International Approvals: Ralivia, Rasilez, Avastin

Yael Waknine

September 10, 2007

September 10, 2007 -- Health Canada has approved a once-daily, extended-release formulation of tramadol HCl tablets for the management of continuous, moderately severe pain. The European Commission has approved aliskirin 150- and 300-mg tablets for use alone or with other agents in the treatment of hypertension, as well as a new indication for bevacizumab infusion, allowing its use with chemotherapy in the first-line treatment of non-small cell lung cancer.

Once-Daily Tramadol HCl Tablets ( Ralivia) for Pain Management in Canada

On September 4, Health Canada approved a once-daily, extended-release formulation of tramadol HCl tablets ( Ralivia, Biovail Corp) for the management of moderately severe pain in patients who require continuous treatment for several days or more.

The product uses proprietary Smartcoat technology to provide sustained drug release that maintains blood levels within the therapeutic range for 24 hours, thereby potentially reducing the incidence and severity of adverse events while maintaining efficacy.

According to a company news release, the drug's approval was based on data from a 4 controlled trials of more than 3000 patients who received doses of up to 400 mg daily. The clinical program also included 12 definitive and 5 supportive pharmacokinetic studies. Adverse events most commonly reported included dizziness, nausea, constipation, and headache.

The tablets are expected to be available shortly in 100-, 200-, and 300-mg strengths and are identical to a product previously approved by the US Food and Drug Administration in September 2005 ( Ultram, Biovail, marketed by Ortho-McNeil, Inc [a Johnson & Johnson company]).

Aliskirin Tablets ( Rasilez) for Management of Hypertension in EU

On August 27, the European Commission approved aliskirin 150- and 300-mg tablets ( Rasilez, Novartis AG) for use alone or with other agents in the treatment of hypertension. The approval was based on data from 44 clinical trials (n > 7800) and extends to all 27 member states of the European Union as well as Iceland and Norway.

Aliskiren, the first in a new class of drugs called direct renin inhibitors, has been demonstrated to reduce blood pressure for a 24-hour dosing interval. Studies have also shown its use in adding to the therapeutic efficacy of the diuretic hydrochlorothiazide and the angiotensin-receptor blocker valsartan.

Adverse events most commonly reported in clinical trials included diarrhea (dose related and generally mild and brief), headache, and nasopharyngitis. Women and the elderly appeared more susceptible to diarrhea, with incidence rates at the 150-mg/day dose matching those for 300-mg/day therapy in men and younger patients (2.0% - 2.3% vs placebo, 1%).

The recommended starting dose of aliskiren is 150 mg given once daily; because high-fat meals decrease absorption substantially, patients should be advised to establish a routine pattern for taking the drug with respect to meals. Most (85% - 90%) of the therapeutic effect is attained by 2 weeks, and uptitration to a 300-mg dose may be required for additional response. Doses greater than 300 mg have been observed to increase the risk for diarrhea without increasing blood pressure response and are therefore not recommended.

No initial dose adjustments are required for the elderly or patients with mild-to-severe renal impairment or hepatic insufficiency. However, concomitant use of aliskiren may significantly reduce furosemide exposure and, potentially, its efficacy.

As with all drugs that act on the renin-angiotensin system, aliskiren should not be used in pregnant women because of the risk for fetal and neonatal morbidity and mortality.

Aliskirin (marketed as Tekturna) previously was approved by the US Food and Drug Administration in March 2007. According to a company news release, its use is being evaluated in hypertensive patients with heart or kidney failure.

Bevacizumab ( Avastin) Plus Chemotherapy for First-Line Lung Cancer Therapy in EU

On August 24, the European Commission approved a new indication for bevacizumab intravenous infusion ( Avastin, Roche), allowing its use with platinum-based chemotherapy for the first-line treatment of advanced non-small cell lung cancer (NSCLC).

NSCLC is usually diagnosed at an advanced stage, leaving patients with a life expectancy of 8 to 10 months. According to a company news release, bevacizumab is the only first-line therapy to have shown improved survival benefits beyond 1 year in this population.

Approval of the indication was based in part on data from a phase 3 US study (E4599) of 878 chemotherapy-naive patients, showing that the addition of 15 mg/kg bevacizumab every 3 weeks to chemotherapy increased overall survival by 25% compared with chemotherapy alone (12.3 vs 10.3 months; hazard ratio, 0.80; 95% confidence interval, 0.68 - 0.94). Adverse events most commonly reported in bevacizumab-treated patients included hypertension (5.6%), dyspnea (5.6%), fatigue (5.1%), and proteinuria (4.2%); 2.3% of patients developed pulmonary hemorrhage/hemoptysis compared with 0.5% of those receiving chemotherapy alone (related deaths, 7 vs 1).

These data were supported by findings from the international phase 3 Avastin in Lung (AVAiL) study of more than 1000 patients, showing that the addition of 7.5 or 15 mg/kg bevacizumab to cisplatin/gemcitabine increased progression-free survival by 20% to 30% compared with chemotherapy alone. Bevacizumab previously was approved for this indication by the US Food and Drug Administration in October 2006; additional US indications include first- and second-line treatment of metastatic colorectal cancer.

Previously approved European indications include use for the first-line treatment of metastatic colorectal and breast cancer.

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