News from the FDA

FDA Approval of TECFIDERA (dimethyl fumarate) for the treatment of patients with relapsing forms of multiple sclerosis (MS).

On February 26, 2013, the FDA approved OSPHENA for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, associated with menopause. It is the first estrogen receptor agonist/antagonist, non-estrogenic product, with tissue selective effects approved for this indication. Ospemifene is available in 60 mg immediate-release tablets and should be taken orally once daily with food.

The effectiveness and safety of OSPHENA in postmenopausal women were demonstrated in three clinical trials (two 12-week efficacy trials and one 52-week long-term safety trial). In both 12-week efficacy trials, statistically significant improvement in the moderate to severe most bothersome symptom of dyspareunia was demonstrated and a statistically significant increase in the proportion of superficial cells and a corresponding statistically significant decrease in the proportion of parabasal cells on a vaginal smear was also demonstrated (p<0.0001 for both). In addition, the mean reduction in vaginal pH between baseline and Week 12 was statistically significant (p<0.0001).

OSPHENA carries a Boxed Warning for endometrial cancer and cardiovascular disease. In the endometrium, OSPHENA has estrogen agonistic effects. Use of unopposed estrogens increases the risk of endometrial cancer in women with a uterus and estrogen-alone therapy increases the risk of stroke and deep vein thrombosis. Hot flush, vaginal discharge, muscle spasms, genital discharge, and hyperhidrosis are common adverse reactions with OSPHENA.

In a cross-study comparison, single dose OSPHENA 60 mg tablet administered with a high fat/high calorie meal in postmenopausal women increased AUC_0-inf and C_max of ospemifene by 1.9- and 2.4-fold, respectively, compared to fasted administration. Elimination half-life and T_max were unchanged in the presence of food. The two Phase 3 studies and long-term endometrial safety study were conducted with food (no specific type indicated) and the proposed dosing instruction states OSPHENA be taken with food.

Ospemifene is highly (> 99%) bound to serum proteins. Following a single oral administration of ospemifene, T_max was approximately 2 hours and approximately 75% and 7% of the dose was excreted in feces and urine, respectively. Less than 0.2% of the ospemifene dose was excreted unchanged in urine. The mean terminal half-life of ospemifene in postmenopausal women is approximately 26 hours.

No dose adjustment of OSPHENA is required in women with mild or moderate hepatic impairment. The pharmacokinetics of ospemifene has not been studied in women with severe hepatic impairment; therefore, OSPHENA should not be used in women with severe hepatic impairment. No dose adjustment of OSPHENA is required in women with renal impairment.

Ospemifene is metabolized primarily by CYP3A4 and CYP2C9. CYP2C19 and other pathways also contribute to the metabolism of ospemifene. Ketoconazole 400 mg moderately increased the concentrations of ospemifene: AUC0-inf increased 1.4-fold and Cmax increased 1.5-fold. Fluconazole, a moderate CYP3A /strong CYP2C9 /moderate CYP2C19 inhibitor, increased the AUC_0-inf and C_max of ospemifene by 2.7- and 1.7-fold, respectively. Omeprazole, a moderate CYP2C19 inhibitor, increased both AUC_0-inf and C_max of ospemifene by 1.2-fold. Concomitant administration of fluconazole with ospemifene is not recommended. If ospemifene is co-administered with a drug(s) known to inhibit both CYP3A4 and CYP2C9, there may be an increased risk of adverse reactions.

Full prescribing information is available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203505s000lbl.pdf

By LaiMing Lee, Ph.D., Clinical Pharmacology Reviewer, Myong-Jin Kim, Pharm.D., Reproductive and Urologic Team Leader, Division of Clinical Pharmacology III, Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA

On March 27th, 2013, the FDA approved TECFIDERA (dimethyl fumarate, DMF) for the treatment of patients with relapsing forms of multiple sclerosis (MS). The exact mechanism by which DMF exerts its therapeutic effect is unknown. DMF and its metabolite, monomethyl fumarate (MMF), have been shown to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which is involved in the cellular response to oxidative stress. The recommended starting dose for TECFIDERA is 120 mg twice a day orally. After 7 days, the dose should be increased to the maintenance dose of 240 mg twice a day orally. TECFIDERA can be taken with or without food. Administration with food may reduce the incidence of flushing.

The safety and effectiveness of TECFIDERA were evaluated in two Phase 3 trials that assessed the effects of TECFIDERA 240 mg twice a day, 240 mg three times a day, or placebo in patients with relapsing-remitting multiple sclerosis (RRMS). The starting dose for TECFIDERA was 120 mg twice or three times a day for the first week, followed by an increase to 240 mg twice or three times a day. Titration was implemented in an attempt to alleviate flushing and gastrointestinal side effects. The primary endpoint was the proportion of patients relapsed at 2 years for one study, and the annualized relapse rate at 2 years for the other. TECFIDERA was shown to have a statistically significant effect compared to placebo in both studies. The 240 mg three times daily dose did not provide additional benefit over 240 mg twice daily dosing.

The most common adverse reactions for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea. TECFIDERA may decrease lymphocyte counts. Although the incidence of infections following treatment with TECFIDERA was similar to that in patients treated with placebo, a recent complete blood cell count (CBC) (i.e., within 6 months) is recommended before initiation of therapy to identify patients with pre-existing low lymphocyte counts.

After oral administration, DMF is not detectable in plasma. MMF is the only active metabolite of DMF. Following administration of TECFIDERA in the fasted state, the peak plasma concentration of MMF was reached in 2-2.5 hours on average. A high-fat meal decreased MMF peak concentration by 40% and increased the T_max from 2.0 to 5.5 hours, but had no effect on AUC. Intake of TECFIDERA with a high-fat meal mildly decreased the incidence of flushing (by approximately 25% in one study). In Phase 3 studies, patients were instructed to take TECFIDERA with food.

Following oral administration, the major elimination route of DMF is exhalation as CO₂, which accounts for approximately 60% of the dose. Renal and fecal excretion are minor routes of elimination, accounting for 16% and 1% of the administered dose, respectively, with a trace amount of unchanged MMF in urine. Though not studied, renal or hepatic impairment is not expected to affect the pharmacokinetics of MMF and no dose adjustments are recommended in these populations. Sex, age, and body weight did not significantly affect efficacy of TECFIDERA, thus, no dose adjustment is needed for these factors.

After oral administration, DMF is rapidly hydrolyzed to MMF by esterases before reaching systemic exposure. Metabolism of MMF occurs through the tricarboxylic acid cycle, which does not involve cytochrome P450 (CYP) system. MMF and DMF did not significantly inhibit or induce major CYP enzymes or P-glycoprotein. Single doses of interferon β-1a or glatiramer acetate had no effects on the pharmacokinetics of MMF when co-administered with TECFIDERA.

Full prescribing information is available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204063lbl.pdf

By, Jagan Parepally, Ph.D., Senior Clinical Pharmacologist, Xinning Yang, Ph.D., Acting Team Leader, Division of Clinical Pharmacology I, Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

In cooperation with the Food and Drug Administration (FDA), and as a service to our members, ACCP will periodically distribute information about newly approved therapies or significant changes to approved therapies. This helps the FDA to inform professionals in the patient care arena of recent approvals in a timely manner. Included in the e-mail from the FDA is a link to the product label, which will provide the relevant clinical pharmacology information on the indication, contraindications, dosing, and safety. In sending this information, ACCP does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.