Ziagen receives traditional approval status from FDA

RESEARCH TRIANGLE PARK, N.C., April 16, 2004 -- GlaxoSmithKline (GSK) announced that the FDA has granted traditional approval status to Ziagen (abacavir sulfate) (ABC) for the treatment of HIV infection in combination with other antiretroviral medications. Ziagen is a nucleoside reverse transcriptase inhibitor (NRTI) brought to market in December 1998 under the accelerated approval regulations. The FDA's traditional approval was based on results of pivotal clinical trials that confirmed the clinical benefits of Ziagen in combination with other antiretrovirals.

"We are pleased to receive traditional approval for Ziagen, an important component of antiretroviral therapy that can be successfully combined with other NRTIs, nonnucleoside reverse transcriptase inhibitors (NNRTIs) and/or protease inhibitors (PIs). Ziagen also offers limited drug-drug interactions," said Doug Manion, M.D., vice president of clinical development and medical affairs at GSK. According to Dr. Manion, 509,000 patient years of post- marketing exposure support the use of Ziagen or abacavir-containing products.

Data from the following study were presented at ICAAC in 2003.

Study CNA30024

In this international multicenter study submitted to the FDA as part of the application for traditional approval of Ziagen, 649 therapy-naive adults were randomized to receive one of two treatments:

1. Ziagen 300mg twice daily (BID) plus lamivudine (3TC) 150mg BID plus the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV) 600mg once daily (QD), or
2. Zidovudine (ZDV) 300mg BID plus 3TC 150mg BID plus EFV 600mg QD.

  Results at 48 Weeks:

• Among all the patients, median viral load (VL) at baseline was approximately 62,000 copies/mL and 39 percent had baseline VL >100,000 copies/mL.  Median baseline CD4+ cell count was 264 cells/mm(3).
• 69 percent of subjects in the group taking Ziagen/3TC/EFV and 69 percent of subjects in the group taking ZDV/3TC/EFV achieved plasma HIV-1 RNA level below 50 copies/mL.
• Safety profiles for both regimens were comparable.
• Drug hypersensitivity reactions were reported in both treatment groups (9 percent Ziagen+3TC+EFV and <1 percent ZDV+3TC+EFV).
• Virologic failure (VF) was infrequent and similar between the treatment groups, with 21 of 324 patients (6 percent) failing treatment on Ziagen+3TC+EFV compared to 13 of 325 patients (4 percent) on ZDV+3TC+EFV.
• VF was associated with higher viral loads and lower CD4+/CD8+ cell counts at baseline in both study groups.
• Subjects in the Ziagen/3TC/EFV group gained 209 CD4+cells/mm(3) compared to subjects in the ZDV/3TC/EFV group who gained 155 CD4+cells/mm(3).

Product Information

HIV medicines do not cure HIV infection/AIDS or prevent passing HIV to others. Ziagen Tablets and Oral Solution, in combination with other antiretroviral agents, are indicated for the treatment of HIV-1 infection.

When used as part of a combination regimen, Ziagen is a potent nucleoside reverse transcriptase inhibitor (NRTI). The most serious adverse event associated with Ziagen administration is a hypersensitivity reaction occurring in approximately 5 percent of patients and which can be life threatening and has been fatal in some cases. It is characterized by fever, skin rash, fatigue and gastrointestinal symptoms, such as nausea, vomiting, diarrhea or abdominal pain. Respiratory symptoms such as dyspnea, pharyngitis or cough may also occur. The diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of acute respiratory diseases, even if alternative respiratory diagnoses (pneumonia, bronchitis, flu-like illness) are possible. Therefore, patients and healthcare professionals should also watch for respiratory symptoms such as shortness of breath, sore throat or cough.

To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity reaction, Ziagen should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (e.g. acute onset respiratory disease, gastroenteritis, or reactions to other medication). Rechallenge is contraindicated after a diagnosis of hypersensitivity. Symptoms of this reaction usually occur within the first six weeks of treatment although these reactions can occur at any time during therapy. The symptoms of this reaction get progressively worse with continued treatment with Ziagen, but generally resolve following permanent discontinuation of Ziagen. Patients experiencing these symptoms should stop taking Ziagen and contact a physician immediately. Patients experiencing this reaction must not take Ziagen again as restarting the drug after a hypersensitivity reaction has resulted in cases of life-threatening and fatal reactions. When therapy with Ziagen has been discontinued and reinitiation of therapy is under consideration, the reason for discontinuation should be evaluated to ensure that the patient did not have a hypersensitivity reaction. A Medication Guide and Warning Card for Ziagen must be provided by pharmacists to patients with each new and refilled prescription in order to provide further information to the patient on this drug.

Epivir in combination with other antiretroviral agents is indicated for the treatment of HIV infection. Epivir should be used with caution in pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis. Patients with HIV or coinfected with HIV and hepatitis B should only receive the recommended HIV dosage of Epivir (300mg/day) and not Epivir-HBV (100mg/day). Epivir has not been adequately studied for treatment of chronic hepatitis B in coinfected patients. Clinical and laboratory exacerbations of hepatitis B have occurred after discontinuation of Epivir and may be severe in patients with decompensated liver disease.

Retrovir in combination with other antiretroviral agents is indicated for the treatment of HIV infection. Retrovir has been associated with hematologic toxicity including neutropenia and severe anemia particularly in patients with advanced HIV disease. Prolonged use of Retrovir has been associated with symptomatic myopathy.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Ziagen, Epivir, Retrovir and other antiretrovirals.

Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy. The causal relationship, mechanism and long-term consequences of these events are currently unknown.

• The most common side effects with Ziagen are nausea, vomiting, tiredness, headache, diarrhea and loss of appetite.
• The most common side effects with Epivir are headache, upset stomach, tiredness, and nasal signs and symptoms.
• The most common side effects with Retrovir are headache, tiredness, nausea, loss of appetite and vomiting.

The recommended dose of Ziagen is 300mg twice a day. The recommended dose of Epivir is 150mg twice a day or 300mg once a day. The recommended dose of Retrovir is 300mg twice a day.

Recombinant laboratory strains of HIV-1 (HXB2) containing multiple reverse transcriptase mutations conferring Ziagen resistance exhibited cross- resistance to Epivir, didanosine, and zalcitabine in vitro.

Source: GlaxoSmithKline

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