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New from the Food and Drug Administration (FDA)

March 1996

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

3TC (Lamivudine, Epivir)

On November 17, 1995, the FDA approved 3TC plus AZT as the first new initial treatment option for HIV infection since the approval of AZT in 1987. The specific language in the package inserts is the following: "Epivir is indicated for use in combination with Retrovir (AZT) for the treatment of HIV infection when antiretroviral therapy is warranted based on clinical and/or immunological evidence of disease progression." No mention is made of CD4 cell counts or prior therapy with alternative regimens. This approval is based on data from four clinical trials with approximately 1,000 HIV-infected adult patients who received either 3TC plus AZT, 3TC monotherapy or AZT monotherapy. The drug has been available since October, 1993 through an open-label protocol for expanded access with 35,000 participants, a new record. Further information on this drug is provided elsewhere in the Moore News.

Saquinavir (Invirase)

On December 7, 1995, the FDA granted accelerated approval to Saquinavir (Invirase) as the first drug in a new class of anti-HIV agents: protease inhibitors. The specific language of the package insert is the following: "Invirase in combination with nucleoside analogues is indicated for the treatment of advanced HIV infection in selected patients. This indication is based on changes in surrogate markers in patients who initiated Invirase concomitantly with either AZT (in previously untreated patients) or ddC, (HIVID) (in patients previously treated with prolonged AZT therapy)." Thus, it is approved only for use in combination, and the nucleoside analog partner is not defined, although the clinical trials were done with AZT or ddC. The approved dose is 600 mg three times daily, although recent studies indicate higher doses are more effective. Additional information about saquinavir is presented elsewhere in the Moore News.

d4T (Zerit, Stavudine)

The FDA Advisory Committee recommended full approval for d4T. This drug was tentatively approved in June, 1994 based on CD4 cell response. Full approval is based on subsequent studies demonstrating clinical efficacy in the company-sponsored trial (BMS 019) that compared AZT versus d4T in patients with prior AZT treatment for at least six months. The switch to d4T was superior in rates of progression to AIDS or death (p-0.007).

Oral Ganciclovir (Cytovene)

This drug was previously approved for maintenance treatment of CMV retinitis. The FDA has now approved oral Cytovene to prevent initial episodes of CMV retinitis and other forms of CMV disease in patients with advanced AIDS defined as CD4 cell count<100/mm 3. The recommended dose for both prophylaxis and treatment is 3 gm/day at an average wholesale price of about $50.00/day. There have been two large studies of prophylaxis with oral ganciclovir: Syntex 1654 showed a statistically significant benefit with oral Ganciclovir for prevention of CMV retinitis and CMV disease in patients with CD4 cell counts <50 3; CPCRA 023 failed to show any benefit. Differences between the studies are debated, but the FDA had access to data from both studies at the time of its approval. It should be noted that the guidelines of the U.S. Public Health Service do not include oral Ganciclovir despite availability of data from Syntex 1654 at the time these were written.

Cidofovir (Vistide, HPMPC)

Intravenous Cidofovir is now available through a Treatment Investigational New Drug program for patients with CMV retinitis that has progressed despite treatment with an approved agent (Ganciclovir or Foscarnet) or those who cannot tolerate these drugs. Further information is available from Gilead Sciences at 1-800-445-3235.

Liposomal Doxorubicin (Doxil)

This drug received accelerated approval from the FDA on November 10, 1995 for patients with Kaposi Sarcoma who failed conventional therapy or were unable to tolerate conventional therapy. Doxil is the liposomal formulation of Doxorubicin that has a half-life of 50 hours compared to 2 hours for doxorubicin. For more information call 1-800-375-1658.

Amphotericin B Lipid (Abelcet)

The FDA approved Abelcet in November, 1995 as the first approved amphotericin B Lipid Complex. The indication is "for patients with aspergilliosis refractory to or intolerant of amphotericin B." This drug is obviously active against all fungi that are susceptible to amphotericin B, but FDA approval is restricted to aspergillus because this was the condition treated in the trial that was submitted to the FDA. The major advantage of this drug is reduced nephroxicity, and the recommended dose is 5 mg/kg given intravenously at a rate of 2.5 mg/kg/hour. The cost of this drug is about $430/daily compared to conventional Amphotericin B at $21.60/50 mg vial. For additional information call 1-800-335-5476 or fax requests to 1-800-236-4507. A full profile is available elsewhere in the Moore News.

Liposomal daunorubicin (Daunoxome)

Daunorubicin is a cancer chemotherapeutic agent sometimes used for Kaposi sarcoma. Liposomal daunorubicin (Daunoxome) utilizes the liposomal carrier system that provides a favorable pharmacokinetic profile at the site of KS lesions resulting in a 10-fold increase in concentrations compared to that which is achieved with conventional preparations. The therapeutic trial justifying acceptance was a comparison of this preparation (40 mg/m 2 given intravenously every 2 weeks) compared to standard chemotherapy with adriamycin, bleomycin and vincristine. Results showed comparable clinical results with significantly fewer side effects in Daunoxome recipients. This drug may take on special significance because it is easily given by primary care providers who are generally reluctant to become involved in cancer chemotherapy. A full profile on this drug is provided elsewhere in the Moore News.

Clarithromycin (Biaxin)

The FDA has approved clarithromycin (500 mg bid) for MAC prophylaxis. This decision was based on the placebo-controlled trial with 682 participants that showed clarithromycin was associated with a 69% reduction in rates of breakthrough bacteremia and a statistically significant reduction in mortality. The relative merits of rifabutin and clarithromycin for MAC prophylaxis are reviewed elsewhere in this issue of Moore News.

FDA Meeting (2/29-3/1/96)

As Moore News went to press, the FDA approved two protease inhibitors: ritonavir and indinavir (Crixivan). Ritonavir is the only protease inhibitor to date that has demonstrable efficacy in a controlled trial with clinical endpoints. The study was in patients with DC4 counts <100/mm 3 receiving nucleoside analog therapy; one group had ritonavir added, and the other continued nucleoside analog treatment. There was a 58% reduction in the frequency of progression to a new AIDS-defining diagnosis or death, and a 42% reduction in death in the ritonavir recipients.

The FDA provides two types of approval: traditional approval or accelerated approval. Traditional approval means standard acceptance and no further clinical studies are required. Accelerated approval means provisional approval usually based on surrogate marker data with traditional approval contingent on the demonstration of clinical benefit in at least two separate studies within two years. In this case, ritonavir received traditional approval for treatment of patients with advanced HIV infection (defined as a CD4 count <200/mm 3.

Indinavir (Crixivan) in combination with AZT and 3TC showed a decrease in viral burden that averaged over 2 logs (99%), a decrease that was below detectable limits (500 copies/ml) in 85% of participants at 24 weeks. The antiviral effect persisted throughout the one year study. Based on these and other surrogate marker studies, indinavir received accelerated approvals.

An unusual and celebrated feature of these approvals was the speed with which they occurred. The FDA Advisory Committee is advisory to the FDA; this group met February 29-March 1, 1996. Within 12 hours of their meeting, the FDA letters of approval were delivered to Merck (indinavir) and Abbott (ritonavir). For indinavir, the time from submission to approval was 29 days, which represents an FDA record. The time from initiation of the therapeutic trial to approval was about 2 years--another FDA record.

At the close of the meeting it was also announced that President Clinton proposed legislation to add $52 million to Ryan White Care Act funding for ADAP programs (AIDS Drug Assistance Programs). According to HRSA records, ADAP programs served 50,000 patients with about $100 million in Ryan White funding in 1994. The supplemental funds will add about $1,000/participant or about 20% of the anticipated cost of protease inhibitors for a program that serves about 7% of the projected number of persons living with HIV infection.

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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This article was provided by Johns Hopkins AIDS Service. It is a part of the publication Moore News for Care Providers.
See Also
More on the FDA Drug Approval Process and Other Regulatory Issues