INDICATIONS AND USAGE
HIVID is indicated in combination with antiretroviral agents for the treatment of HIV infection. This indication is based on study results showing a reduction in the rate of disease progression (AIDS-defining events or death) in patients with limited prior antiretroviral therapy who were treated with the combination of HIVID and zidovudine (see Description of Clinical Studies ). This indication is also based on a study showing a reduction in both mortality and AIDS-defining clinical events for patients who received INVIRASE® (saquinavir mesylate) in combination with HIVID compared to patients who received either HIVID or INVIRASE alone.
Description of Clinical Studies
The use of HIVID in combination with zidovudine is based on the clinical results from study ACTG 175. ACTG 175 was a randomized, double-blind, controlled trial that compared zidovudine 200 mg three times daily; didanosine 200 mg twice daily; zidovudine+didanosine; and zidovudine+HIVID 0.750 mg three times daily. A total of 2467 HIV-infected adults (mean baseline CD4 count = 352 cells/mm3) with no prior AIDS-defining event enrolled with the following demographics: male (82%), Caucasian (70%), mean age of 35 years, asymptomatic HIV infection (81%) and prior antiretroviral use (57%, mean duration = 89.5 weeks). The overall mean duration of study treatment was 99 weeks. The incidence of AIDS-defining events or death is shown in Table 1.
Table 1 First AIDS-defining Event or Death and Death Only by Study Arm and Antiretroviral Experience in ACTG 175 | Antiretroviral Experience | Event | Treatment |
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| zidovudine | Zidovudine + didanosine | zidovudine + HIVID | didanosine |
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| Overall | n | 619 | 613 | 615 | 620 |
| AIDS/Death | 96 (16%) | 65 (11%) | 76 (12%) | 71 (11%) |
| Death Only | 54 (9%) | 31 (5%) | 40 (7%) | 29 (5%) |
| Naive | n | 269 | 263 | 267 | 268 |
| AIDS/Death | 32 (12%) | 20 (8%) | 16 (6%) | 23 (9%) |
| Death Only | 18 (7%) | 11 (4%) | 9 (3%) | 11 (4%) |
| Experienced | n | 350 | 350 | 348 | 352 |
| AIDS/Death | 64 (18%) | 45 (13%) | 60 (17%) | 48 (14%) |
| Death Only | 36 (10%) | 20 (6%) | 31 (9%) | 18 (5%) |
Although no antiretroviral agent should be used as monotherapy, a description of CPCRA 002 is included here as it provides a comparison of the safety and efficacy of HIVID compared to ddI.
CPCRA 002 was a randomized, multicenter, open-label study in which HIVID was compared to ddI as treatment for patients with advanced HIV infection (median CD4 cell count = 37 cells/mm3) who were clinically intolerant to ZDV, or who had met criteria for having disease progression while receiving ZDV.2 Patients in this study had a mean of 17.5 months of prior ZDV use. The median duration of treatment for both HIVID and ddI was 34 weeks. The results demonstrate that HIVID was at least as efficacious as ddI in terms of time to an AIDS-defining event or death, while for survival alone the results favored HIVID. However, most of the patients (66%) in either group had disease progression over the median 16 months of follow-up. Overall rates of study drug intolerance, discontinuation and adverse events were similar for the two groups, although the types of events were different.
A clinical study (N3300/ACTG 114) has demonstrated ZDV to be superior to HIVID as monotherapy for advanced HIV disease (CD4 cell count ≤200 cells/mm3) in previously untreated patients.3,4 The final analysis of this study indicated that 134 patients (42%) in the HIVID group with a median follow-up of 85 weeks and 120 patients (38%) in the ZDV group with a median follow-up of 96 weeks died with a relative risk for mortality of ZDV to HIVID of 0.54.
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DOSAGE AND ADMINISTRATION
Patients should be advised that HIVID is recommended for use in combination with active antiretroviral therapy. Greater activity has been observed when new antiretroviral therapies are begun at the same time as HIVID. Concomitant therapy should be based on a patient's prior drug exposure. The recommended regimen is one 0.750 mg tablet of HIVID orally every 8 hours (2.25 mg HIVID total daily dose) in combination with other antiretroviral agents. Please refer to the complete product information for each of the other antiretroviral agents for the recommended doses of these agents. Based on preliminary data, the recommended HIVID dosage reduction for patients with impaired renal function is: creatinine clearance 10 to 40 mL/min: 0.750 mg of HIVID every 12 hours; creatinine clearance <10 mL/min: 0.750 mg of HIVID every 24 hours.
Monitoring of Patients
Complete blood counts and clinical chemistry tests should be performed prior to initiating HIVID therapy and at appropriate intervals thereafter. For comprehensive patient monitoring recommendations for other antiretroviral therapies, physicians should refer to the complete product information for these drugs. Serum amylase levels should be monitored in those individuals who have a history of elevated amylase, pancreatitis, ethanol abuse, who are on parenteral nutrition or who are otherwise at high risk of pancreatitis. Careful monitoring for signs or symptoms suggestive of peripheral neuropathy is recommended, particularly in individuals with a low CD4 cell count or who are at a greater risk of developing peripheral neuropathy while on therapy (see WARNINGS).
Dose Adjustment for HIVID
For toxicities that are likely to be associated with HIVID (eg, peripheral neuropathy, severe oral ulcers, pancreatitis, elevated liver function tests especially in patients with chronic Hepatitis B), HIVID should be interrupted or dose reduced. FOR SEVERE TOXICITIES OR THOSE PERSISTING AFTER DOSE REDUCTION, HIVID SHOULD BE INTERRUPTED. For recipients of combination therapy with HIVID and other antiretroviral agents, dose adjustments or interruption for each drug should be based on the known toxicity profile of the individual drugs. SEE INFORMATION FOR EACH DRUG USED IN COMBINATION FOR A DESCRIPTION OF KNOWN DRUG-ASSOCIATED ADVERSE REACTIONS.
Patients developing moderate discomfort with signs or symptoms of peripheral neuropathy should stop HIVID. HIVID-associated peripheral neuropathy may continue to worsen despite interruption of HIVID. HIVID should be reintroduced at 50% dose — 0.375 mg every 8 hours only if all findings related to peripheral neuropathy have improved to mild symptoms. HIVID should be permanently discontinued if patients experience severe discomfort related to peripheral neuropathy or moderate discomfort that progresses. If other moderate to severe clinical adverse reactions or laboratory abnormalities (such as increased liver function tests) occur, then HIVID and/or the other potential causative agent(s) should be interrupted until the adverse reaction abates. HIVID and/or the other potential causative agent(s) should then be carefully reintroduced at lower doses if appropriate. If adverse reactions recur at the reduced dose, therapy should be discontinued. The minimum effective dose of HIVID in combination with zidovudine for the treatment of adult patients with advanced HIV infection has not been established.
In patients with poor bone marrow reserve, particularly those patients with advanced symptomatic HIV disease, frequent monitoring of hematologic indices is recommended to detect serious anemia or granulocytopenia. Significant toxicities, such as anemia (hemoglobin of <7.5 gm/dL or reduction of >25% of baseline) and/or granulocytopenia (granulocyte count of <750 cells/mm3 or reduction of >50% from baseline), may require a treatment interruption of HIVID and zidovudine until evidence of marrow recovery is observed. For less severe anemia or granulocytopenia, a reduction in daily dose of zidovudine in those patients receiving combination therapy may be adequate. In patients who experience hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks after initiation of therapy, and granulocytopenia usually occurs after 6 to 8 weeks of therapy. In patients who develop significant anemia, dose modification does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose modification, gradual increases in dose may be appropriate depending on hematologic indices and patient tolerance. For more details, refer to the complete product information for zidovudine.
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HOW SUPPLIED
HIVID 0.375 mg tablets are oval, beige, film-coated tablets with "HIVID 0.375" imprinted on one side and "ROCHE" on the other side — bottles of 100 (NDC 0004-0220-01). HIVID 0.750 mg tablets are oval, gray, film-coated tablets with "HIVID 0.750" imprinted on one side and "ROCHE" on the other side — bottles of 100 (NDC 0004-0221-01).
The tablets should be stored in tightly closed bottles at 59° to 86°F (15° to 30°C).
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