Tracleer and PPH News
International Approvals: Tasmar, Amplimexon, IV Remodulin
Yael Waknine
Jan. 17, 2006 — Tolcapone tablets have been reintroduced in the UK market after a 7-year suspension by the European Medicines Evaluation Agency; the European Commission has approved orphan drug status for imexon injection in the treatment of ovarian cancer; and Israel has approved treprostinil sodium injection for intravenous administration in the treatment of pulmonary arterial hypertension.
Tolcapone (Tasmar) Reintroduced to UK Market After 7-Year EU Suspension
On January 9, tolcapone (Tasmar tablets, made by Valeant Pharmaceuticals) was reintroduced in the United Kingdom after a 7-year suspension from the market in the European Union (EU).
The selective, potent, and reversible catechol-O-methyltransferase (COMT) inhibitor is indicated for use in combination with levodopa/benserazide or levodopa/carbidopa in patients with idiopathic Parkinson's disease (PD) and motor fluctuations who are unresponsive to or intolerant of other COMT inhibitors.
Tolcapone was suspended from the EU market by the European Medicines Evaluation Agency (EMEA) in November 1998 due to the risks for neuroleptic syndrome and rare but potentially fatal acute hepatotoxicity. The action followed 3 deaths from liver injury in elderly women whose liver function had not been assessed prior to initiation of therapy, and who had not been monitored during treatment as directed. In a fourth woman, symptoms of liver dysfunction resolved completely upon discontinuation of therapy.
The ban was lifted on the basis of data from an international 32-center, double-blind study in 150 patients optimized on levodopa and entacapone who were randomized to continue on entacapone or switch to tolcapone. Results showed that substitution of tolcapone led to improvement for 1.6 hours daily compared with 0.8 hours for entacapone. The frequency and severity of adverse events were similar between groups.
Because of the potential risks associated with its use, tolcapone may only be prescribed by physicians experienced in the management of severe PD. The recommended daily dose is 100 mg in combination with levodopa treatment, although a maximum 200-mg dose may be used in exceptional circumstances.
Liver function should be determined at baseline and then every 2 weeks for the first year of therapy, every 4 weeks for the next 6 months, and every 8 weeks thereafter.
Tolcapone was approved by the US Food and Drug Administration in January 1988 for use as an adjunct to levodopa and carbidopa for the treatment of signs and symptoms of idiopathic PD; the recommended schedule for monitoring of hepatic function is similar to that approved in Europe.
Orphan Drug Imexon (Amplimexon) for Ovarian Cancer in EU
On January 11, the European Commission approved a new orphan drug indication for imexon injection (Amplimexon, made by AmpliMed Corporation), allowing its use in the treatment of ovarian cancer.
Imexon is an injectable formulation of a cyanoaziridine compound that functions as a potent mitochondrial oxidant, scavenging glutathione and other sulfhydryl-containing compounds and inducing apoptosis.
The approval was based on the results of preclinical efficacy studies demonstrating the product's ability to kill ovarian cancer cells at doses that can be achieved in humans.
Imexon has also demonstrated synergistic effects with common cancer therapies such as docetaxel and platinum-containing agents. According to a company news release, study results suggest that imexon may resensitize certain types of ovarian cancer to these therapies, thereby overcoming drug resistance and extending the period of clinical response.
In prior human trials, imexon was well-tolerated and effective, with moderate myelosuppressive effects only at the highest doses. Full doses can be used in combination with other cytotoxic drugs and in patients with compromised bone marrow function.
Imexon injection was previously approved by the US Food and Drug Administration as an orphan drug for the treatment of ovarian cancer, metastatic malignant melanoma, multiple myeloma, and pancreatic cancer.
It is currently in phase 1/2 clinical studies in combination with gemcitabine for the first-line treatment of advanced pancreatic adenocarcinoma; with dacarbazine for the treatment of metastatic melanoma in chemotherapy-naive patients; with docetaxel injection for the treatment of lung, breast, and prostate cancer; and as monotherapy for refractory multiple myeloma.
Intravenous Use of Treprostinil Sodium (Remodulin) for PAH in Israel
On January 10, the Drug Registration Department of Israel's Ministry of Health approved a new route of administration for treprostinil sodium injection (Remodulin, made by United Therapeutics Corporation and distributed by Pharmateam Marketing), allowing its use as an intravenous infusion for the treatment of primary pulmonary arterial hypertension (PAH) and PAH associated with connective tissue disorders.
Intravenous use of treprostinil was previously approved by the US Food and Drug Administration and the Canadian Therapeutic Products Directorate in November 2004 and October 2005, respectively. According to a company news release, it is currently under consideration for approval by France's Ministry of Health.
Reviewed by Gary D. Vogin, MD
Long-term bosentan safe for pulmonary hypertension in congenital heart disease
By David Douglas
Aug. 17, 2007 - NEW YORK (Reuters Health) - The dual receptor endothelin antagonist bosentan appears to be safe and well tolerated in patients with pulmonary arterial hypertension associated with congenital heart disease, particularly those with Eisenmenger's syndrome, UK and German researchers report in the August issue of Heart.
In fact, senior investigator Dr. Michael A. Gatzoulis told Reuters Health. "bosentan has revolutionized the management of patients with Eisenmenger's syndrome, and opens new therapeutic opportunities for these very limited patients, including other advanced forms of oral therapy currently under investigation."
Dr. Gatzoulis of Royal Brompton Hospital, London and colleagues conducted a retrospective examination of data on 18 patients with congenital heart disease and associated pulmonary hypertension. Fifteen of this group had Eisenmenger's syndrome.
Following titration, most patients were given 125 mg of bosentan twice daily. One received 62.5 mg twice daily after experiencing dizziness with the higher dose.
Arterial oxygen saturation remained stable over the median 29-month follow-up period. Mean functional class improved significantly during follow-up. None of the patients felt worse during follow-up, although 1 patient died during this period.
The 6-minute walk distance rose from 284 meters at baseline to 363 meters within 6 months, 380 meters after a year and 408 meters after 2 years of treatment.
As well as indicating that the agent is safe and effective, concluded Dr. Gatzoulis, "the long-term data also challenge the notion that patients with Eisenmenger's complex had irreversible pulmonary vascular disease."
Heart 2007;93:974-976.
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