Novartis To Pull Valturna From U.S. Market As FDA Warns Of Risks With Aliskiren Meds
This article was originally published in The Pink Sheet Daily
Executive Summary
FDA warns that use of aliskiren-containing blood pressure drugs with ACE inhibitors or angiotensin receptor blockers may increase risk of kidney impairment, hypotension and hyperkalemia; Novartis to continue to sell four other aliskiren products.
Novartis Pharmaceuticals Corp. is withdrawing its hypertension drug Valturna (aliskiren/valsartan) from the U.S. market in response to an FDA finding of increased risks when aliskiren products are taken with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with diabetes or kidney impairment. The company will continue to market its four other aliskiren-containing drugs with revised labeling.
FDA announced on April 20 that it had conducted a review of preliminary data from a clinical study called ALTITUDE in which the risks of kidney impairment, low blood pressure and high potassium blood levels increased in patients taking these drug combinations relative to those patients taking a placebo plus an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.
The agency said preliminary data from the study also demonstrated a slight excess of cardiovascular events (death or stroke) in the aliskiren group but added that “FDA has reached no definite conclusion regarding an actual link between these drugs and death.” The agency said it will evaluate the final ALTITUDE trial results and the results from other aliskiren trials.
Novartis sent a letter to health care professionals informing them that the company, in consultation with FDA, had decided to voluntarily cease marketing Valturna. The drug will be available until July 20 to give physicians time to switch patients to an alternative treatment. The components of the drug – aliskiren and Diovan (valsartan) – will continue to be sold separately.
Valsartan is itself an angiotensin receptor blocker so its combination with aliskiren would be problematic given the new labeling. A blockbuster important to Novartis’ bottom line, Diovan goes off patent later this year.
In a “Frequently Asked Questions” document, Novartis said that after discussions with FDA, the company decided to remove Valturna from the U.S. market “to make it less likely that this medicine is used by a patient population who should not be taking it.” Valturna is available only in the U.S.
Aliskiren Drugs Without An ARB Component Will Remain On Market
Novartis will continue to market Tekturna (aliskiren), Tekturna HCT (aliskiren/hydrochlorothiazide), Tekamlo (aliskiren/amlodipine) and Amturnide (aliskiren/amlodipine/hydrochlorothiazide) with new labeling.
The revised labeling will include a contraindication against use of the drugs with ARBs or ACE inhibitors in patients with diabetes and a warning against their use in patients with moderate renal impairment who are also taking an ARB or ACE inhibitor.
In its letter to health care providers, Novartis said it believes the four remaining drugs “will continue to be important treatment options for the management of high blood pressure.”
Novartis dealt with a double dose of negative labeling news. The same day FDA issued a warning about its aliskiren products, Novartis announced it had reached an agreement with the agency to change the labeling for its multiple sclerosis drug Gilenya (fingolimod). The new labeling will state that patients should have an electrocardiogram prior to the first dose and six hours after the first dose (Also see "EU And U.S. Regulators Toughen CV Monitoring Requirements For Novartis's Gilenya" - Pink Sheet, 20 Apr, 2012.).
The European Medicines Agency also reviewed the ALTITUDE study and in February recommended that aliskiren-containing medicines be contraindicated in both patients with diabetes and those with moderate to severe renal impairment who are taking ARBs or ACE inhibitors (Also see "EU's CHMP Warns About Boceprevir In HIV, Aliskiren In Diabetes, But Clears Orlistat And Reinstates Trasylol" - Pink Sheet, 17 Feb, 2012.).
FDA explained that the purpose of ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) was to determine whether aliskeren compared to placebo, on top of conventional treatment, reduces death and disease caused by the heart, circulatory system and kidney. A total of 8,579 patients with type 2 diabetes and renal disease were randomized to aliskiren 300 mg daily or placebo, and all received an ARB or ACE inhibitor.
The primary efficacy endpoint was the time to the first event of the primary composite endpoint, which consisted of cardiovascular death, resuscitated sudden death, non-fatal myocardial infarction, non-fatal stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease, renal death, and doubling of serum creatinine concentration from baseline sustained for at least one month.
FDA said that after a median patient follow up of about 27 months, the trial was terminated early for lack of efficacy. The incidence of a serious adverse renal event was 4.7% in the aliskiren group and 3.3% in the placebo group. The incidence of any adverse renal event was 12.4% in the aliskiren group and 10.4% in the placebo group.
For hypotension, the incidence of a serious adverse event was 2% in the aliskiren group and 1.7% in the placebo group, and the incidence of any adverse event was 18.6% in the aliskiren group and 14.8% in the placebo group. For hyperkalemia, the incidence of serious adverse event was 1.1% in the aliskiren group and 0.3% in the placebo group, and the incidence of any adverse event was 36.9% in the aliskiren group versus 27.1% in the placebo group.
Aliskiren is a renin inhibitor used to treat hypertension by lowering blood pressure. FDA noted that in 2011 approximately 2.4 million prescriptions for aliskiren-containing products were dispensed to 451,000 patients from U.S. outpatient retail pharmacies. Valturna’s 20011 net sales were approximately 10% of Tekturna net sales of $557 million.
At one time, Novartis had considered developing Tekturna for treatment of diabetic kidney disease (Also see "Phase III Tekturna Diabetes Data Could Further Differentiate Drug From Competing Hypertension Products" - Pink Sheet, 5 Nov, 2007.).