New Drugs Arriving at Pharmacies

M Pharmacia
&Upjohn
delavirdine mesylate tablets
WARNING: RESCRIPTOR Tablets are indicated for the
treatment of HIV-1 infection in combination with appropriate antiretroviral agents when therapy is warranted.
This indicatioo is baoed on ourrogate marker changes in
clinrcal studies. Clinical benefit wao not demonstrated
for RESCRIPTOR baoed on survival or incidence of
AIDS-defining clinical events in a completed trial comparinghRESCRIPTOR plus didanosine with didanosine
morotherapy 1000 DESCRIPTION OF CLINICAL STUDIES),
Resistant virus emerges rapidly when RESCRIPTOR is
administered as mono-therapy. Therefore, RESCRIPTOR
should always be administered in combination with
appropriate antiretroviral therapy.
DESCRIPTION
RESCRIPTOR Tablets contain delavirdine mesylate, a synthetic non-nucleoside reverse transcriptase inhibitor of the
human immunodeficiency virus type 1 (HIV-1). The chemical
name of delavirdine mesylate is piperazine, 1-[3-[(1-methylethyllamino] -2pyridinyl]-4-[[5-1(methylsulfonyl)amino)-1H-indol-2-yl carbonyl] -.
monomethanestonate. ItsCHH
molecular formula is vv-so -,.
C22H -N3S *CH403S,
and its molecularweight isH
552.68. The structural for- 0
mula is.*CH-so,-o_0
Delavirdine mesylate is an odorless white-to-tan crystalline
powder. The aqueous solubility of delavirdine free base at 23* C
is 2,942 pg/mL at pH 1.0. 295 g/mL at pH 2.0, and 0.81
yg/mL at pH 7.4.
RESCRIPTOR Tablets, for oral administration, contain
100 mg of delavirdine mesylate (henceforth referred to as
delavirdine). Inactive ingredients consist of lactose, microcrystalline cellulose, croscarmellose sodium. colloidal silicon
dioxide, magnesium stearate, Opadry YS-1-7000-E White and
carnauba way.
MICROBIOLOGY
Mechanism of action: Delavirdine is a non-nucleoside reverse
transcriptase inhibitor (NNRTI) of HIV-t. Delavirdine binds
directly to reverse transcriptase )RTI and blocks RNA-deperdent and DNA-dependent DNA polymerase activities.
Delavirdine does not compete with template: primer or
deoxynucleoside triphosphates. HIV-2 RT and human cellular
DNA polymerasess.-y or8 are not inhibited by delavirdine. In
addition. HIV-1 group 0, a group of highly divergent strains
that are uncommon in North America, may not be inhibited by
delavirdine.
In vitro HIV-i susceptibility: In vitro anti-HIH-1 activity of
delavirdine was assessed by infecting cell lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes
with laboratory and clinical isolates of HIV-1. C50 and IC9t valves 1500 and 90% inhibitory concentrations) for laboratory
isolatesN=5) ranged from 0.005 to 0.030 pM and 0.04 to
0.10 yM respectively. Mean IC50 of clinical isolates IN=74)
was 0.038 pM (range 0.001 to 0.69 IM): 73 of 74 clinical isolates had an IC50 mo0.10 pM. The IC90 of 24 of these clinical
isolates ranged from 0.05 to 0.10 pM. In drug combination
studies of delavirdine with zidovudine. didanosine.pzalcitabine,
lamivudine, interferon-a, and protease inhibitors, additive to
synergistic anti-HlN-1 activity was observed in cell culture.
The relationship between the in vitro susceptibility of HIV-1 RT
inhibitors and the inhibition of HIV replication in humanohas
not been established.
Dreg resistance: Phenotypic analyses of isolates from patients
treated with delavirdine as monotherapy showed a 50-fold to
500-fold reduction in sensitivity in 14 of 15 patients by week 8
of therapy. Genotypic analyses of HIV-1 isolates from patients
receiving delavirdine plus zidovudine combination therapy
(N=19) showed mutations in 16 of 19 isolates by week 24 of
therapy. Mutations occurred predominantly at position 103 and
less frequently at positions 181 and 236. In a separate study,
an average 86-oad increase in the zidovudinesensitivity of
patient isolates (N=24) was observed after 24 weeks on
delavirdine and zidovudine combination therapy. The clinical
relevance of the phenotypic and the genotypic changes associated with delavirdine therapy has not been determined.
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Theotn tafocrs-eist ance betwee delavirdine a0 gtd(=7 I - nfetd
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hr) and trough concentration (Cm,,) was 15 t 10 pM (range 0.1
to 45 pM). The single-dose bioavailability of delavirdine tablets
relative to an oral solution was 85 t 25% (n=16, nonHIV-infected subjects). The single-dose bioavailability of
delavirdine tablets was increased by approximately 20% when
a slurry of drug was prepared by allowing delavirdine tablets to
disintegrate in water before administration (n=16, nonHIV-infected subjects).
Delavirdine may be administered with or without food.
Following single-dose administration of delavirdine tablets with
a high-fat meal (874 kcal. 57 g fat), mean C,, was decreased
by 60% and mean AUC was decreased by 26%. relative to
fasted administration (n=12, non-HIV-infected subjects). In a
multiple-dose study, delavirdine was administered every eight
hours with food or every eight hours, one hour before or two
hours after a meal (n=13, HIV-1-infected patients). Patients.
remained on their typical diet throughout the study: meal con
tent was not standardized When multiple doses of delavirdine
were administered with food, mean C, was reduced by 22%
but AUC and C,, were not altered.
Distribution: Delavirdine is extensively bound (approximately
98%) to plasma proteins, primarily albumin. The percentage of
delavirdine that is protein bound is constant over a delavirdine
concentration range of 0.5 to 196 pM. In five HIV-1-infected
patients whose total daily dose of delavirdine ranged from 600
to 1200 mg, cerebrospinal fluid concentrations of delavirdine
averaged 0.4% ~ 0.07% of the corresponding plasma delavirdine concentrations: this represents about 20% of the traction
not bound to plasma proteins. Steady-state delavirdine concentrations in saliva (n=5. HIl-i-infected patients who
received delavirdine 400 mg id) and semen (n=5 healthy volunteers who received delavirdine 300 mg tid) were about 6%
and 2%. respectively, of the corresponding plasma delavirdine
concentrations colfected at the end of a dosing interval.
Metabolism and Elimination: Delavirdine is extensivelymconverted to several inactive metabolites. Delavirdine is primarily
metabolized by cytochrome P450 3A (CYP3A), but in vitro data
suggest that delavirdine may also be metabolized by CYP2D6.
The major metabolic pathways for delavirdine are N-desalkylation and pyridine hydroxylation. Delavirdine exhibits nonlinear
steady-state elimination pharmacokinetics. with apparent oral
clearance decreasing by about 22-fold as the total daily dose of
delavirdine increases from 60 to 1200 mg/day. In a study of
aC-delavirdine in six healthy volunteers who received multiple
doses of delavirdine tablets 300 mg tid, approximately 44% of
the radiolabeled dose was recovered in feces, and approximately 51=% of the dose was excreted in urine. Less than 5% of
the dose was recovered unchanged in urine. The apparent
plasma half-life of delavirdine increases with dose: mean halflife following 400 mg tid is 5.8 hours, with a range of 2 to
11 hours.
In vitro and in vivo studies have shown that delavirdine
reduces CYP3A activity and inhibits its own metabolism. In
vitro studies have also shown that delavirdine reduces CYP2C9
and CYP2C19 activity. Inhibition of CYP3A by delavirdine is
reversible within 1 week after discontinuation of drug.
Special Populations
Hepatic or Renal Impairment: The pharmacokinetics of
delavirdine in patients with hepatic or renal impairment have
not been investigated (see PRECAUTIONS).
Age: The pharmacokinetics of delavirdine have not been studied in patients <16 years or >65 years of age.
Gender: Following administration of delavirdine (400 mg every
eight hours), median delavirdine AUC was 31% higher in
female patients (n=12) than in male patients (n=55).
Race: No significant differencesbin the mean trough delavirdine
concentrations were observed between different racial or ethnic groups.
DrugIneractions (see also PRECAUTIONS-Drug Interactions)
Antacids: In a single-dose study in twelve healthy volunteers,
simultaneous administration of 300 mg delavirdixe with alumina and magnesia oral suspension resulted in a 41 a 19%1
reduction in delavirdine AUC (see PRECAUTIONS-Drug
Interactions).
Clarithromycin: in a study in six HIV-1-infected patients,
coadministration of clarithrumycin (500 mg bid) with delavirdine (300 mg tid) resulted in a 44 ~ 50% increase in delavirdine AUC. Compared to historical data. clarithromycin AUC was
increased by approximately 100% and 14-hydroxyclarithromycin AUC was decreased by '75%.
Didanouine: In a study in nine HIV-1 -infected patients, simultaneous administration of didanosine (125 mg or 250 mg bid)
with delavirdine (400 mg tid) fur two weeks resulted in an
approximately 20% decrease in both didanosine AUC and
delavirdine AUC. relative to when administration of delavirdine
and didanosine was separated by at least one hour (see PRECAUTIONS-Drug Interactions).
Fluconazole: In a study in eight HIV-1-infected patients, coadministration of fluconazole (400 mg once daily) with delavirdine (300 mg tid) did not significantly alter the pharmacokinetics of delavirdine. Compared to historical data. fluconazole
pharmacokinetics were not altered by delavirdine.
Fluoetine: Population pharmacokinetic data available for 36
patients suggest that fluoxetine increases trough plasma
delavirdine concentrations by about 50%.
Indinavir: Preliminary data (n=14) indicate that delavirdine
inhibits the metabolism of indinavir such that coadministration
of a 400 mg single dose of indinavir with delavirdine (400 mg
tid) resulted in indinavir AUC values slightly less than those
observed following administration of an 800 mg dose of indinavir alone. Also. coadministration of a 600 mg dose of indinavir with delavirdine (400 mg tid) resulted in indinavir AUC
values approximately 40% greater than those observed following administration of an 800 mg dose of indinavir alone.
Indinavir had no effect on delavirdine pharmacokinetics (see
PRECAUTIONS-Drug Interactions).
Ketecenazele: Population pharmacokinetic data available for
26 patients suggest that ketocoxasole increases trough plasma
delavirdine concentrations by about 50%/.
Pbenytoin, Pbenebarbltal. and Carbamazepine: Population
pharmacokinetic data available for eight patients suggest that
coadministration of phenytoin. phenobarbital, or carbamazepine with delavirdine results in a substantial reduction
in trough plasma delavirdine concentrations )see PRECAUTIONS-Drug Interactions).
Rilabetin: In a study in seven HIVl-i-infected patients, coadministration of rifabutin (300 mg once daily) with delavirdine
(400 mg tid) resulted in an 80 u 10% decrease in delavirdine
AUC. Compared to historical data. rifabutin AUC was increased
by at least 100% f(see PRECAUTIONS-Drug Interactions)
Rilmpi: n astd nsen HIll- -neted piens cod
(see PRECAUTIONS-Drug nteractions)
Ritenavir: Preliminary data (n=13( indicate that coadministratron of delaxirdine (400 mg or 600 mg bid) with ritonavir
(300 mg bid) did not alter ritonavir pharmacokinetics.
Cuadministration of ritonavir (300 mg bid) with delavirdine
(400 mg bid) did nut significantly alter delavirdine pharmacoki
netics (n=9). The pharmacokinetic interaction between delavirdine and ritonavir at their recommended doses has not been
studied (see PRECAUTIONS-Drug Interactions).
Saquinavir: In seven healthy volunteers, coadministration of
saquinavir (600 mg tid) with delavirdine (400 mg tid) resulted
in a five-fold increase in saquinavir AUC. In 13 healthy volunteers, coadministration of saquinavir (600 mg tid) with delavirdine (400 mg tid) resulted in a 15 a 16% decrease in delavirdine AUC (see PRECAUTIONS-Drug interactions).
Sullamethoxazole and Trimethoprim/Sultamethexazole
(TMP/SMX): Population pharmacokinetic data available for 311
patients suggest that the pharmacokinetics of delavirdine are
not affected by sulfamethoxazole or TMP/SMX.
Zidovudine: Zidovudine and delavirdine do not alter one
anothers pharmacokinetics.

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 shoula
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 circulatisq HIll RNA in plasma. In the clinical study ACTG 261. also
described below, an approved HIll nucleic acid amplification
assay was used.
Figures 1-3 below present results for all patients with data
available at the time points shown. 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 wprp treatment ex'=e yr hW
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
loglo 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. The mean change
from baseline in log0 cxpies/mL plasma Hill-i RNA is summarised in Fig 1 fxr RESCRIPTOR 400 mg id plus zidovudine and
zidovadine monotherapy. All patients had not completed 52
weeks at the time of this analysis.
Fig 1:Mean Change From Baseline in Plasma HIV-1 RNA
Study 0021
> 0 /
5 -D -0 1- 9~1 i e ~
ciaxu snxance of changesinaPa sm Va- eAeshasnot
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% nonCaucasian). 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/mm0 (range 0
to 541 cells/mm0) 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). Mean changes from baseline in
CD4 cell count and logo copies/mL plasma HIV-1 RNA are
summarized in Figs 2 and 3, respectively. All patients had not
completed 52 weeks at the time of this analysis.
Fig 2: Mean Change From Baseline in CD4 Cell Counts
Study 0017

Fig 4 Time to Clnical Progression or Deat
Studs 0017

0 Ks
ACTG 261: RESCRIPTOR-Zidovdine-Didanosiee Triple
Therapy Trial
AIDS Clinical Trials Group (ACTG) Protocol 261 was a randomized trial comparing the folowing tour treatment req
mens: RESCRIPTOR plus didanosine. RESCRIPTOR plus
ziaovudine. RESCRIPTOR plus diaanosine and zidovudine. anc
zidovudine plus didanosine The study enrolled 544 HIV1-infected patients (median age 35 years. 18% female anc
44% non-Caucasian patients) who were either nucleoside
treatment naive or had prior treatment with zidovudine o
didanosine Inot both) for less than 6 months Thirty-seven percent reported previous antiretroviral therapy (194 patients wit
zidovudine and 6 with didanosine). Mean baseline CD4 cel
count was 296 cells/mm0 (range 55 to 640 cellsimm3). Median
baseline plasma HIV-1 RNA level (available for 229 patients
was 4 45 log0 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 ditterence in plasma HIV-1 RNA tor the three-drug
comoination of RESCRIPTiR, zidovudine. and ddanosine
compared with the combination of zidovudine plus didanosine
was observed. The mean change from baseline in CD4 cell
count is shown in Fig 5. The mean change from baseline in
plasma HIV-1 RNA is displayed through week 32 due to the
small number of subjects having HIV-1 RNA determinations at
week 48 and is shown in Fig 6.
Fig 5: Mean Change From Baseline in CD4 Cell Counts
ACTG 261
0 1
Fig 6Mean Change From Baseline in
Plsm il 1RA ACTno 261..
00. o a -
c~a a samiaxioiasapasm~aeiv-1ROMeae
CONTRAINDICATIONS
RESCRIPTOR Tablets are contraindicated in patients with
previously demonstrated clinically significant hypersensitivity
lx any of the components of the formulation
WARNINGS
Coadministration of RESCRIPTOR Tablets with certain
nonsedating antihistamises, sedative hypnotics, antiarehythmics, calcium channel blockers, ergot alkaloid preparations
amhtmiean iaprdemareutiponilysros
(see PRECAUTIONS section).
PRECAUTIONS
General: Delavmrdine is metabolized primarily by the liver
Therefore, caution shuuld be exercised whex administering
RESCRIPTOR Tablets to patients with impaired hepatic lunction.
Reslstance/Creo-Resistaece: Non-nucleoside reverse transcriptase inhibitors, when used alone or in combinatin, may
confer cross-resistance to other non-nucleoside reverse Iranscriptase inhibitors.

Skin Rash: Skin rash attributable to RESCRIPTOR has
occurred in 18% of all patients in combination regimens in
phase II and III controlled trials who received RESCRIPTOR
400 mg tid. Forty-two percent to 50% of patients treated with
RESCRIPTOR 400 mg tid in Studies 0021 and 0017 experienced rash compared with 24% to 32% of patients receiving
monotherapy with zidovudine or didanosine, respectively. In
Studies 0021 and 0017. 4.3% of patients treated with
RESCRIPTOR 400 mg tid discontinued treatment due to rash.
Dose titration did not significantly reduce the incidence of
rash. Rash was typically diffuse. maculopapular, erythematous,
and often pruritic. Skin rash was more common in patients

Fig 3: Mean Change From Baseline in Plasma HIV-1 RNA*
-C Study 0017
E gRESCRIFTOR Deaemm
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-4 -E -0,,,
8 a em 2 40 52
Nit 4" ax4 25 53 i 159
a-six sy avxiaoaean sa ivie,isai
10 is sm 47 4U 318 256 164
clowa sedme cheanges tn USma HIV-RWees
hano be stawsw"
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. Refer to Fig 4.