FDA Approvals: Singulair and Tykerb

May 3, 2007 — The US Food and Drug Administration has approved a new indication for montelukast sodium tablets, allowing their use for the prevention of exercise-induced bronchoconstriction in patients 15 years and older, and lapatinib for use with capecitabine in the treatment of refractory, advanced, or metastatic human epidermal receptor type 2 (HER2)–positive breast cancer.
Montelukast Sodium Tablets (Singulair) to Prevent Exercise-Induced Bronchoconstriction

On April 13, the FDA approved a new indication for montelukast sodium tablets (Singulair; Merck & Co Inc), allowing their use for the prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years and older.

The approval was based on data from 3 double-blind crossover studies in which 160 patients were randomized to receive a single dose of 10-mg montelukast sodium or placebo, followed by exercise challenge testing at 2, 8.5, or 12 and 24 hours. Typically, EIB begins after several minutes of physical activity and peaks 5 to 10 minutes after exercise before resolving to some degree in about an hour.

Results showed that use of montelukast significantly protected pulmonary function when taken 2 hours prior to exercise, as defined by mean maximum percentage of fall in forced expiratory volume in 1 second (FEV1) following exercise (study A, 13% vs 22%; change, -9%; 95% confidence interval [CI], -12% to -5%). For some patients, protection extended to the exercise sessions at 8.5 hours (12% vs 17%; change, -5%; 95% CI, -9% to -2%) and 24 hours (10% vs 14%; change, -4%; 95% CI, -7% to -1%).

Adverse events varied by age and were similar to those previously reported with montelukast sodium, most commonly including headache, ear infection, sore throat, and respiratory tract infection.

The recommended dose for EIB is a single 10-mg tablet taken at least 2 hours prior to exercise. Because additional doses should not be taken within 24 hours of a prior dose, patients taking 1 tablet daily for another indication (including chronic asthma) should not take a second dose to prevent EIB. All patients should have a short-acting ?-agonist available for rescue therapy.

The FDA notes that daily use of montelukast sodium for chronic asthma has not been established to prevent acute episodes of EIB.

Montelukast sodium previously was approved by the FDA for the prophylaxis and long-term treatment of asthma in patients 1 year and older. It may also be used to relieve symptoms of seasonal allergic rhinitis in patients 2 years and older and to relieve symptoms of perennial allergic rhinitis in those 6 months and older.
Lapatinib (Tykerb) for Refractory Advanced/Metastatic HER2-Positive Breast Cancer

On March 13, the FDA approved lapatinib 250-mg tablets (Tykerb; GlaxoSmithKline) for use with capecitabine (Xeloda; Hoffmann-La Roche Inc) in the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress human epidermal receptor type 2 (HER2) and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab (Herceptin; Genentech Inc).

Lapatinib, a new molecular entity, is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of epidermal growth factor receptor (EGFR, also known as ErbB1) and HER2 (also known as ErbB2) receptors. In contrast with trastuzumab, lapatinib is a small molecule that enters the cell to block the function of HER2 and other proteins.

The approval was based on a priority review of pivotal phase 3 trial data (n = 399) showing that the addition of lapatinib to capecitabine significantly increased the tumor response rate (23.7% vs 13.9%) and the median time to disease progression (27.1 vs 18.6 weeks) relative to capecitabine alone (hazard ratio

, 0.57; 95% CI, 0.43 - 0.77; P = .00013) as rated by an independent reviewer.

Differences between treatment groups based on unblended investigator assessments were smaller but remained significant for both tumor response (32.8% vs 17.4%) and median time to disease progression/death (23.9 vs 18.3 weeks; HR, 0.72; 95% CI, 0.56 - 0.92; P = .00762). "The survival data are not yet mature," the FDA noted in a news release.

The most commonly reported (> 20%) adverse events in patients receiving lapatinib plus capecitabine included diarrhea (65%), hand-foot syndrome (53%), nausea (44%), rash (28%), vomiting (26%), and fatigue. Diarrhea was the most common cause of treatment discontinuation. Of the 198 patients who received the drug combination, 3 cases of grade 2 (asymptomatic) decrease in left ventricular ejection fraction (LVEF) were reported, and 1 patient had grade 3 (symptomatic) LVEF.

The recommended dosage of lapatinib is 1250 mg (5 tablets) administered once daily on days 1 to 21 in combination with capecitabine, 2000 mg/m2 per day (given in 2 doses approximately 12 hours apart) on days 1 to 14 in the repeating 21-day cycle. Lapatinib should be taken without food or at least 1 hour after consuming food; dividing the daily dose is not recommended. Capecitabine, however, should be taken with food or within 30 minutes after food. If a dose is missed, the next day's dose should not be doubled. Treatment should continue until disease progression or unacceptable toxicity occurs.

Lapatinib use should be discontinued if LVEF decreases to a level of grade 2 or greater according to the National Cancer Institute's Common Terminology Criteria for Adverse Events or is below the institution's lower limit of normal. Treatment may be resumed at a reduced dose (1000 mg/day) after a minimum of 2 weeks if LVEF returns to normal and the patient is asymptomatic.

Also, discontinuation or dose interruption should be considered in patients who develop any grade 2 or greater toxicity according to the National Cancer Institute common toxicity criteria, and restarted at 1250 mg/day when the toxicity improves to grade 1 or less. If toxicity recurs, lapatinib should be restarted at a reduced dosage of 1000 mg/day.

For patients with severe hepatic impairment (Child-Pugh class C), a dose reduction to 750 mg/day is predicted to adjust the area under the curve to the normal range and should be considered; however, no clinical data are available in this setting.

Because lapatinib is extensively metabolized by cytochrome P 450 isoenzyme 3A4 (CYP 3A4), concomitant use of strong CYP 3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) and grapefruit juice can increase lapatinib plasma concentrations and should be avoided.

If a strong CYP 3A4 inhibitor is required, pharmacokinetic study data suggest that a dosage reduction to 500 mg/day of lapatinib may adjust the area under the curve to the appropriate range. The FDA advises, if use of a strong inhibitor is discontinued, a washout period of approximately 1 week prior to adjusting the lapatinib dose upwards.

Similarly, concomitant use of strong CYP 3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort) should be avoided because of the resulting decrease in lapatinib plasma levels. If a strong inducer is required, lapatinib dosing should be gradually titrated from 1250 to 4500 mg/day based on tolerability. Normal dosing of lapatinib should be resumed after discontinuation of the CYP 3A4 inducer.

The company noted in a news release that a comprehensive program has been established (Tykerb CARES) to answer product-related questions from patients and clinicians, assist them in obtaining lapatinib, and provide information on financial resources for treatment.

Lapatinib (marketed as Tykerb or Tyverb) currently is under consideration for approval by various regulatory agencies, including those of the European Union, Switzerland, Canada, Brazil, Australia, and South Korea.

http://www.fda.gov/cder/foi/label/2007/020829s036,020830s038,021409s016lbl.pdf

http://www.fda.gov/cder/foi/label/2007/022059s001lbl.pdf