Copaxone Approved for Multiple Sclerosis

Teva Pharmaceutical Industries Ltd. today announced that the U.S. Food and Drug Administration (FDA) has approved an expanded indication for Copaxone (glatiramer acetate injection) to include the treatment of patients who have experienced a first clinical episode and have magnetic resonance imaging (MRI) features consistent with multiple sclerosis (MS). The FDA's approval follows a similar decision by the Medicines and Healthcare Products Regulatory Agency (MHRA) in February 2009 under which 24 EU member states have mutually recognized an expanded label for Copaxone to include the treatment of patients with clinically isolated syndrome (CIS) suggestive of MS. Up to 85% of MS patients initially experience a single neurological event suggestive of MS, known as CIS, and it has been demonstrated that early treatment initiation delays conversion from CIS to clinically definite MS (CDMS). This expanded indication in the U.S. and Europe allows patients to begin treatment with Copaxone from the very early stages of the disease. "Copaxone, the world's leading MS disease modifying therapy, has demonstrated the ability to provide treatment benefits very early on, when patients present with a first clinical episode and have MRI features consistent with MS," said Moshe Manor, Teva's Vice President, Global Branded Products, "This milestone, along with the existing long-term safety and efficacy data, further position Copaxone as a cornerstone in MS treatment." The FDA granted approval after reviewing the results of the PreCISe study, which indicated time to development of a second exacerbation was significantly delayed in patients treated with Copaxone compared to placebo (Hazard Ratio = 0.55; 95% Confidence Interval 0.40 to 0.77; p=0.0005). The cumulative probability of developing the second attack during the three year study period was significantly lower in the Copaxone group versus the placebo group (24.7% vs. 42.9%). Copaxone is the only RRMS treatment with prospective long-term data demonstrating 8 out of 10 patients adhering to therapy are still able to walk unassisted after 15 years of therapy and 22 years of disease duration. An approval for an expanded label for Copaxone was also granted by the Australian Health Authority (Therapeutic Goods Administration, TGA) in December 2008.

Tyramine Study

The tyramine study, submitted to the FDA as the basis for the change in the prescribing information, supported the selectivity of Azilect for inhibition of MAO-B at approved doses, 1 mg and 0.5 mg. Non selective MAO inhibitors may interfere with the breakdown and elimination of tyramine in the body, which can induce hypertensive reactions. The tyramine study was a double-blind, placebo-controlled, randomized, dose-ranging study of rasagiline using a positive control (phenelzine), a known non-selective MAO inhibitor, and a comparator drug (selegiline). This study was part of a Phase IV commitment to the FDA at the time of Azilect approval. The study results were based on Tyramine Sensitivity Factor (TSF), which measures the ratio of tyramine pressor dose before (baseline) and after MAO inhibitor administration. In the study, 179 healthy male and female volunteers, aged 40 to 70 years received escalating doses of oral tyramine from 25 mg up to 800 mg administered under fasting conditions. TSF was calculated as the tyramine dose associated with three consecutive increases from baseline in systolic blood pressure (SBP) 30 mm Hg over 10 minutes (tyramine pressor dose) in period one divided by the dose associated with the same change in SBP in period three. Geometric mean TSFs of all doses of rasagiline were substantially lower than the TSF for phenelzine. TSFs of various doses of rasagiline were comparable to those of selegiline and placebo. Azilect (rasagiline tablets) is indicated for the treatment of the signs and symptoms of Parkinson's disease (PD) as initial therapy alone and to be added to levodopa later in the disease. Azilect is now available in 39 countries, including the U.S., Canada, Israel, Mexico and all of the European Union countries, where it is marketed by Teva in collaboration with Lundbeck A/S as part of a long-term strategic alliance. Parkinson's disease is an age-related degenerative disorder of the brain. Symptoms can include: tremor, stiffness, slowness of movement, and impaired balance. An estimated five million people worldwide suffer from the disease, with an average age of onset of about 60 years.

Newly Revised Prescribing Information for Azilect

eva Pharmaceutical Industries, Ltd. today announced the U.S. Food and Drug Administration (FDA) approved the newly revised prescribing information for Azilect (rasagiline tablets) reducing medication and food restrictions. This update was based on clinical data that confirmed the mechanism of action of Azilect as a selective MAO-B (monoamine oxidase-B) inhibitor at the recommended doses of 1 mg and 0.5 mg. The newly approved prescribing information reflects reduced concerns regarding the use of Azilect together with certain medications, including many over-the-counter cough/cold medications. In addition, patients taking Azilect no longer need to follow a general dietary restriction of ordinary levels of tyramine, an amino acid found in certain foods and beverages, such as air-dried and fermented meats, aged cheeses and most soybean products. However, due to potential mild increased sensitivity in some patients, ingestion of very high levels of tyramine (e.g., >150 mg) should be avoided by patients taking MAO inhibitors. "The FDA's decision to modify the Azilect prescribing information emphasizes the benefit to patients of Azilect MAO-B selectivity at recommended doses," said Daniel Kremens, M.D., Assistant Professor of Neurology and Co-Director of the Parkinson's Disease and Movement Disorders Division at Jefferson Medical College of Thomas Jefferson University in Philadelphia. "This is good news for patients and physicians as it reconfirms the safety and convenience of Azilect." "We are pleased with this important change in the prescribing information of Azilect as it removes a barrier for some physicians, and some patients, living with Parkinson's disease," said Jon Congleton, VP and General Manager, U.S., Teva Neuroscience. "Physicians can now better focus on what is really most important, which is helping patients receive a proven efficacious and safe treatment, at diagnosis early in Parkinson's disease, and throughout the course of the disease."

Final approval for generic version of Neurontin

Alpharma Inc. announced that its subsidiary Purepac Pharmaceutical Co. has received final approval from the FDA for gabapentin capsules, 100 mg, 300 mg, and 400 mg. Alpharma's gabapentin capsules, to be marketed under the Purepac brand, are the generic equivalent of Neurontin brand capsules, marketed by Pfizer. In January 2003, Alpharma announced that Purepac Pharmaceutical Co. received confirmation from the FDA that it was eligible for 180-day market exclusivity on gabapentin 100 mg, 300 mg and 400 mg capsules. The company also previously announced that the FDA's position on exclusivity is being challenged by Torpharm, Inc. The Torpharm action is presently before the U.S. Court of Appeals for the District of Columbia based upon a ruling by the District Court upholding the FDA's exclusivity determination. Unless the Court of Appeals should hold in favor of Torpharm, Purepac's exclusivity for this product will be triggered by the earlier of either Purepac's commercial marketing of gabapentin or a court decision holding the relevant Pfizer gabapentin patent invalid or not infringed. The company has not yet received a trial date in the litigation with Pfizer regarding gabapentin and has not announced a launch date for this product. While the January 2003 FDA ruling on capsules did not address the tablet form of gabapentin, the company expects the FDA position on market exclusivity for the 600 mg and 800 mg gabapentin tablets to be consistent with its position on capsules. Neurontin capsules and tablets are indicated as adjunctive therapy in the treatment of partial seizures of epilepsy and post-herpetic neuralgia.

Considerations for Physicians

Data from 199 placebo-controlled clinical studies covering eleven different antiepileptic drugs were reviewed and analyzed for reports of suicidal behavior (completed suicides, suicide attempts and preparatory acts) and suicidal ideation. The studies examined the effectiveness of the drugs in epilepsy, psychiatric disorders (e.g., bipolar disorder, depression and anxiety) and other conditions (e.g., migraine and neuropathic pain syndromes). The analysis included a total of 43,892 patients ages five and older (27,863 in drug treatment groups and 16,029 in placebo groups). There was a statistically significant increased risk of suicidal behavior and suicidal ideation in the patients randomized to receive an antiepileptic drug compared to patients who received a placebo. The estimated overall risk was about twice that of the placebo group. There were an estimated 2.1 per 1000 (95% CI: 0.7, 4.2) more patients in the drug treatment groups who experienced suicidal behavior or ideation than in the placebo groups. Four of the patients who were taking one of the antiepileptic drugs committed suicide, whereas none of the patients in the placebo group did. The increased risk of suicidal behavior and suicidal ideation was observed at one week after starting the drug and continued to at least 24 weeks. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be reliably assessed. FDA will be working with manufacturers of marketed antiepileptic drugs to include this new information in the labeling for these products. FDA is also planning to discuss these data at an upcoming advisory committee meeting. All patients treated with antiepileptic drugs should be monitored for suicidality and other unusual changes in behavior. Symptoms such as anxiety, agitation, hostility, mania and hypomania may be precursors to emerging suicidality.

Antiepileptic Drugs

FDA informed healthcare professionals that the Agency has analyzed reports of suicidality (suicidal behavior or ideation) from placebo-controlled clinical studies of eleven drugs used to treat epilepsy as well as psychiatric disorders, and other conditions. In the FDA's analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs. The relative risk for suicidality was higher in patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions. Healthcare professionals should closely monitor all patients currently taking or starting any antiepileptic drug for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression. The drugs included in the analyses include (some of these drugs are also available in generic form): Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR) Felbamate (marketed as Felbatol) Gabapentin (marketed as Neurontin) Lamotrigine (marketed as Lamictal) Levetiracetam (marketed as Keppra) Oxcarbazepine (marketed as Trileptal) Pregabalin (marketed as Lyrica) Tiagabine (marketed as Gabitril) Topiramate (marketed as Topamax) Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon) Zonisamide (marketed as Zonegran) Although the 11 drugs listed above were the ones included in the analysis, FDA expects that the increased risk of suicidality is shared by all antiepileptic drugs and anticipates that the class labeling changes will be applied broadly.

Neurontin for post-herpetic neuralgia

Pfizer has received approval from the U.S. Food and Drug Administration to market Neurontin (gabapentin) for the management of post-herpetic neuralgia (PHN). PHN is most commonly described as pain in the area affected by herpes zoster, persisting at least three months after healing of the herpes zoster skin rash. Herpes zoster is a painful viral infection also known as shingles. Patients variously describe this intense pain as "burning," "deeply aching," "tearing," and "electric shock-like". In the United States alone, more than one million new cases of herpes zoster are diagnosed each year. Approximately 10 percent to 15 percent of all patients with herpes zoster develop PHN, which, once established, can persist for many years. Neurontin is the first oral medication approved in the U.S. for this condition. Discovered and developed by Warner-Lambert, which merged with Pfizer in 2000, Neurontin was first approved by the FDA in 1993 as an add-on treatment for partial epileptic seizures. More than 8 million patients have been prescribed Neurontin in the United States since its approval. Neurontin also is approved in more than 50 countries for the adjunctive treatment of epilepsy and for a range of neuropathic pain conditions.