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P T. 2013;38(5): 246-248, 258

Pharmaceutical Approval Update May 2013

Marvin M. Goldenberg PhD, RPh, MS

Dimethyl Fumarate Delayed-Release Capsules (Tecfidera, BG-12)

Manufacturer: Biogen Idec, Weston, Mass.

Indication: Dimethyl fumarate (DMF) has been approved for patients with relapsing forms of multiple sclerosis (MS).

Drug Class: DMF is the methyl ester of fumaric acid. It was initially recognized as an effective hypoxic cell radiosensitizer. Later, when combined with three other fumaric acid esters, DMF was licensed in Germany as an oral therapy for psoriasis (Fumaderm, Fumapharm AG). More recently, DMF (BG-12) successfully reduced relapse rates and time to progression of disability in patients with MS. DMF is thought to have immunomodulatory properties without significant immunosuppression.

The medication is an α,β-unsaturated electrophilic compound that can quickly undergo Michael additions with nucleophiles. DMF is also an effective diene acceptor in the ordinary Diels–Alder reaction, where the reactivity of its vinylidenic bond is enhanced by the two electron-withdrawing ester groups. Because of the geometry of the starting ester, the Diels–Alder product has a trans configuration. With this reaction, compounds with bicyclo-skeletons can be synthesized.

Uniqueness of Drug: The drug’s mechanism of action is thought to activate the nuclear factor–like-2 (NFR-2) transcriptional pathway, reducing oxidative stress (which contributes to demyelination) and protecting nerve cells from damage and inflammation. DMF is rapidly attacked by the detoxifying agent glutathione (GSH) in a Michael addition reaction. DMF is highly reactive: when administered orally, it does not survive long enough to be absorbed into blood without being attacked by GSH. However, part of it is hydrolyzed by esterases to produce monomethyl fumarate, which is more resistant. The depletion of GSH and the subsequent induction of the anti-inflammatory stress protein HO-1 are thought to be one of the mechanisms responsible for the immunomodulatory actions of DMF.

Warnings and Precautions:

Lymphocytopenia. DMF therapy may cause a decrease in lymphocyte counts. Before treatment is initiated, a complete blood count (CBC), taken within the previous 6 months, should be available. A CBC is recommended annually.

Flushing. DMF may cause warmth, redness, itching, or a burning sensation. Administration of DF with food may reduce the incidence of flushing.

Dosage and Administration: The recommended starting dose is one gelatin 120-mg capsule taken by mouth twice daily for 7 days. The recommended dose after 7 days is one 240-mg capsule taken by mouth twice daily. DMF can be taken with or without food, and it should be swallowed whole. Patients should not crush, chew, or sprinkle the capsule’s contents on food. The capsules should be protected from light and stored in their original container. If the product is opened, it should be discarded after 90 days.

Commentary: MS is a chronic, inflammatory, autoimmune disease of the central nervous system that disrupts communication between the brain and other parts of the body. For most patients, relapses are initially followed by remissions. Over time, recovery periods may be incomplete, leading to progressive decline in function and increased disability.

Biogen already sells the MS drugs interferon-beta 1a (Avonex) and natalizumab (Tysabri), which together account for about 30% of the market. Teva’s glatiramer acetate (Copaxone) is the current market leader, with a roughly 29% share and annual sales last year of more than $4 billion.

Unlike Copaxone, Avonex, and Tysabri, which are injected or infused, DMF (Tecfidera) is available in convenient capsule form. It will compete with fingolimod (Gilenya, Novartis). Although fingolimod was the first oral MS product to be marketed, it has been dogged by concerns about heart safety. Gilenya holds an 8.5% share of the market and generated worldwide sales of $1.2 billion in 2012. The cost is about $60,000 per patient per year.

Another competitor product is teriflunomide (Aubagio, Sanofi/Genzyme), which carries a boxed warning about a risk of liver problems. Aubagio is estimated to cost $48,000 per patient per year.


Ado-Trastuzumab Emtansine Injection (Kadcyla)

Manufacturer: Genentech, San Francisco, Calif.

Indication: Intravenous (IV) ado-trastuzumab emtansine is indicated for the treatment of patients with HER-2–positive, late-stage metastatic breast cancer who previously received trastuzumab (Herceptin) and a taxane, separately or in combination. Patients should have either received previous therapy for metastatic disease or experienced disease recurrence during or within 6 months of completing adjuvant therapy.

Drug Class: In this new class of drugs, toxins are linked to proteins known as monoclonal antibodies. The antibodies latch onto tumors and deliver the toxic payload. Because the toxin is not activated until it reaches the tumor, healthy cells are spared and some adverse effects are avoided. These medications are called antibody–drug conjugates.

This HER-2–targeted antibody–drug conjugate contains humanized anti–HER-2 immunoglobulin G1 (IgG1), trastuzumab, covalently linked to the microtubule inhibitory drug, DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC–DM1 complex. Trastuzumab is a recombinant monoclonal antibody produced by mammalian (Chinese hamster ovary) cells, and the small-molecule components (DM1 and MCC) are produced by chemical synthesis. Ado-trastuzumab contains an average of 3.5 DM1 molecules per antibody.

Uniqueness of Drug: Upon binding to subdomain IV of the HER-2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxic catabolites. Binding of DM1 to tubulin disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell death. In vitro studies have shown that ado-trastuzumab emtansine, similar to trastuzumab, inhibits HER-2 receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity (ADCC), and inhibits shedding of the HER-2 extra-cellular domain in human breast cancer cells that overexpress HER-2 protein.

Boxed Warning: Ado-trastuzumab emtansine should not be substituted for (or with) trastuzumab.

Hepatotoxicity. Serious reactions have included liver failure and death in treated patients. Serum transaminases and bilirubin should be monitored before each dose. The dose of ado-trastuzumab should be reduced or interrupted, as appropriate, in cases of elevated serum transaminase or total bilirubin levels.

Cardiac toxicity. Treatment with ado-trastuzumab emtansine may lead to reductions in left ventricular ejection fraction (LVEF). LVEF should be monitored in all patients before and during treatment. The drug should be withheld if LVEF decreases significantly.

Embryofetal toxicity. Exposure to ado-trastuzumab emtansine can result in embryofetal death or birth defects. Patients should be advised of these risks and the need for effective contraception before treatment.

Warnings and Precautions:

Hepatotoxicity. Asymptomatic, transient elevations in serum transaminases and serious hepatobiliary disorders have been observed in clinical trials with ado-trastuzumab emtansine. There were at least two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy. Some of the cases might have been confounded by patients’ comorbidities or concomitant medications with known hepatotoxic potential.

Serum transaminases and bilirubin levels should be monitored before treatment is initiated and before each dose. Patients with known active hepatitis B virus or hepatitis C virus infections were excluded from the randomized trial (Study 1). The dose should be reduced or discontinued, as appropriate, if transaminases or total bilirubin elevations occur.

Ado-trastuzumab emtansine should be permanently discontinued if serum transaminase levels exceed three times the upper limit of normal (ULN) and if bilirubin levels exceed twice the ULN. Ado-trastuzumab emtansine has not been studied in patients with serum transaminase levels above 2.5 times the ULN or with bilirubin levels above 1.5 times the ULN before treatment.

In clinical trials, nodular regenerative hyperplasia (NRH) of the liver was identified from liver biopsies in three of 884 patients. NRH is a rare hepatic condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules and may lead to noncirrhotic portal hypertension.

NRH should be considered in all patients with clinical symptoms of portal hypertension but with normal transaminase levels and no manifestations of cirrhosis. If NRH occurs, ado-trastuzumab emtansine should be permanently discontinued.

Left ventricular dysfunction. Patients receiving ado-trastuzumab emtansine are at an increased risk of left ventricular (LV) dysfunction. A decrease in LVEF to less than 40% has been observed. In Study 1, LV dysfunction occurred in 1.8% of patients receiving ado-trastuzumab emtansine and in 3.3% of patients receiving lapatinib (Tykerb, GlaxoSmithKline) plus capecitabine (Xeloda, Roche).

LVEF should be assessed before ado-trastuzumab emtansine therapy begins and at regular intervals (every 3 months) during treatment to ensure that LVEF readings are within the institution’s normal limits. Ado-trastuzumab emtansine has not been studied in patients with LVEF readings below 50% before treatment. If routine monitoring shows that the LVEF is below 40% or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, ado-trastuzumab emtansine should be withheld and LVEF function should be assessed again within approximately 3 weeks.

Therapy should be permanently discontinued if the LVEF has not improved or has declined further. Patients with a history of symptomatic congestive heart failure, serious cardiac arrhythmias, or a history of myocardial infarction (MI) or unstable angina within the previous 6 months were excluded from Study 1.

Embryofetal toxicity. Ado-trastuzumab emtansine can cause fetal harm when administered to pregnant women. No well-controlled trials of ado-trastuzumab emtansine have been conducted in pregnant women; however, the use of trastuzumab (the antibody component of ado-trastuzumab emtansine) during pregnancy in the postmarketing setting has resulted in oligohydramnios, with some associated with fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal deaths.

DM1 (the cytotoxic component of ado-trastuzumab emtansine) can be expected to cause embryofetal toxicity based on its mechanism of action. If ado-trastuzumab emtansine is used during pregnancy or if the patient becomes pregnant during treatment, she should be apprised of the potential hazard to the fetus.

Pregnancy status should be verified before ado-trastuzumab emtansine is initiated, and patients should be advised about the risk of embryofetal deaths and birth defects and the need for contraception during and after treatment. Women should contact their health care practitioner immediately if they suspect that they might be pregnant. They should be encouraged to enroll in the MotHER Pregnancy Registry if they are exposed to the drug during pregnancy.

Pulmonary toxicity. Interstitial lung disease has been reported in clinical trials with ado-trastuzumab emtansine, with some cases leading to acute respiratory distress syndrome or fatal outcomes. Pneumonitis has also been reported, with one case of grade 3 disease. Signs and symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates. These events may occur following infusion reactions. In Study 1, the overall frequency of pneumonitis was 1.2%. Treatment with ado-trastuzumab emtansine should be permanently discontinued in patients with interstitial lung disease or pneumonitis.

Patients with dyspnea at rest that is caused by complications of advanced malignancy and comorbidities may be at an increased risk of pulmonary toxicity.

Infusion and hypersensitivity reactions. Ado-trastuzumab emtansine has not been studied in patients who had to discontinue trastuzumab permanently because of infusion-related reactions or hypersensitivity; therefore, ado-trastuzumab emtansine is not recommended for these patients.

Infusion reactions characterized by flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, or tachycardia have been reported in clinical trials. In Study 1, the overall frequency of infusion reactions in patients treated with ado-trastuzumab emtansine was 1.4%. In most patients, these reactions resolved over the course of several hours to a day after the infusion was terminated. Treatment should be interrupted in patients with severe infusion-related reactions and should be permanently discontinued if a life-threatening infusion reaction occurs. Patients should be observed closely for these reactions, especially during the first infusion.

One case of a serious allergic or anaphylactic-like reaction was observed in clinical trials of single-agent ado-trastuzumab emtansine. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use.

Thrombocytopenia. Decreased platelet counts were reported in clinical trials, with most patients having grade 1 or 2 events. The nadir occurred by day 8 and generally improved to grade 0 or 1 by the next scheduled dose. In the trials, the incidence and severity of thrombocytopenia were greater in Asian patients. Independent of race, the incidence of severe hemorrhagic events in patients treated with ado-trastuzumab emtansine was low.

In Study 1, the overall frequency of thrombocytopenia was 31% in patients receiving ado-trastuzumab emtansine and 3% in patients receiving lapatinib plus capecitabine. The incidence of grade 3 thrombocytopenia or higher was 15% with ado-trastuzumab emtansine and 0.4% with lapatinib plus capecitabine. In Asian patients, the incidence of grade 3 thrombocytopenia or higher was 45% with ado-trastuzumab emtansine and 1% with lapatinib plus capecitabine.

Platelet counts should be monitored before initiation of ado-trastuzumab emtansine therapy and before each dose. Ado-trastuzumab emtansine has not been studied in patients with platelet counts below 100,000/mm3 before the initiation of treatment. If the platelet count falls to grade 3 or higher (less than 50,000/mm3) ado-trastuzumab emtansine should not be administered until counts recover to grade 1 (75,000/mm3 or higher). Patients with thrombocytopenia (100,000/mm3) and patients taking anticoagulants should be closely monitored during treatment.

Neurotoxicity. Peripheral neuropathy, predominantly sensory and mainly classified as grade 1, was reported in the clinical trials. In Study 1, the overall frequency of peripheral neuropathy was 21% with ado-trastuzumab emtansine and 14% with lapatinib plus capecitabine. The incidence of grade 3 or higher peripheral neuropathy was 2% with ado-trastuzumab emtansine and 0.2% with lapatinib plus capecitabine. For patients experiencing grade 3 or 4 peripheral neuropathy, ado-trastuzumab emtansine should be temporarily discontinued until the condition is resolved to grade 2 or lower. Patients should be monitored on an ongoing basis for signs or symptoms of neurotoxicity.

Dosage and Administration. Ado-trastuzumab emtansine is a sterile, white to off-white, preservative-free, lyophilized powder in single-use vials containing 100 mg or 160 mg. The recommended regimen is 3.6 mg/kg administered as an IV infusion every 3 weeks (on a 21-day cycle) until disease progression or unacceptable toxicity. The dose should not exceed 3.6 mg/kg, and the medication should not be substituted for or with trastuzumab.

Commentary: Approximately 20% of breast cancers contain increased amounts of HER-2 protein. Ado-trastuzumab emtansine is a drug that links toxins to proteins (monoclonal antibodies). HER-2 is found in increased amounts on some types of cancer cells (HER-2–positive), including some breast cancers. In these women, the increased amount of the HER-2 protein contributes to cancer cell growth and survival. The toxin in the medication is not activated until it reaches the tumor; therefore, healthy cells are generally not affected. In a clinical trial, the drug extended the median survival of women with advanced breast cancer by nearly 6 months.

Genentech lists an approximate price of $9,800 per month, or $94,000 for a typical course of treatment. That is about twice the price of the company’s trastuzumab (Herceptin), which was approved in 1998, but it is similar in price to other new cancer drugs. Other FDA-approved drugs used to treat HER-2–positive breast cancer include lapatinib (Tykerb), approved in 2007, and pertuzumab (Perjeta, Genentech), approved in 2012.


Ospemifene Tablets (Osphena)

Manufacturer: Shionogi, Florham Park, N.J.

Indication: Ospemifene is indicated for the treatment of moderate-to-severe dyspareunia (painful intercourse), a symptom of vulvar and vaginal atrophy occurring in postmenopausal women 50 to 79 years of age.

Drug Class: Ospemifene is an estrogen agonist/antagonist with tissue-selective agonistic effects on the endometrium. The chemical designation is Z-2-[4-(4-chloro-1,2-diphenylbut-1-enyl) phenoxy]ethanol. The drug’s molecular weight is 378.9. Taken with food once daily, the drug has some estrogen-like effects on vaginal tissues, making them thicker and less fragile and thus helping to reduce the amount of pain experienced during sexual intercourse.

Uniqueness of Drug: Biological actions are mediated through binding to estrogen receptors. This binding results in the activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). Generally, when a product with estrogen agonistic effects on the endometrium is prescribed for postmenopausal women with a uterus, a progestin should be considered to reduce the risk of endometrial cancer. Women without a uterus do not need a progestin.

Boxed Warning:

Endometrial cancer. There is an increased risk of endometrial cancer in women with a uterus who use unopposed estrogens. Adding a progestin to estrogen therapy reduces the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Diagnostic measures, including endometrial sampling, when indicated, should be undertaken to rule out malignancies in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

Cardiovascular disorders. The risk of stroke and deep vein thrombosis (DVT) was increased in postmenopausal women taking daily oral conjugated estrogens (0.625 mg) alone for a period of 7.1 years as part of the Women’s Health Initiative (WHI). Ospemifene should be prescribed for the shortest duration feasible.

Warnings and Precautions:

Cardiovascular disorders. Risk factors for cardiovascular disorders, arterial vascular disease (hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity), or venous thromboembolism (VTE) (personal or family history of VTE, obesity, and systemic lupus erythematosus), should be managed appropriately.

Stroke. In the WHI estrogen-alone substudy, an increased risk of stroke was reported in postmenopausal women 50 to 79 years of age receiving daily conjugated estrogens 0.625 mg alone compared with women in the same age group receiving placebo (45% vs. 33% per 10,000 women-years). The increase in risk was noted in year 1 and persisted.

In clinical trials lasting up to 15 months, the incidence rates of thromboembolic and hemorrhagic stroke were 0.72% and 1.5% per 1,000 women receiving ospemifene 60 mg and 1% and 0% per 1,000 women receiving placebo. If thromboembolic or hemorrhagic stroke occurs or is suspected, ospemifene should be discontinued immediately.

Coronary heart disease. In the WHI estrogen-alone sub-study, no overall effect on coronary heart disease (CHD) events (MI or CHD deaths) was reported in women receiving estrogen alone compared with those receiving placebo. In clinical trials, a single MI occurred in a woman receiving ospemifene 60 mg.

Venous thromboembolism. In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily conjugated estrogens 0.625 mg alone compared with women receiving placebo, although only the increased risk of DVT reached statistical significance. The increased risk of VTE was observed during the first 2 years.

In clinical trials, incidence rates for DVT were 1.45% per 1,000 women receiving ospemifene 60 mg and 1.04% per 1,000 women receiving placebo. If VTE occurs or is suspected, ospemifene should be discontinued immediately.

If feasible, ospemifene should be discontinued for at least 4 to 6 weeks before any surgical procedure that might be associated with an increased risk of thromboembolism or during periods of prolonged immobilization.

Malignant neoplasms.

Endometrial cancer. Ospemifene has agonistic effects in the endometrium. In women taking 60 mg, no cases of endometrial cancer were seen up to 52 weeks. There was a single case of simple hyperplasia without atypia. Endometrial thickening (5 mm or greater) was noted at a rate of 60% per 1,000 treated women and at a rate of 21% per 1,000 women receiving placebo. Incidence rates of proliferative endometrium changes were 86% per 1,000 women receiving the study drug and 13% per 1,000 women receiving placebo.

Uterine polyps occurred at incidence rates of approximately 6% per 1,000 treated women and at 2% per 1,000 women receiving placebo.

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about two to 12 times greater than that in non-users and appears to depend on the length of treatment and on the estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year.

The greatest risk appears to be associated with prolonged use, namely an increase by 15-fold to 24-fold for 5 to 10 years or more. This risk persists for at least 8 to 15 years after estrogen therapy is discontinued.

Adding a progestin to postmenopausal estrogen therapy decreases the risk of endometrial hyperplasia, considered a precursor to endometrial cancer. However, a risk of breast cancer might be associated with the use of progestins with estrogens, compared with estrogen-alone regimens. The use of progestins with ospemifene was not evaluated in the trials.

Clinical surveillance is important for all women using ospemifene. Endometrial sampling should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

Breast cancer. Ospemifene 60 mg has not been adequately studied in women with breast cancer. This medication, therefore, should not be used in women with known or suspected breast cancer or with a history of breast cancer.

Severe hepatic impairment. Ospemifene should not be prescribed for women with severe hepatic impairment.

Dosage and Administration: Ospemifene should be used for the shortest duration consistent with treatment goals and risks for each woman. Postmenopausal women should be reevaluated periodically to determine whether treatment is still necessary. The dose is one 60-mg tablet taken with food once daily.

Commentary: Dyspareunia is associated with declining levels of estrogen hormones during menopause. In 1990, a survey on the topic of sexual experience and dyspareunia was sent to 428 women, with 76% responding. Of the 313 evaluable responders, 39% had never had dyspareunia; 28% responded that it resolved either spontaneously or with treatment; 22% reported pain only rarely; 55% occasionally had discomfort; and 24% had dyspareunia frequently or virtually all the time. The frequency of intercourse did not differ among the groups, although 48% of the women reported a decrease in sexual frequency and 34% reported an important adverse effect on their relationships as a result of dyspareunia. Most of the women had not discussed dyspareunia with a health care professional and were unaware of the cause of their problem.

Severe dyspareunia affects more than 1 million women in the U.S. Possible causes include chlamydia, pelvic inflammatory disease, Peyronie’s disease, Sjögren’s syndrome, and trichomoniasis.

Dyspareunia is best treated by a health care skilled physician. A physical examination allows the identification of organic factors that may contribute to the dyspareunia, and laboratory tests are required to make the initial diagnosis.

Sources:; Medscape, March 20, 2013,;