPT Elevation 1.5% 1.1%

The frequency of less common adverse events was comparable between Resma and placebo.

Rarely, elevations of one or more liver enzymes have occurred in patients receiving Resma 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 Resma (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 Resma. In rare cases, patients have presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death.

In clinical trials, an increased proportion of Resma 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 Resma exposure, and were associated with coadministration of inhaled corticosteroids. The clinical significance of this finding is unknown.

In rare cases, patients with asthma on Resma 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 Resma may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established.

Neuropsychiatric adverse events, including insomnia and depression, have been reported in association with Resma therapy. Hypersensitivity reactions, including urticaria, angioedema and rashes, with or without blistering, have also been reported in association with Resma therapy. Additionally, there have been reports of patients experiencing agranulocytosis, bleeding, bruising, or edema, arthralgia, myalgia, malaise, and pruritus in association with Resma therapy.

Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of theophylline toxicity after the addition of Resma to an existing theophylline regimen have been reported. The mechanism of the interaction between Resma and theophylline in these patients is unknown and not predicted by available in vitro metabolism data and the results of two clinical drug interaction studies.

Pediatric Patients 5 through 11 years of age

Resma has been evaluated for safety in 788 pediatric patients 5 through 11 years of age. Cumulatively, 313 pediatric patients were treated with Resma 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 Resma 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 Resma 20 mg twice daily.

In pediatric patients receiving Resma 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.