INDICATIONS
CRIXIVAN in combination with antiretroviral agents is
indicated for the treatment of HIV infection. This
indication is based on two clinical trials of approximately
1 year duration that demonstrated: 1) a reduction in the
risk of AIDS defining illnesses or death; 2) a prolonged
suppression of HIV RNA.
Description of Studies
In all clinical studies, with the exception of ACTG 320,
the AMPLICOR HIV MONITOR assay was used to determine the
level of circulating HIV RNA in serum. This is an experimental
use of the assay. HIV RNA results should not be directly
compared to results from other trials using different
HIV RNA assays or using other sample sources.
Study ACTG 320
Study ACTG 320 was a multicenter, randomized, double-blind
clinical endpoint trial to compare the effect of CRIXIVAN
in combination with zidovudine and lamivudine with that
of zidovudine plus lamivudine on the progression to an
AIDS-defining illness (ADI) or death. Patients were protease
inhibitor and lamivudine naive and zidovudine experienced,
with CD4 cell counts of <200 cells/mm3.
The study enrolled 1156 HIV-infected patients (17% female,
28% Black, 18% Hispanic, mean age 39 years). The mean
baseline CD4 cell count was 87 cells/mm3. The
mean baseline HIV RNA for a subset of 190 patients was
4.98 log10 copies/mL (95,432 copies/mL). The
study was terminated after a planned interim analysis,
resulting in a median follow-up of 38 weeks and a maximum
follow-up of 52 weeks. Results are shown in Table 1.
Table 1
ACTG 320
| Endpoint15
|
Number
(%) of Patients with AIDS-defining Illness or
Death
|
|
>IDV+ZDV+L
(n=577)
|
ZDV+L
(n=579)
|
| HIV
Progression or Death |
35 (6.1)
|
63 (10.9)
|
| Death* |
10 (1.7)
|
19 (3.3)
|
*The number of deaths is inadequate
to assess the impact of Indinavir on survival. IDV = Indinavir,
ZDV = Zidovudine, L = Lamivudine
Study 028
Study 028, a double-blind, multicenter, randomized,
clinical endpoint trial conducted in Brazil, compared
the effects of CRIXIVAN plus zidovudine with those of
CRIXIVAN alone or zidovudine alone on the progression
to an ADI or death, and on surrogate marker responses.
All patients were antiretroviral naive with CD4 cell counts
of 50 to 250 cells/mm3. The study enrolled
996 HIV-1 seropositive patients [28% female, 11% Black,
1% Asian/Other, median age 33 years, mean baseline CD4
cell count of 152 cells/mm3, mean serum viral
RNA of 4.44 log10 copies/mL (27,824 copies/mL)].
Treatment regimens containing zidovudine were modified
in a blinded manner with the optional addition of lamivudine
(median time: week 40). The median length of follow-up
was 56 weeks with a maximum of 97 weeks. The study was
terminated after a planned interim analysis, resulting
in a median follow-up of 56 weeks and a maximum follow-up
of 97 weeks. Results are shown in Table 2.
Table 2
Protocol 028
| Endpoint |
Number
(%) of Patients with AIDS-defining Illness or
Death
|
|
IDV+ZDV
(n=332)
|
IDV
(n=332)
|
ZDV
>(n=332)
|
| HIV
Progression or Death |
21 (6.3)
|
27 ( 8.1)
|
62 (18.7)
|
| Death* |
8 (2.4)
|
5 (1.5)
|
11 (3.3)
|
*The number of deaths is inadequate
to assess the impact of Indinavir on survival.
Study 035
Study 035 was a multicenter randomized trial in 97 HIV-1
seropositive patients who were zidovudine-experienced
(median exposure 30 months), protease-inhibitor- and lamivudine-naive,
with mean baseline CD4 count 175 cells/mm3
and mean baseline serum viral RNA 4.62 log10
copies/mL (41,230 copies/mL). Comparisons included CRIXIVAN
plus zidovudine plus lamivudine vs. CRIXIVAN alone vs.
zidovudine plus lamivudine. After at least 24 weeks of
randomized, double-blind therapy, patients were switched
to open-label CRIXIVAN plus lamivudine plus zidovudine.
Mean changes in log10 viral RNA in serum, the
proportions of patients with viral RNA below 500 copies/mL
in serum, and mean changes in CD4 cell counts, during
24 weeks of randomized, double-blinded therapy are summarized
in Figures 5, 6, and 7, respectively. A limited number
of patients remained on randomized, double-blind treatment
for longer periods; based on this extended treatment experience,
it appears that a greater number of subjects randomized
to CRIXIVAN plus zidovudine plus lamivudine demonstrated
HIV RNA levels below 500 copies/mL during one year of
therapy as compared to those in other treatment groups.
Genotypic Resistance in Clinical Studies
Study 006 (10/15/93-10/12/94) was a dose-ranging study
in which patients were initially treated with CRIXIVAN
at a dose of <2.4 g/day followed by 2.4 g/day. Study
019 (6/23/94-4/10/95) was a randomized comparison of CRIXIVAN
600 mg every 6 hours, CRIXIVAN plus zidovudine, and zidovudine
alone. Table 3 shows the incidence of genotypic resistance
at 24 weeks in these studies.
Table 3
| Treatment
Group |
Resistance to IDV
n/N*
|
Resistance to ZDV
n/N*
|
| IDV |
|
|
| <
2.4 g/day |
31/37 (84%)
|
-
|
| 2.4
g/day |
>9/21 (43%)
|
/17 (6%)
|
| IDV/ZDV |
4/22 (18%)
|
1/22 (5%)
|
| ZDV |
1/18 (6%)
|
11/17 (65%)
|
* N - includes patients with non-amplifiable
virus at 24 weeks who had amplifiable virus at week 0.
DOSAGE AND ADMINISTRATION
The recommended dosage of CRIXIVAN is 800 mg (two 400-mg
capsules) orally every 8 hours. The dosage is the same
whether CRIXIVAN is used alone or in combination with
other antiretroviral agents.
CRIXIVAN must be taken at intervals of 8 hours. For optimal
absorption, CRIXIVAN should be administered without food
but with water 1 hour before or 2 hours after a meal.
Alternatively, CRIXIVAN may be administered with other
liquids such as skim milk, juice, coffee, or tea, or with
a light meal, e.g., dry toast with jelly, juice, and coffee
with skim milk and sugar; or corn flakes, skim milk and
sugar. (See CLINICAL PHARMACOLOGY, Effect
of Food on Oral Absorption)
To ensure adequate hydration, it is recommended that
the patient drink at least 1.5 liters (approximately 48
ounces) of liquids during the course of 24 hours.
Concomitant Therapy
Rifabutin: Dose reduction of rifabutin
to half the standard dose (consult the manufacturer's
product circular for rifabutin) and a dose increase of
CRIXIVAN to 1000 mg every 8 hours are recommended when
rifabutin and CRIXIVAN are coadministered (see DRUG
INTERACTIONS section.)
Ketoconazole: Dose reduction of CRIXIVAN
to 600 mg every 8 hours should be considered when administering
ketoconazole concurrently.
Didanosine: If indinavir and didanosine
are administered concomitantly, they should be administered
at least one hour apart on an empty stomach (consult the
manufacturer's product circular for didanosine).
Hepatic Insufficiency: The dosage of CRIXIVAN
should be reduced to 600 mg every 8 hours in patients
with mild-to-moderate hepatic insufficiency due to cirrhosis.
Nephrolithiasis: In addition to adequate
hydration, medical management in patients who experience
nephrolithiasis may include temporary interruption (e.g.,
1-3 days) or discontinuation of therapy.
HOW SUPPLIED
CRIXIVAN Capsules are supplied as follows: No. 3756 -
200 mg capsules: semi-translucent white capsules coded
"CRIXIVAN™ 200 mg" in blue. Available as:
NDC 0006-0571-42 unit-of-use bottles of 270 (with desiccant)
NDC 0006-0571-43 unit-of-use bottles of 360 (with desiccant).
No. 3758 - 400 mg capsules: semi-translucent white capsules
coded "CRIXIVAN™ 400 mg" in green. Available
as:
NDC 0006-0573-62 unit-of-use bottles of 180 (with desiccant)
NDC 0006-0573-54 unit-of-use bottles of 90 (with desiccant).
Storage
Store in a tightly-closed container at room temperature,
15-30 °C (59-86 °F). Protect from moisture. CRIXIVAN
Capsules are sensitive to moisture. CRIXIVAN should be
dispensed and stored in the original container. The desiccant
should remain in the original bottle.
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