LA JOLLA, Calif., Jan. 22 /PRNewswire/ -- Agouron Pharmaceuticals, Inc.
(Nasdaq: AGPH) today announced approval of the company's HIV protease
inhibitor VIRACEPT(R) (nelfinavir mesylate) in Europe. The European
Commission granted VIRACEPT European marketing authorization for the treatment
of HIV infection in adults and children in combination with antiretroviral
nucleoside analog(s). VIRACEPT is the first HIV protease inhibitor to receive
simultaneous approval of adult and pediatric formulations in the European
Union. F. Hoffmann-La Roche, Ltd based in Basel, Switzerland, will be
responsible for the sales and marketing of VIRACEPT throughout Europe.
"We believe that the anti-HIV potency, durability, safety, and
tolerability of VIRACEPT will distinguish the product in Europe as an
important element in the arsenal of anti-HIV drugs," said Agouron's president
and CEO Peter Johnson. The European Union is comprised of 15 countries:
Austria, Belgium, Denmark, Finland, France, Germany, Greece, Netherlands,
Ireland, Italy, Luxembourg, Portugal, Spain, Sweden, and the United Kingdom.
VIRACEPT was approved in Switzerland last June.
European approval of VIRACEPT was based on data evaluated by the Committee
for Proprietary Medicinal Products (CPMP), which showed that VIRACEPT was well
tolerated and safe in more than 800 patients in controlled clinical trials and
over 4000 patients in compassionate use programs. Data from Study 511, a key
clinical trial, demonstrated long-term virologic and immunologic activity in
297 patients treated with either VIRACEPT in combination with Retrovir(R)
(zidovudine or AZT) and Epivir(R) (lamivudine or 3TC), or Retrovir and Epivir
alone. After 48 weeks of treatment, approximately 80% of patients treated
with VIRACEPT combination therapy had viral loads that remained below the
level of detection of the assay (a branch DNA-based assay with a lower limit
of quantification of <500copies/mL). Mean CD4+ T-cell counts (infection-
fighting cells of the immune system) increased by more than 170 cells/mm3.
The most commonly observed adverse event of moderate or greater severity
in clinical trials of VIRACEPT was diarrhea, which was generally controlled
with over-the-counter medications. New onset or exacerbation of diabetes
mellitus, hyperglycemia, as well as increased bleeding in patients with
hemophilia types A and B, have been reported with protease inhibitors.
The VIRACEPT Expanded Access Program in Europe has provided drug free of
charge to people living with HIV infection prior to approval. In the United
States, more than 75,000 people are estimated to be taking VIRACEPT, and
VIRACEPT has been evaluated in more than 8000 people throughout the world.
Europe has played an important role in all phases of VIRACEPT clinical
trials. Currently underway is a large European study of approximately 500
patients in which twice-daily dosing (BID) of VIRACEPT is being evaluated in
combination with nucleoside analogs. Preliminary data from this BID study
will be presented at the 5th Conference on Retroviruses and Opportunistic
Infections next month in Chicago, Illinois.
In the United States, 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 analogs 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.
Agouron Pharmaceuticals, Inc. is an integrated pharmaceutical company
committed to discovery, development, manufacturing, and marketing of
small-molecule drugs engineered to inactivate proteins which play key roles in
cancer, AIDS, and other serious diseases.
Full prescribing information for VIRACEPT follows.
For further information about Agouron Pharmaceuticals, Inc., please see
Agouron's website: http://www.agouron.com
VIRACEPT(R) is a registered trademark of Agouron Pharmaceuticals, Inc.
Retrovir(R) and Epivir(R) are registered trademarks of Glaxo Wellcome
Oncology/HIV.
AGOURON PHARMACEUTICALS, INC.
La Jolla, CA 92037, USA
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(R) (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 and
FD&C blue #2 powder. 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 196 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 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 750 mg q8h 11 up 10% up 31%
Single Dose x 7-10 days (1-20%) (5-62%)
Stavudine 30-40 mg 750 mg tid 8 <-> <->
bid x 56 days x 56 days
Zidovudine 200 mg 750 mg q8h 11 down 35% down 31%
Single Dose x 7-10 days (28-41%) (8-49%)
Indinavir 800 mg 750 mg q8h 6 up 51% <->
Single Dose x 7 days (25-83%)
Ritonavir 500 mg 750 mg q8h 10 <-> Pending <-> Pending
Single Dose x 5 doses
Saquinavir 1200 mg * 750 mg tid 14 up 392% up 179%
Single Dose x 4 days (271-553%) (105-280%)
Ethinyl estradiol 750 mg q8h 12 down 47% down 28%
35 ug qd x 15 days x 7 days (41-63%) (14-39%)
Norethindrone 0.4 mg 750 mg q8h 12 down 18% <->
qd x 15 days x 7 days (12-27%)
Rifabutin 300 mg 750 mg q8h 10 up 207% up 146%
qd x 8 days x 7-8 days (151-276%) (112-186%)
Terfenadine 60 mg 750 mg q8h 12 Terfenadine plasma
Single Dose x 7 days concentrations were
transiently measurable
when coadministered
with VIRACEPT**
Table 2
Effect of Coadministered Drug on Nelfinavir Plasma AUC and Cmax
Nelfinavir
Coadministered Drug Nelfinavir Dose N AUC (95%CI) Cmax (95%CI)
Didanosine 200 mg 750 mg 9 <-> <->
Single Dose Single Dose
Zidovudine 200 mg 750 mg q8h 11 <-> <->
+ Lamivudine x 7-10 days
150 mg Single Dose
Indinavir 800 mg 750 mg 6 up 83% up 31%
q8h x 7 days Single Dose (34-150%) (13-52%)
Ritonavir 500 mg 750 mg 10 up 152% up 44%
q8h x 3 doses Single Dose (86-242%) (25-67%)
Saquinavir 1200 mg * 750 mg 14 up 18% <->
tid x 4 days Single Dose (5-33%)
Ketoconazole 400 mg 500 mg q8h 12 up 35% up 25%
qd x 7 days x 5-6 days (21-49%) (8-44%)
Rifabutin 300 mg 750 mg q8h 10 down 32% down 25%
qd x 8 days x 7-8 days (10-48%) (6-38%)
Rifampin 600 mg 750 mg q8h 12 down 82% down 76%
qd x 7 days x 5-6 days (77-86%) (67-83%)
<-> 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 HIV RNA was
153,044 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 1 and
2, respectively.
Figure 1 demonstrates Study 511: Mean Log10 Change From Baseline in Plasma
HIV RNA.* 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.
Figure 2 demonstrates Study 511: Mean Change From Baseline in CD4 Cell
Counts.*
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.
Figure 3 demonstrates 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.
Figure 4 demonstrates Study 506: Mean Change From Baseline in CD4 Cell
Counts.*
* To receive a copy of Figures 1 - 4, please contact Agouron
Pharmaceuticals through the contact person indicated for this release.
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 CLINICAL PHARMACOLOGY: 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 agents rifabutin
Other Potentially Clinically Significant Drug Interactions With VIRACEPT*
Anticonvulsants:
carbamazepine, phenobarbital, May decrease nelfinavir
phenytoin plasma concentrations**
Anti-HIV protease inhibitors: May increase nelfinavir
indinavir, ritonavir plasma concentrations
Oral contraceptives: Plasma concentrations
ethinyl estradiol, may be decreased
norethindrone 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. 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-Emergent(1) Adverse Events of
Moderate or Severe Intensity Reported in >2% of Patients
Study 511
Naive Patients
Adverse Events Placebo 500 mg TID 750 mg TID
+ ZDV/3TC VIRACEPT VIRACEPT
+ ZDV/3TC + ZDV/3TC + ZDV/3TC
(n=101) (n=97) (n=100)
Body as a Whole
Abdominal Pain 1% 0 0
Asthenia 2% 1% 1%
Digestive System
Diarrhea 3% 14% 20%
Nausea 4% 3% 7%
Flatulence 0 5% 2%
Skin/Appendages
Rash 1% 1% 3%
Study 506
Experienced Patients
Adverse Events 500 mg TID 750 mg TID
Placebo VIRACEPT VIRACEPT
+ d4T + d4T + d4T
(n=109) (n=98) (n=101)
Body as a Whole
Abdominal Pain 3% 2% 4%
Asthenia 4% 3% 1%
Digestive System
Diarrhea 10% 28% 32%
Nausea 1% 3% 2%
Flatulence 4% 8% 3%
Skin/Appendages
Rash 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,
creatine 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
Naive Patients
Placebo 500 mg TID 750 mg TID
+ ZDV/3TC VIRACEPT VIRACEPT
+ ZDV/3TC + ZDV/3TC
(n=101) (n=97) (n=100)
Hematology
Hemoglobin 6% 3% 2%
Neutrophils 4% 3% 5%
Lymphocytes 1% 6% 1%
Chemistry
ALT (SGPT) 6% 1% 1%
AST (SGOT) 4% 1% 0
Creatine Kinase
Triglycerides 7% 2% 2%
Study 506
Experienced Patients
Placebo 500 mg TID 750 mg TID
VIRACEPT VIRACEPT
+ d4T + d4T + d4T
(n=109) (n=98) (n=101)
Hematology
Hemoglobin 0 0 0
Neutrophils 1% 1% 4%
Lymphocytes 1% 1% 0
Chemistry
ALT (SGPT) 1% 3% 2%
AST (SGOT) 0 3% 3%
Creatine Kinase 4% 5% 6%
Triglycerides
(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 recommended dose is 750 mg (three 250 mg tablets) three times
daily. VIRACEPT should be taken with a meal or light snack. Antiviral
activity 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): 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
Number of Number of
Body Weight 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 --
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
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 degrees C
(59 to 86 degrees F).
SOURCE Agouron Pharmaceuticals, Inc.
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Related links:
http://www.agouron.com
CONTACT:
Investors: Donna Nichols, Vice President,
Corporate Communications, 619-622-3009, or Media: Joy Schmitt,
Manager, Product Public Relations, 619-622-3220, both of Agouron
Pharmaceuticals, Inc.
CNOC: http://www.prnewswire.com or fax, 800-758-5804, ext.
019650
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