LA JOLLA, Calif., Oct. 7 /PRNewswire/ -- Agouron Pharmaceuticals, Inc.
(Nasdaq: AGPH) today announced net income of $3,630,000, or $.11 per share, on
total revenues of $91,857,000 for the quarter ended September 30, 1997. Prior
year results for the same period were a net loss of $14,447,000, or $.57 per
share, on total revenues of $17,514,000. First quarter sales of the
Company's anti-HIV drug VIRACEPT(R) (nelfinavir mesylate) were $79,502,000, an
82% increase from the immediately preceding quarter. VIRACEPT was cleared for
marketing in March 1997.
Agouron Pharmaceuticals, Inc. is an integrated pharmaceutical company
committed to the discovery, development, manufacturing, and marketing of
small-molecule drugs engineered to inactivate proteins which play key roles in
cancer, AIDS, and other serious diseases.
This press release may contain forward-looking statements or predictions.
These statements represent our judgment as of this date and are subject to
risks and uncertainties, that could cause the actual results to differ
materially. Important factors concerning these risks are discussed in our
Form 10-K currently on file with the Securities and Exchange Commission.
VIRACEPT is indicated for the treatment of HIV infection when
antiretroviral therapy is warranted. This indication is based on analyses of
surrogate marker changes in patients who received VIRACEPT in combination with
nucleoside analogues or alone for up to 24 weeks. At present, there are no
results from controlled trials evaluating the effect of therapy with VIRACEPT
on clinical progression of HIV infection, such as survival or the incidence of
opportunistic infections.
Full prescribing information for VIRACEPT follows.
For more information on Agouron, you may visit the Agouron Web Site at:
http://www.agouron.com
VIRACEPT(R) is a registered trademark of Agouron Pharmaceuticals, Inc.
CONSOLIDATED STATEMENT OF INCOME (LOSS)
(Unaudited)
(In thousands, except per share amounts)
Three Months Ended
September 30,
1997 1996
Revenues:
Product sales $79,502 $0
Contracts 10,003 17,514
License fees and royalties 2,352 0
91,857 17,514
Operating expenses:
Cost of product sales 34,073 0
Research and development 26,932 29,634
Selling, general and administrative 12,546 3,736
Royalties 13,376 0
86,927 33,370
Operating income (loss) 4,930 (15,856)
Other income (expense):
Interest and other income 1,281 1,779
Interest expense (161) (64)
1,120 1,715
Income (loss) before income taxes 6,050 (14,141)
Income tax provision 2,420 306
Net income (loss) $3,630 $(14,447)
Earnings (loss) per share:
Primary $.11 $(.57)
Fully diluted $.11 $(.57)
Shares used in calculation of:
Primary 33,158 25,152
Fully diluted 33,194 25,152
CONSOLIDATED BALANCE SHEET
(In thousands)
September 30, June 30,
1997 1997
(Unaudited) (Audited)
Assets:
Cash, cash equivalents and
short term investments $98,865 $91,317
Accounts receivable, net 42,187 31,375
Inventories 57,911 58,800
Current deferred tax assets 459 500
Other current assets 2,548 2,209
Total current assets 201,970 184,201
Property and equipment, net 24,716 22,613
Deferred tax assets 56,600 56,000
Purchased intangibles 3,950 4,100
$287,236 $266,914
Liabilities and
stockholder's equity:
Accounts payable
and accrued liabilities $44,850 $37,722
Deferred contract revenue 28,223 27,567
Current deferred tax liabilities 704 600
Current portion of long-term debt 2,506 2,526
Total current liabilities 76,283 68,415
Long-term debt, less current portion 5,723 5,940
Accrued rent 1,232 1,277
Stockholder's equity 203,998 191,282
$287,236 $266,914
Shares outstanding 30,329 29,430
VIRACEPT(R)
(nelfinavir mesylate)
TABLETS and ORAL POWDER
VIRACEPT is indicated for the treatment of HIV infection when
antiretroviral therapy is warranted. This indication is based on surrogate
marker changes in patients who received VIRACEPT in combination with
nucleoside analogues or alone for up to 24 weeks. At present, there are no
results from controlled trials evaluating the effect of therapy with VIRACEPT
on clinical progression of HIV infection, such as survival or the incidence of
opportunistic infections.
DESCRIPTION
VIRACEPT" (nelfinavir mesylate) is an inhibitor of the human
immunodeficiency virus (HIV) protease. VIRACEPT Tablets are available for
oral administration as a light blue, capsule-shaped tablet in a 250 mg
strength (as nelfinavir free base). Each tablet also contains the following
inactive ingredients: calcium silicate, crospovidone, magnesium stearate,
FD&C blue #2 powder and FD&C blue #2 aluminum lake. VIRACEPT Oral Powder is
available for oral administration in a 50 mg/g strength (as nelfinavir free
base) in bottles. The oral powder also contains the following inactive
ingredients: microcrystalline cellulose, maltodextrin, dibasic potassium
phosphate, crospovidone, hydroxypropyl methylcellulose, aspartame, sucrose
palmitate, and natural and artificial flavor. The chemical name for
nelfinavir mesylate is [3S-[2(2S*, 3S*), 3a,4ab,8ab]]-N-(1,1-
dimethylethyl)decahydro-2-[2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-
(phenylthio)butyl]-3-isoquinolinecarboxamide mono-methanesulfonate (salt) and
the molecular weight is 663.90 (567.79 as the free base).
Nelfinavir mesylate is a white to off-white amorphous powder, slightly
soluble in water at pH <4 and freely soluble in methanol, ethanol, isopropanol
and propylene glycol.
Microbiology
Mechanism of Action: Nelfinavir is an inhibitor of the HIV-1 protease.
Inhibition of the viral protease prevents cleavage of the gag-pol polyprotein
resulting in the production of immature, non-infectious virus.
Antiviral Activity In Vitro: The antiviral activity of nelfinavir in
vitro has been demonstrated in both acute and/or chronic HIV infections in
lymphoblastoid cell lines, peripheral blood lymphocytes and
monocytes/macrophages. Nelfinavir was found to be active against several
laboratory strains of HIV-1 and several clinical isolates of HIV-1 and the
HIV-2 strain ROD. The EC95 (95% effective concentration) of nelfinavir ranged
from 7 to 196111 nM. In combination with reverse transcriptase inhibitors,
nelfinavir demonstrated additive (didanosine or stavudine) to synergistic
(zidovudine, lamivudine or zalcitabine) antiviral activity in vitro without
enhanced cytotoxicity. Drug combination studies with protease inhibitors
(ritonavir, saquinavir or indinavir) showed variable results ranging from
antagonistic to synergistic. The clinical relevance of these in vitro
findings is not known.
Drug Resistance: HIV-1 isolates with reduced susceptibility to nelfinavir
have been selected in vitro. HIV isolates from selected patients treated with
nelfinavir alone or in combination with reverse transcriptase inhibitors were
monitored for phenotypic (n=19) and genotypic (n=55) changes in phase I/II
trials over a period of 2 to 52 weeks. One or more virus protease mutations
at amino acid positions 30, 35, 36, 46, 71, 77 and 88 were detected in >10% of
patients with evaluable isolates. Of 19 patients for which both phenotypic
and genotypic analyses were performed on clinical isolates, 9 showed reduced
susceptibility (5- to 93-fold) to nelfinavir in vitro. All 9 patients
possessed one or more mutations in the virus protease gene. Amino acid
position 30 appeared to be the most frequent mutation site. Phenotypic
resistance was defined as a >5-fold decrease in viral sensitivity (EC90) in
vitro compared to baseline. The incidence of the D30N mutation in the virus
protease of randomly selected patients receiving nelfinavir monotherapy (n=64)
or nelfinavir in combination with zidovudine and lamivudine (n=49) at 12 to 16
weeks of therapy was 56% and 6%, respectively. However, the sample size
includes patients with non-amplifiable virus at 12 to 16 weeks of therapy.
The clinical relevance of phenotypic and genotypic changes associated with
nelfinavir therapy has not been established.
Cross-resistance: HIV isolates obtained from 5 patients during nelfinavir
therapy showed a 5- to 93-fold decrease in nelfinavir susceptibility in vitro
when compared to matched baseline isolates, but did not demonstrate a
concordant decrease in susceptibility to indinavir, ritonavir, saquinavir or
141W94, in vitro. Conversely, following ritonavir therapy, 6 of 7 clinical
isolates with decreased ritonavir susceptibility (8- to 113-fold) in vitro
compared to baseline also exhibited decreased susceptibility to nelfinavir in
vitro (5- to 40-fold). An HIV isolate obtained from a patient receiving
saquinavir therapy showed decreased susceptibility to saquinavir (7-fold), but
did not demonstrate a concordant decrease in susceptibility to nelfinavir in
vitro. Cross-resistance between nelfinavir and reverse transcriptase
inhibitors is unlikely because different enzyme targets are involved. One
zidovudine-resistant HIV-1 isolate and one pyridinone-resistant HIV-1 isolate
tested in vitro retained susceptibility to nelfinavir. Because the potential
for HIV cross-resistance between nelfinavir and other protease inhibitors has
not been fully explored, it is unknown what effect nelfinavir therapy will
have on the activity of coadministered or subsequently administered protease
inhibitors.
CLINICAL PHARMACOLOGY
Pharmacokinetics
The pharmacokinetic properties of nelfinavir were evaluated in healthy
volunteers and HIV-infected patients; no substantial differences were observed
between the two groups.
Absorption: After single and multiple oral doses of 500 to 750 mg (two to
three 250 mg tablets) with food, peak nelfinavir plasma concentrations were
typically achieved in 2 to 4 hours. After multiple dosing with 750 mg every 8
hours three times daily (TID) for 28 days (steady-state), peak plasma
concentrations (Cmax) averaged 3-4 ug/mL and plasma concentrations prior to
the morning dose (trough) were 1-3 ug/mL (trough sample collection times
averaged 11 hours after the previous evening dose). A greater than dose-
proportional increase in nelfinavir plasma concentrations was observed after
single doses; however, this was not observed after multiple dosing.
Effect of Food on Oral Absorption: Maximum plasma concentrations and area
under the plasma concentration-time curve (AUC) were 2 to 3-fold higher under
fed conditions compared to fasting. The effect of food on nelfinavir
absorption was evaluated in two studies (n=14, total). The meals evaluated
contained 517 to 759 Kcal, with 153 to 313 Kcal derived from fat.
Distribution: The apparent volume of distribution following oral
administration of nelfinavir was 2-7 L/kg. Nelfinavir in serum is extensively
protein-bound (>98%).
Metabolism: Unchanged nelfinavir comprised 82-86% of the total plasma
radioactivity after a single oral 750 mg dose of 14C-nelfinavir. In vitro,
multiple cytochrome P-450 isoforms including CYP3A are responsible for
metabolism of nelfinavir. One major and several minor oxidative metabolites
were found in plasma. The major oxidative metabolite has in vitro antiviral
activity comparable to the parent drug.
Elimination: The terminal half-life in plasma was typically 3.5 to
5 hours. The majority (87%) of an oral 750 mg dose containing 14C-nelfinavir
was recovered in the feces; fecal radioactivity consisted of numerous
oxidative metabolites (78%) and unchanged nelfinavir (22%). Only 1-2% of the
dose was recovered in urine, of which unchanged nelfinavir was the major
component.
Special Populations
Hepatic or Renal Insufficiency: The pharmacokinetics of nelfinavir have
not been studied in patients with hepatic or renal insufficiency; however,
less than 2% of nelfinavir is excreted in the urine, so the impact of renal
impairment on nelfinavir elimination should be minimal.
Gender and Race: No significant pharmacokinetic differences have been
detected between males and females. Pharmacokinetic differences due to race
have not been evaluated.
Pediatrics: see PRECAUTIONS: Pediatric Use
Drug Interactions (also see PRECAUTIONS, Drug Interactions)
The potential ability of nelfinavir to inhibit the major human cytochrome
P450 isoforms (CYP3A, CYP2C19, CYP2D6, CYP2C9, CYP1A2 and CYP2E1) has been
investigated in vitro. Only CYP3A was inhibited at concentrations in the
therapeutic range.
Specific drug interaction studies were performed with nelfinavir and a
number of drugs. Tables 1 and 2 summarize the effects of coadministration of
nelfinavir on the geometric mean AUC and Cmax.
Table 1
Effect of Nelfinavir on Coadministered Drug Plasma AUC and Cmax
Coadministered Drug
Coadministered Drug Nelfinavir Dose N AUC (95%CI) Cmax (95%CI)
Lamivudine 150 mg
Single Dose 750 mg q8h x 7-10 11 10% 31%
days (1-20%) (5-62%)
Stavudine 30-40 mg
bid x 56 days 750 mg tid x 56 days 8 ' '
Zidovudine 200 mg
Single Dose 750 mg q8h x 7-10 11 -35% -31%
days (28-41%) (8-49%)
Indinavir 800 mg
Single Dose 750 mg q8h x 7 days 6 51% '
(25-83%)
Ritonavir 500 mg
Single Dose 750 mg q8h x 5 10 'Pending 'Pending
doses
Saquinavir 1200 mg
Single Dose* 750 mg tid x 4 days 14 392% 179%
(271-553%) (105-280%)
Ethinyl estradiol
35 mg qd x 15 days 750 mg q8h x 7 days 12 -47% -28%
(41-63%) (14-39%)
Norethindrone 0.4 mg
qd x 15 days 750 mg q8h x 7 days 12 -18% '
(12-27%)
Rifabutin 300 mg
qd x 8 days 750 mg q8h x 7-8 10 207% 146%
days (151-276%) (112-186%)
Terfenadine 60 mg
Single Dose 750 mg q8h x 7 days 12 Terfenadine plasma
concentrations were
transiently measurable
when coadministered with
VIRACEPT**
Table 2
Effect of on Coadministered Drug on Nelfinavir Plasma AUC and Cmax
Nelfinavir
Coadministered Drug Nelfinavir Dose N AUC (95%CI) Cmax (95%CI)
Didanosine 200 mg
Single Dose 750 mg Single Dose 9 ' '
Zidovudine 200 mg + 750 mg q8h x 7-10 11 ' '
Lamivudine 150 mg days
Single Dose
Indinavir 800 mg
q8h x 7 days 750 mg Single Dose 6 83% 31%
(34-150%) (13-52%)
Ritonavir 500 mg
q8h x 3 doses 750 mg Single Dose 10 152% 44%
(86-242%) (25-67%)
Saquinavir 1200 mg
tid x 4 days* 750 mg Single Dose 14 18% '
(5-33%)
Ketoconazole 400 mg
qd x 7 days 500 mg q8h x 5-6 12 35% 25%
days (21-49%) (8-44%)
Rifabutin 300 mg
qd x 8 days 750 mg q8h x 7-8 10 -32% -25%
(10-48%) (6-38%)
Rifampin 600 mg
qd x 7 days 750 mg q8h x 5-6 12 -82% -76%
(77-86%) (67-83%)
Indicates increase
- Indicates decrease
' Indicates no change
* Using an experimental (soft-gelatin capsule) formulation of saquinavir
1200mg
** Terfenadine and VIRACEPT should not be coadministered (see WARNINGS)
For information regarding clinical recommendations, see PRECAUTIONS, Drug
Interactions.
INDICATIONS AND USAGE
VIRACEPT is indicated for the treatment of HIV infection when
antiretroviral therapy is warranted. This indication is based on surrogate
marker changes in patients who received VIRACEPT in combination with
nucleoside analogues or alone for up to 24 weeks. At present, there are no
results from controlled trials evaluating the effect of therapy with VIRACEPT
on clinical progression of HIV infection, such as survival or the incidence of
opportunistic infections.
Description of Studies
In the clinical studies described below, an experimental branched DNA
signal amplification assay was used to estimate the level of circulating
HIV-RNA in plasma. Using this assay, values below an estimated 1,200
copies/mL could not be reliably quantified and were set to 1,200 copies/mL in
all analyses. The units reported, copies/mL, may not represent actual viral
copies on an absolute scale. Consequently, HIV-RNA results summarized below
should not be directly compared to results from other trials utilizing
different HIV-RNA assays.
Study 511: VIRACEPT + zidovudine + lamivudine versus zidovudine +
lamivudine
Study 511 was a double-blind, randomized, placebo controlled trial
comparing treatment with zidovudine and lamivudine plus 2 doses of VIRACEPT to
zidovudine and lamivudine alone in 297 antiretroviral naive HIV-1 infected
patients (median age 35 [range 21 to 63], 89% male and 78% Caucasian ). Mean
baseline CD4 cell count was 288 cells/mm3 and mean baseline plasma serum HIV
RNA was 153,044 copies/mL (mean of log10 baseline plasma HIV RNA was 4.86).
At 24 weeks of therapy, 59, 73 and 30 patients randomized to receive
VIRACEPT 500 mg TID plus zidovudine and lamivudine, VIRACEPT 750 mg TID plus
zidovudine and lamivudine, or zidovudine and lamivudine, respectively, had
plasma HIV RNA assigned a value of 1,200 copies/mL. The clinical significance
of changes in plasma HIV RNA has not been established.
Study 506: VIRACEPT + stavudine versus stavudine
Study 506 is an ongoing double-blind, randomized, placebo controlled trial
comparing treatment with 2 doses of VIRACEPT + stavudine and stavudine
monotherapy in 308 HIV-1 infected patients (median age 37 [range 21 to 69],
89% male and 75% Caucasian). Sixty-one out of 308 (20%) patients were
antiretroviral naive; the remaining patients were experienced (mean duration
of antiretroviral therapy 32 months). The mean baseline CD4 cell count for
all patients was 279 cells/mm3 and the mean baseline plasma HIV RNA was
141,369 copies/mL (mean of log10 baseline plasma HIV RNA was 4.86). Mean
changes in plasma HIV RNA and CD4 cell count are summarized in Figures 3 and
4, respectively. The study allowed for treatment changes in the three study
arms based on surrogate marker response or toxicity. By 24 weeks 43, 2 and 4
patients remaining on this study in the stavudine, stavudine plus VIRACEPT 500
mg TID, and stavudine plus VIRACEPT 750 mg TID arms, respectively, had altered
initial therapy based primarily on their surrogate marker response. For
patients receiving stavudine monotherapy, alteration of therapy was primarily
the addition of nelfinavir. Figures 3 and 4 represent surrogate marker
changes by original randomization group, without regard to treatment
modification.
Study 506: Mean Log10 Change From Baseline in Plasma HIV RNA
At 24 weeks of therapy, 24, 22 and 13 patients randomized to receive
VIRACEPT 500 mg TID plus stavudine, VIRACEPT 750 mg TID plus stavudine, or
stavudine alone, respectively, had plasma HIV RNA levels assigned a value of
1,200 copies/mL. The clinical significance of changes in plasma HIV RNA has
not been established.
Study 506: Mean Change From Baseline in CD4 Cell Counts
CONTRAINDICATIONS
VIRACEPT is contraindicated in patients with clinically significant
hypersensitivity to any of its components.
WARNING
Patients with Phenylketonuria: VIRACEPT Oral Powder contains 11.2 mg
phenylalanine per gram of powder.
VIRACEPT should not be administered concurrently with terfenadine,
astemizole, cisapride, triazolam, midazolam, ergot derivatives, amiodarone or
quinidine because VIRACEPT may effect the hepatic metabolism of these drugs
and create the potential for serious and/or life-threatening adverse events.
(see PRECAUTIONS, Drug Interactions)
New onset diabetes mellitus, exacerbation of pre-existing diabetes
mellitus and hyperglycemia have been reported during post-marketing
surveillance in HIV-infected patients receiving protease inhibitor therapy.
Some patients required either initiation or dose adjustments of insulin or
oral hypoglycemic agents for treatment of these events. In some cases
diabetic ketoacidosis has occurred. In those patients who discontinued
protease inhibitor therapy, hyperglycemia persisted in some cases. Because
these events have been reported voluntarily during clinical practice,
estimates of frequency cannot be made and a causal relationship between
protease inhibitor therapy and these events has not been established.
PRECAUTIONS
General
Nelfinavir is principally metabolized by the liver. Therefore, caution
should be exercised when administering this drug to patients with hepatic
impairment.
Resistance/Cross Resistance: Because the potential for HIV cross
resistance between protease inhibitors has not been fully explored, it is
unknown what effect nelfinavir therapy will have on the activity of
subsequently administered protease inhibitors. (See Microbiology)
Hemophilia
There have been reports of increased bleeding, including spontaneous skin
hematomas and hemarthrosis, in patients with hemophilia type A and B treated
with protease inhibitors. In some patients, additional factor VIII was given.
In more than half of the reported cases, treatment with protease inhibitors
was continued or reintroduced. A causal relationship has not been
established.
Information For Patients
For optimal absorption, patients should be advised to take VIRACEPT with
food (see Pharmacokinetics and DOSAGE AND ADMINISTRATION).
Patients should be informed that VIRACEPT is not a cure for HIV infection
and that they may continue to acquire illnesses associated with advanced HIV
infection, including opportunistic infections.
Patients should be told that the long-term effects of VIRACEPT are unknown
at this time. They should be told that there is currently no data
demonstrating that VIRACEPT therapy can reduce the risk of transmitting HIV to
others through sexual contact or blood contamination.
Patients should be advised to take VIRACEPT every day as prescribed.
Patients should not alter the dose or discontinue therapy without consulting
with their doctor. If a dose is missed, patients should take the dose as soon
as possible and then return to their normal schedule. However, if a dose is
skipped, the patient should not double the next dose.
The most frequent adverse event associated with VIRACEPT is diarrhea,
which can usually be controlled with non-prescription drugs, such as
loperamide, which slow gastrointestinal motility.
VIRACEPT may interact with some drugs, therefore, patients should be
advised to report to their doctor the use of any other prescription or non-
prescription medication.
Patients receiving oral contraceptives should be instructed that alternate
or additional contraceptive measures should be used during therapy with
VIRACEPT.
Drug Interactions
Nelfinavir is an inhibitor of CYP3A (cytochrome P450 3A).
Coadministration of VIRACEPT and drugs primarily metabolized by CYP3A (e.g.,
dihydropyridine calcium channel blockers) may result in increased plasma
concentrations of the other drug that could increase or prolong both its
therapeutic and adverse effects. Nelfinavir is metabolized in part by CYP3A.
Coadministration of VIRACEPT and drugs that induce CYP3A may decrease
nelfinavir plasma concentrations and reduce its therapeutic effect.
Coadministration of VIRACEPT and drugs that inhibit CYP3A may increase
nelfinavir plasma concentrations.
Based on known metabolic profiles, clinically significant drug
interactions are not expected between VIRACEPT and dapsone,
trimethoprim/sulfamethoxazole, clarithromycin, azithromycin, erythromycin,
itraconazole or fluconazole.
Drugs That Should Not be Coadministered
With VIRACEPT
Drug Class Drugs Within Class Not to
be Coadministered With
VIRACEPT
Antiarrhythmics amiodarone, quinidine
Antihistamines astemizole, terfenadine
Antimigraine ergot derivatives
Antimycobacterial
agents rifampin
Benzodiazepines midazolam, triazolam
GI motility agents cisapride
Drugs Which Require a Dose Reduction When
Coadministered With VIRACEPT
Drug Class Drugs Within Class Which
Require Dose Reduction
Antimycobacterial rifabutin
agents
Other Potentially Clinically Significant Drug
Interactions With VIRACEPT*
Anticonvulsants: May decrease
carbamazepine, phenobarbital, nelfinavir plasma
phenytoin concentrations**
Anti-HIV protease inhibitors: May increase
indinavir, ritonavir nelfinavir plasma
concentrations
Oral contraceptives: ethinyl Plasma
estradiol, norethindrone concentrations
may be decreased
by VIRACEPT
* This table is not all inclusive.
** VIRACEPT may not be effective due to decreased nelfinavir plasma
concentrations in patients taking these agents concomitantly
Antihistamines
Terfenadine: Administration of terfenadine with VIRACEPT resulted in the
appearance of unchanged terfenadine in plasma; therefore, VIRACEPT should not
be administered concurrently with terfenadine because of the potential for
serious and/or life-threatening cardiac arrhythmias. Because a similar
interaction is likely, VIRACEPT should also not be administered concurrently
with astemizole.
Anti-HIV protease inhibitors
Indinavir: Coadministration of indinavir with VIRACEPT resulted in an 83%
increase in nelfinavir plasma AUC and a 51% increase in indinavir plasma AUC.
Currently, there are no safety and efficacy data available from the use of
this combination.
Ritonavir: Coadministration of ritonavir with VIRACEPT resulted in a 152%
increase in nelfinavir plasma AUC and very little change in ritonavir plasma
AUC. Currently, there are no safety and efficacy data available from the use
of this combination.
Saquinavir: Coadministration of saquinavir (using an experimental soft-
gelatin capsule formulation of saquinavir 1200 mg) with VIRACEPT resulted in
an 18% increase in nelfinavir plasma AUC and a 4-fold increase in saquinavir
plasma AUC. If used in combination with saquinavir hard gelatin capsules at
the recommended dose of 600 mg tid, no dose adjustments are needed.
Currently, there are no safety and efficacy data available from the use of
this combination.
Antifungal agents
Ketoconazole: Coadministration of ketoconazole with VIRACEPT resulted in
a 35% increase in nelfinavir plasma AUC. This change was not considered
clinically significant and no dose adjustment is needed when ketoconazole and
VIRACEPT are coadministered.
Anti-HIV reverse transcriptase inhibitors
Didanosine: It is recommended that didanosine be administered on an empty
stomach; therefore, nelfinavir should be administered (with food) one hour
after or more than 2 hours before didanosine.
Zidovudine: Coadministration of zidovudine and lamivudine with VIRACEPT
resulted in a 35% decrease in zidovudine plasma AUC. A dose adjustment is not
needed when zidovudine is administered with VIRACEPT.
Little or no change in the pharmacokinetics of either drug was observed
when VIRACEPT was coadministered with lamivudine or stavudine.
Antimycobacterial agents
Rifabutin: Coadministration of rifabutin and VIRACEPT resulted in a 32%
decrease in nelfinavir plasma AUC and a 207% increase in rifabutin plasma AUC.
It is recommended that the dose of rifabutin be reduced to one-half the usual
dose when administered with VIRACEPT.
Rifampin: Coadministration of rifampin and VIRACEPT resulted in an 82%
decrease in nelfinavir plasma AUC. VIRACEPT and rifampin should not be
coadministered.
Oral Contraceptives
Ethinyl estradiol and norethindrone: Coadministration of VIRACEPT with
OVCON-35 resulted in a 47% decrease in ethinyl estradiol and an 18% decrease
in norethindrone plasma concentrations. Alternate or additional contraceptive
measures should be used during therapy with VIRACEPT.
Carcinogenesis and Mutagenesis
Carcinogenicity studies in animals have not yet been completed. Nelfinavir
was not, however, mutagenic or clastogenic in a battery of in vitro and in
vivo tests including microbial mutagenesis (Ames), mouse lymphoma, chromosome
aberrations in human lymphocytes, and an in vivo rat micronucleus assay.
Pregnancy, Fertility and Reproduction - Pregnancy Category B
Comparisons of systemic exposure are based on the steady-state area under
the plasma concentration time curve (AUC) observed in humans receiving the
recommended therapeutic dose. Nelfinavir produced no effects on either male
or female mating and fertility or embryo survival in rat studies at exposures
comparable to human therapeutic exposure. There were also no effects on fetal
development or maternal toxicity when nelfinavir was administered to pregnant
rats at systemic exposures comparable to human exposure at the recommended
therapeutic dose. Administration of nelfinavir to pregnant rabbits resulted
in no fetal development effects up to a dose at which a slight decrease in
maternal body weight was observed; however, even at the highest dose
evaluated, systemic exposure in rabbits was significantly lower than human
exposure. Additional studies in rats indicated that exposure to nelfinavir in
females from mid-pregnancy through lactation had no effect on the survival,
growth, and development of the offspring to weaning. Subsequent reproductive
performance of these offspring was also not affected by maternal exposure to
nelfinavir. However, there are no adequate and well-controlled studies in
pregnant women. Because animal reproduction studies are not always predictive
of human response, VIRACEPT should be used during pregnancy only if clearly
needed.
Nursing Mothers
The US Public Health Service Centers for Disease Control and Prevention
advises HIV-infected women not to breast-feed to avoid postnatal transmission
of HIV to a child who may not yet be infected. Studies in lactating rats have
demonstrated that nelfinavir is excreted in milk. It is not known whether
nelfinavir is excreted in human milk.
Pediatric Use
Nelfinavir was studied in one open-label, uncontrolled trial in 38
pediatric patients ranging in age from 2 to 13 years. In order to achieve
plasma concentrations in pediatric patients which approximate those observed
in adults, the recommended pediatric dose is 20-30 mg/kg given three times
daily with a meal or light snack, not to exceed 750 mg three times a day. (see
DOSAGE AND ADMINISTRATION).
A similar adverse event profile was seen during the pediatric clinical
trial as in adult patients. The evaluation of the antiviral activity of
nelfinavir in pediatric patients is ongoing.
The safety, effectiveness and pharmacokinetics of nelfinavir have not been
evaluated in pediatric patients below the age of 2 years.
ADVERSE REACTIONS
The safety of VIRACEPT was studied in over 1500 patients who received
drug either alone or in combination with nucleoside analogues (d4T or
ZDV/3TC). The majority of adverse events were of mild intensity. The most
frequently reported adverse event among patients receiving VIRACEPT was
diarrhea, which was generally of mild to moderate intensity.
Drug-related clinical adverse experiences of moderate or severe intensity in
>2% of patients treated with VIRACEPT coadministered with ZDV plus 3TC (Study
511) or in combination with d4T (Study 506) for up to 24 weeks are presented
in Table 3.
Table 3
Percentage of Patients with Treatment-Emergent1 Adverse Events of Moderate
or Severe Intensity Reported in >2% of Patients
Study 511 Study 506
Naive Patients Experienced Patients
Adverse Events Placebo 500 mg TID 750 mg TID Placebo 500 mg TID 750 mg TID
+ VIRACEPT VIRACEPT + d4T VIRACEPT VIRACEPT
ZDV/3TC + ZDV/3TC + ZDV/3TC (n=109) +d4T +d4T
(n=101) (n=97) (n=100) (n=98) (n=101)
Body as a
Whole
Abdominal
Pain 1% 0 0 3% 2% 4%
Asthenia 2% 1% 1% 4% 3% 1%
Digestive
System
Diarrhea 3% 1412% 2019% 10% 2812% 3219%
Nausea 46% 3% 7% 16% 3% 2%
Flatulence 0 5% 23% 4% 8% 33%
Skin/Appendages
Rash 1% 1% 3% 0 4% 3%
1 Includes those adverse events at least possibly related to study drug or
of unknown relationship and excludes concurrent HIV conditions
Adverse events occurring in less than 2% of patients receiving VIRACEPT in
all phase II/III clinical trials and considered at least possibly related or
of unknown relationship to treatment and of at least moderate severity are
listed below.
Body as a Whole: accidental injury, allergic reaction, back pain, fever,
headache, malaise, and pain.
Digestive System: anorexia, dyspepsia, epigastric pain, gastrointestinal
bleeding, hepatitis, mouth ulceration, pancreatitis and vomiting.
Hemic/Lymphatic System: anemia, leukopenia and thrombocytopenia.
Metabolic/Nutritional System: increases in alkaline phosphate, amylase,
creatinine phosphokinase, lactic dehydrogenase, SGOT, SGPT and gamma glutamyl
transpeptidase; hyperlipemia, hyperuricemia, hyperglycemia, hypoglycemia,
dehydration, and liver function tests abnormal.
Musculoskeletal System: arthralgia, arthritis, cramps, myalgia,
myasthenia and myopathy.
Nervous System: anxiety, depression, dizziness, emotional lability,
hyperkinesia, insomnia, migraine, paresthesia, seizures, sleep disorder,
somnolence and suicide ideation.
Respiratory System: dyspnea, pharyngitis, rhinitis, and sinusitis.
Skin/Appendages: dermatitis, folliculitis, fungal dermatitis, maculopapular
rash, pruritus, sweating, and urticaria.
Special Senses: acute iritis and eye disorder.
Urogenital System: kidney calculus, sexual dysfunction and urine
abnormality.
Laboratory Abnormalities
Few patients experienced significant laboratory abnormalities while
receiving VIRACEPT. The percentage of patients with marked laboratory
abnormalities in Studies 511 and 506 are presented in Table 4. Marked
laboratory abnormalities are defined as a Grade 3 or 4 abnormality in a
patient with a normal baseline value or a Grade 4 abnormality in a patient
with a Grade 1 abnormality at baseline.
Table 4
Percentage of Patients by Treatment Group With Marked Laboratory
Abnormalities 1 in >2% of Patients
Study 511 Study 506
Naive Patients Experienced Patients
Placebo 500 mg TID 750 mg TID Placebo 500 mg TID 750 mg TID
+ VIRACEPT VIRACEPT VIRACEPT VIRACEPT
ZDV/3TC + ZDV/3TC + ZDV/3TC + d4T + d4T + d4T
(n=101) (n=97) (n=100) (n=109) (n=98) (n=101)
Hematology
Hemoglobin 65% 3% 2% 0 0 0
Neutrophils 4% 3% 53% 1% 1% 43%
Lymphocytes 1% 65% 10% 1% 15% 0
Chemistry
ALT (SGPT) 65% 1% 1% 15% 3% 2%
AST (SGOT) 4% 10% 0 0 30% 3%
Creatine
KinaseTrigly
cerides 70% 20% 2% 40% 50% 6%
1 Marked laboratory abnormalities are defined as a shift from Grade 0 at
baseline to at least Grade 3 or from Grade 1 to Grade 4
OVERDOSAGE
Human experience of acute overdose with VIRACEPT is limited. There is no
specific antidote for overdose with VIRACEPT. If indicated, elimination of
unabsorbed drug should be achieved by emesis or gastric lavage.
Administration of activated charcoal may also be used to aid removal of
unabsorbed drug. Since nelfinavir is highly protein bound, dialysis is
unlikely to significantly remove drug from blood.
DOSAGE AND ADMINISTRATION
Adults: The recommendedusual dose is 750500 mg (threetwo 250 mg tablets)
three times daily. Patients with more advance disease may have a superior
reduction in viral RNA with 750 mg three times daily. VIRACEPT should be taken
with a meal or light snack. The aAntiviral activity of VIRACEPT is enhanced
when VIRACEPT is administered in combination with nucleoside analogues.
Therefore, it is recommended that VIRACEPT be used in combination with
nucleoside analogues.
Pediatric Patients (2-13 years): For children, the generally The
recommended oral dose of VIRACEPT for pediatric patients 2 to 13 years of age
is 20-30 mg/kg per dose, three times daily with a meal or a light snack. For
children unable to take tablets, VIRACEPT Oral Powder may be administered.
The oral powder may be mixed with a small amount of water, milk, formula, soy
formula, soy milk or dietary supplements; once mixed, the entire contents must
be consumed in order to obtain the full dose. The recommended use period for
storage of the product in these media is 6 hours. Acidic food or juice (e.g.,
orange juice, apple juice or apple sauce) are not recommended to be used in
combination with VIRACEPT, because the combination may result in a bitter
taste. VIRACEPT Oral Powder should not be reconstituted with water in its
original container. The recommended pediatric dose of VIRACEPT to be
administered three times daily is described in Table 5:
Table 5
Pediatric Dose to be Administered Three Times Daily
Body Weight Number of Number of
Level 1 gm Level Number of
Kg. lbs. Scoops Teaspoons Tablets
7 to < 8.5 15.5 to < 18.5 4 1 -----
8.5 to < 10.5 18.5 to < 23 5 1 1/4 -----1
10.5 to < 12 23 to < 26.5 6 1 1/2 -----
12 to < 14 26.5 to < 31 7 1 3/4 -----
14 to < 16 31 to < 35 8 2 -----
16 to < 18 35 to < 39.5 9 2 1/4 -----
18 to < 23 39.5 to < 50.5 10 2 1/2 2
>/- 23 >/- 50.5 15 3 3/4 3
HOW SUPPLIED
VIRACEPT (nelfinavir mesylate) Tablets, 250 mg are light blue, capsule-
shaped tablets engraved with "VIRACEPT" on one side and "250 mg" on the other.
Available as:
NDC 63010-010-27, bottle containing 270 tablets
NDC 63010-010-18, bottle containing 180 tablets
VIRACEPT (nelfinavir mesylate) Oral Powder, 50 mg/g is an off-white powder
containing 50 mg (as nelfinavir free base) in each level scoopful (1 gram).
Available as:
NDC 63010-011-90, multiple use bottle containing 144 grams of powder with
scoop.
VIRACEPT Tablets and Oral Powder should be stored at 15 to 30 .C (59. to
86 .F).
SOURCE Agouron Pharmaceuticals, Inc.
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CONTACT:
Donna Nichols, Vice President, Head of
Corporate Communications for Agouron Pharmaceuticals, Inc.,
619-622-3009
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