International Approvals: Isentress, WinRho SDF, Cyanokit

Yael Waknine

December 17, 2007

December 17, 2007 -- Health Canada has approved raltegravir tablets with other antiretroviral agents for the treatment of multidrug-resistant HIV-1 infection and a ready-to-use liquid formulation of a Rho (D) intravenous immune globulin [human] product for the treatment of immune thrombocytopenic purpura; the European Commission has approved a hydroxocobalamin kit for the treatment of known or suspected cyanide poisoning.

Raltegravir ( Isentress ) for Adults With Multidrug-Resistant HIV in Canada

On November 11, Health Canada approved raltegravir tablets ( Isentress, Merck Frosst Canada, Ltd) with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adults who have evidence of replication and multidrug-resistant viral strains. The approval was granted with conditions, pending the results of studies confirming clinical benefit.

" Isentress will definitively play an important role in the management of patients who have developed resistance against first-line therapies and furthermore will be welcomed by physicians and patients because it is effective, well-tolerated, and has few side effects," says Mark Wainberg, MD, director, McGill AIDS Centre and professor of medicine and microbiology at McGill University in Montreal, Quebec, in a company news release.

Raltegravir is the first in a class of antiretroviral agents known as HIV-integrase strand transfer inhibitors (HIV-1 INSTIIs) that are designed to slow HIV-1 progression by blocking the integrase enzyme required for viral insertion into human DNA. The recommended dose is 400 mg (1 tablet), taken twice daily either with or without food; no ritonavir boost is necessary for effect.

The approval was based on promising 24-week data from 2 double-blind, placebo-controlled studies (BENCHMRK 1 and BENCHMRK 2) of 699 highly antiretroviral treatment--experienced patients infected with HIV-1 who were aged 16 years and older and who had documented resistance to at least 1 non--nucleoside reverse transcriptase inhibitor, nucleotide reverse transcriptase inhibitor, and protease inhibitor.

A pooled analysis of results revealed that the addition of twice-daily raltegravir to optimized background therapy (OBT) yielded viral loads of less than 400 and 50 HIV-1 RNA copies/mL in 75.5% and 62.6% of patients, respectively, compared with 39.3% and 33.3% of those receiving OBT alone.

In addition, patients experienced significant decreases from baseline in HIV-1 RNA viral load (--1.85 vs --0.84 log 10 HIV-1 RNA copies/mL) and significant increases in CD4+ cell counts (+89 vs +35 cells/mm 3).

The most commonly reported adverse experiences included diarrhea (16.6% vs 19.5% OBT alone), nausea (9.9% vs 14.2%), headache (9.7% vs 11.7%), and pyrexia (4.9% vs 10.3%).

Raltegravir previously was approved by the US Food and Drug Administration on October 12, 2007.

Ready-to-Use Liquid Formulation of Rho (D) IgG ( WinRho SDF) for Immune Thrombocytopenic Purpura in Canada

On November 23, Health Canada approved a liquid formulation of a Rho (D) intravenous immune globulin [human] product ( WinRho SDF, Cangene Corp, distributed by Canadian Blood Services and Héma-Québec) as an alternative to the lyophilized version that requires reconstitution before administration.

"Ease of administration can be an important feature for a drug, and liquid formulations offer increased convenience to physicians," says Dr. John Langstaff, Cangene's president and CEO, in a company news release.

The plasma-derived gamma globulin fraction contains antibodies to the Rho (D) antigen of red blood cells and is indicated for the treatment of immune thrombocytopenic purpura and the prevention of hemolytic disease ofthe newborn.

The liquid formulation previously was approved by the US Food and Drug Administration in April 2005.

Hydroxocobalamin Kit ( Cyanokit ) to Treat Cyanide Poisoning in EU

On November 29, the European Commission approved a hydroxocobalamin kit ( Cyanokit, Merck Serono, a division of Merck KGaA) for the treatment of known or suspected cyanide poisoning.

Cyanide poisoning is primarily caused by smoke inhalation during closed-space structural fires, but it can also be caused by unintentional or intentional ingestion, inhalation, dermal exposure during industrial accidents, or terrorist attacks involving the poison.

Without adequate treatment, exposure to a high dose of cyanide leads to the inhibition of cytochrome oxidase, leading to arrested cellular respiration and death. Each hydroxocobalamin molecule binds to 1 cyanide ion to form cyanocobalamin, which is then renally excreted.

"Clinical data show that Cyanokit is very effective in treating cyanide poisoning, even in patients with extremely toxic levels of cyanide in their bodies, as well as in complex clinical settings including smoke inhalation, in which the presence of cyanide is always presumptive," says Frédéric Baud, MD, professor of critical care medicine at Lariboisiére Hospital, Paris University VII, in a company news release.

The approval was based in part on data from 4 uncontrolled clinical studies of 245 known or suspected cyanide poisoning victims who received the antidote. The overall survival rate for 213 patients with known outcomes was 58%. Most ]patients (63 [71%] of 89) who died were initially found in cardiac arrest, suggesting irreparable brain damage before treatment.

However, 118 (82%) of the 144 patients not in initial cardiac arrest survived, including 21 (62%) of 34 patients with known cyanide concentrations above the lethal threshold (≥100 µmol/L).

Follow-up assessments for 96 of 171 patients who presented with neurologic symptoms before treatment showed that 51 (53%) experienced improvement or complete restoration.

The starting dose of hydroxocobalamin is 5 g (2 vials), administered as an intravenous infusion for 15 minutes (about 15 mL/minute). Depending on the severity of the poisoning and clinical response, a second 5-g dose can be administered for 15 minutes to 2 hours.

The most commonly reported adverse events include reversible discoloration of the urine, mucus membrane, and skin; rash; increased blood pressure; gastrointestinal effects; headache; decreased white blood cell count; and injection site reactions.

The cyanide antidote previously was approved by the US Food and Drug Administration and the Japanese Health Authority in December 2006 and September 2007, respectively.

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