A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rescriptor Indications, Dosage, Storage, Stability - Delavirdine mesylate
Rescriptor Indications, Dosage, Storage, Stability - Delavirdine mesylate
INDICATIONS
AND USAGE
RESCRIPTOR Tablets are indicated for the treatment of HIV-1
infection in combination with appropriate antiretroviral agents when therapy
is warranted. This indication is based on surrogate marker changes in clinical
studies. Clinical benefit was not demonstrated for RESCRIPTOR based on survival
or incidence of AIDS-defining clinical events in a completed trial comparing
RESCRIPTOR plus didanosine with didanosine monotherapy (see DESCRIPTION
OF CLINICAL STUDIES).
Resistant virus emerges rapidly when RESCRIPTOR is administered
as monotherapy. Therefore, RESCRIPTOR should always be administered in combination
with appropriate antiretroviral therapy.
DESCRIPTION OF CLINICAL STUDIES
In two of the clinical studies described below (Study 0021,
Part 1 and Study 0017), an experimental HIV nucleic acid amplification assay
was used to estimate the level of circulating HIV RNA in plasma. In the clinical
study ACTG 261, also described below, an approved HIV nucleic acid amplification
assay was used.
The decrease in sample size reflects patients leaving the study,
missed visits, and those who had not reached specified time points at data cutoff.
In general, patients who left the study had lower CD4 cell counts and higher
plasma HIV RNA values than patients remaining on study. Therefore, absolute
changes from baseline are overstated in all treatment arms, increasingly so
at later time points. However, the added effect of delavirdine treatment relative
to the control arms does not appear to be significantly affected by patient
dropout.
Study 0021, Part 1: RESCRIPTOR-Zidovudine Dual Therapy Trial
Study 0021, Part 1 was a randomized, double-blind trial comparing
treatment with RESCRIPTOR plus zidovudine and zidovudine monotherapy in 718
HIV-1–infected patients (median age 34.3 years [range 17 to 70 years], 19% female,
32% non-Caucasian).
Patients were treatment naive or had received less than 6 months
of prior zidovudine therapy. Mean baseline CD4 cell count was 334 cells/mm3
(range 75 to 696 cells/mm3) and mean baseline plasma HIV-1 RNA was
5.25 log10 copies/mL. Treatment doses were RESCRIPTOR 200 mg, 300
mg, or 400 mg tid plus zidovudine 200 mg tid or zidovudine monotherapy 200 mg
tid. No statistically significant difference in CD4 cell count for the combination
of RESCRIPTOR plus zidovudine compared with zidovudine monotherapy was observed
in a planned analysis at 24 weeks. All patients had not completed 52 weeks at
the time of this analysis.
Study 0017 RESCRIPTOR-Didanosine Dual Therapy Trial
Study 0017 was a randomized, double-blind trial comparing treatment
with RESCRIPTOR plus didanosine versus didanosine monotherapy in 1,190 HIV-1–infected
patients (median age 37.4 years [range 19 to 78 years], 13% female, 32% non-Caucasian).
Patients had received up to 4 months prior didanosine therapy; there were no
restrictions on prior zidovudine use. Mean baseline CD4 cell count was 142 cells/mm3
(range 0 to 541 cells/mm3) and mean baseline plasma HIV-1 RNA was
5.77 log10 copies/mL. Treatment doses were RESCRIPTOR 400 mg tid
plus didanosine or didanosine monotherapy. The dose of didanosine was adjusted
by body weight (<60 kg, 125 mg bid; >60 kg, 200 mg bid). All patients
had not completed 52 weeks at the time of this analysis.
An analysis of clinical efficacy end points (death, clinical
progression defined as time to AIDS or death) was performed when all patients
had completed at least 6 months in the trial. Comparable rates of deaths and
AIDS progression between the didanosine monotherapy arm and the combination
of RESCRIPTOR plus didanosine arm were observed.
ACTG 261: RESCRIPTOR-Zidovudine-Didanosine Triple Therapy Trial
AIDS Clinical Trials Group (ACTG) Protocol 261 was a randomized
trial comparing the following four treatment regimens: RESCRIPTOR plus didanosine,
RESCRIPTOR plus zidovudine, RESCRIPTOR plus didanosine and zidovudine, and zidovudine
plus didanosine. The study enrolled 544 HIV-1–infected patients (median age
35 years, 18% female and 44% non-Caucasian patients) who were either nucleoside
treatment naive or had prior treatment with zidovudine or didanosine (not both)
for less than 6 months. Thirty-seven percent reported previous antiretroviral
therapy (194 patients with zidovudine and 6 with didanosine). Mean baseline
CD4 cell count was 296 cells/mm3 (range 55 to 640 cells/mm3).
Median baseline plasma HIV-1 RNA level (available for 229 patients) was 4.45
log10 copies/mL (28,260 copies/mL). Treatment doses were RESCRIPTOR
400 mg tid, zidovudine 200 mg tid, and didanosine dose adjusted by body weight
(<60 kg, 125 mg bid; >60 kg, 200 mg bid).
Preliminary results showed no statistically significant difference
in CD4 cell count for the three drug combination of RESCRIPTOR, zidovudine,
and didanosine compared with the combination of zidovudine plus didanosine.
No statistically significant difference in plasma HIV-1 RNA for the three-drug
combination of RESCRIPTOR, zidovudine, and didanosine compared with the combination
of zidovudine plus didanosine was observed.
DOSAGE AND ADMINISTRATION
The recommended dosage for RESCRIPTOR Tablets is 400 mg (four
100-mg or two 200-mg tablets) three times daily. RESCRIPTOR should be used in
combination with other appropriate antiretroviral therapy. The complete prescribing
information for other antiretroviral agents should be consulted for information
on dosage and administration.
The 100-mg RESCRIPTOR Tablets may be dispersed in water prior
to consumption. To prepare a dispersion, add four 100-mg RESCRIPTOR Tablets
to at least 3 ounces of water, allow to stand for a few minutes, and then stir
until a uniform dispersion occurs (see CLINICAL
PHARMACOLOGY-Pharmacokinetics-Absorption and Bioavailability). The dispersion
should be consumed promptly. The glass should be rinsed with water and the rinse
swallowed to insure the entire dose is consumed. The 200-mg tablets should
be taken as intact tablets, because they are not readily dispersed in water.
Note: The 200-mg tablets are approximately one third smaller in size than the
100-mg tablets.
RESCRIPTOR Tablets may be administered with or without food
(see CLINICAL PHARMACOLOGY- Pharmacokinetics-Absorption
and Bioavailability). Patients with achlorhydria should take RESCRIPTOR with
an acidic beverage (eg, orange or cranberry juice). However, the effect of an
acidic beverage on the absorption of delavirdine in patients with achlorhydria
has not been investigated.
Patients taking both RESCRIPTOR and antacids should be advised
to take them at least one hour apart.
HOW SUPPLIED
RESCRIPTOR Tablets are available as follows: 100 mg: white,
capsule-shaped tablets marked with "U 3761". Bottles of 360 tablets NDC
0009-3761-03
200 mg: white, capsule-shaped tablets marked with "RESCRIPTOR
200 mg". Bottles of 180 tablets NDC 0009-XXXX-XX
Store at controlled room temperature 20° to 25°C (68° to 77°F)
[see USP]. Keep container tightly closed. Protect from high humidity
ANIMAL TOXICOLOGY
Toxicities among various organs and organ systems in rats,
mice, rabbits, dogs, and monkeys were observed following the administration
of delavirdine. Necrotizing vasculitis was the most significant toxicity that
occurred in dogs when mean nadir serum concentrations of delavirdine were at
least 7-fold higher than the expected human exposure to RESCRIPTOR (Cmin»15
mM) at the recommended dose. Vasculitis in
dogs was not reversible during a 2.5-month recovery period; however, partial
resolution of the vascular lesion characterized by reduced inflammation, diminished
necrosis, and intimal thickening occurred during this period. Other major target
organs included the gastrointestinal tract, endocrine organs, liver, kidneys,
bone marrow, lymphoid tissue, lung, and reproductive organs.
US Patent No. 5,563,142
Pharmacia & Upjohn Company Kalamazoo, Michigan
49001, USA
Revised XXXXX 1999,XXX XXX XXX,692151
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