Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3147
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AGENERASE (Capsule)
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AGENERASE may be taken with or without food; however, a
high-fat meal decreases the absorption of amprenavir and should be avoided
(see CLINICAL PHARMACOLOGY: Effects of Food on Oral Absorption). Adult and pediatric patients should be advised not to take
supplemental vitamin E since the vitamin E content of AGENERASE Capsules exceeds
the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU)
(see DESCRIPTION).<br/>Adults: The recommended oral dose of AGENERASE Capsules for adults
is 1,200 mg (twenty-four 50-mg capsules) twice daily in combination with
other antiretroviral agents.<br/>Concomitant Therapy: If AGENERASE and ritonavir are used in combination, the
recommended dosage regimens are: AGENERASE 1,200 mg with ritonavir 200 mg
once daily or AGENERASE 600 mg with ritonavir 100 mg twice daily.<br/>Pediatric Patients: For adolescents (13 to 16 years), the recommended oral
dose of AGENERASE Capsules is 1,200 mg (twenty-four 50-mg capsules) twice
daily in combination with other antiretroviral agents. For patients between
4 and 12 years of age or for patients 13 to 16 years of age with
weight of<50 kg, the recommended oral dose of AGENERASE Capsules
is 20 mg/kg twice daily or 15 mg/kg 3 times daily (to a maximum
daily dose of 2,400 mg) in combination with other antiretroviral agents.
The recommended dose of AGENERASE for use in combination with ritonavir has
not been established in pediatric patients. Before
using AGENERASE Oral Solution, the complete
prescribing information should be consulted. AGENERASE Capsules and AGENERASE Oral Solution are not interchangeable
on a milligram-per-milligram basis (see CLINICAL PHARMACOLOGY).<br/>Patients with Hepatic Impairment: AGENERASE Capsules should be used with caution in patients
with moderate or severe hepatic impairment. Patients with a Child-Pugh score
ranging from 5 to 8 should receive a reduced dose of AGENERASE Capsules of
450 mg twice daily, and patients with a Child-Pugh score ranging from
9 to 12 should receive a reduced dose of AGENERASE Capsules of 300 mg
twice daily (see CLINICAL PHARMACOLOGY: Hepatic Insufficiency).
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AGENERASE (amprenavir)
is an inhibitor of the human immunodeficiency virus (HIV) protease. The chemical
name of amprenavir is (3S)-tetrahydro-3-furyl N-[(1S,2R)-3-(4-amino-N-isobutylbenzenesulfonamido)-1-benzyl-2-hydroxypropyl]carbamate.
Amprenavir is a single stereoisomer with the (3S)(1S,2R) configuration. It has a molecular formula of CHNOS
and a molecular weight of 505.64. It has the following structural formula: Amprenavir
is a white to cream-colored solid with a solubility of approximately 0.04 mg/mL
in water at 25��C. AGENERASE
Capsules are available for oral administration. Each 50-mg capsule
contains the inactive ingredients d-alpha tocopheryl polyethylene glycol 1000
succinate (TPGS), polyethylene glycol 400 (PEG 400) 246.7 mg, and propylene
glycol 19 mg. The capsule shell contains the inactive ingredients d-sorbitol
and sorbitans solution, gelatin, glycerin, and titanium dioxide. The soft
gelatin capsules are printed with edible red ink. Each 50-mg AGENERASE Capsule
contains 36.3 IU vitamin E in the form of TPGS. The total amount of vitamin
E in the recommended daily adult dose of AGENERASE is 1,744 IU.
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Pharmacokinetics in Adults: The pharmacokinetic properties of amprenavir have been studied
in asymptomatic, HIV-infected adult patients after administration of single
oral doses of 150 to 1,200 mg and multiple oral doses of 300 to 1,200 mg
twice daily.<br/>Absorption and Bioavailability: Amprenavir was rapidly absorbed after oral administration
in HIV-1-infected patients with a time to peak concentration (T)
typically between 1 and 2 hours after a single oral dose. The absolute
oral bioavailability of amprenavir in humans has not been established. Increases
in the area under the plasma concentration versus time curve (AUC) after single
oral doses between 150 and 1,200 mg were slightly greater than dose proportional.
Increases in AUC were dose proportional after 3 weeks of dosing with
doses from 300 to 1,200 mg twice daily. The pharmacokinetic parameters
after administration of amprenavir 1,200 mg twice daily for 3 weeks
to HIV-infected subjects are shown in Table 1. The relative bioavailability of AGENERASE Capsules and
Oral Solution was assessed in healthy adults. AGENERASE Oral Solution was
14% less bioavailable compared to the capsules. Effects of Food on Oral Absorption: The
relative bioavailability of AGENERASE Capsules was assessed in the fasting
and fed states in healthy volunteers (standardized high-fat meal: 967 kcal,
67 grams fat, 33 grams protein, 58 grams carbohydrate). Administration
of a single 1,200-mg dose of amprenavir in the fed state compared to the fasted
state was associated with changes in C(fed: 6.18��2.92 mcg/mL,
fasted: 9.72��2.75 mcg/mL), T(fed: 1.51��0.68,
fasted: 1.05��0.63), and AUC���(fed: 22.06��11.6 mcg���hr/mL,
fasted: 28.05��10.1 mcg���hr/mL). AGENERASE may
be taken with or without food, but should not be taken with a high-fat meal
(see DOSAGE AND ADMINISTRATION). Distribution: The apparent
volume of distribution (V/F) is approximately 430 L in healthy
adult subjects. In vitro binding is approximately 90% to plasma proteins.
The high affinity binding protein for amprenavir is alpha-acid
glycoprotein (AAG). The partitioning of amprenavir into erythrocytes is low,
but increases as amprenavir concentrations increase, reflecting the higher
amount of unbound drug at higher concentrations. Metabolism: Amprenavir is metabolized in
the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system. The 2 major
metabolites result from oxidation of the tetrahydrofuran and aniline moieties.
Glucuronide conjugates of oxidized metabolites have been identified as minor
metabolites in urine and feces. Elimination: Excretion
of unchanged amprenavir in urine and feces is minimal. Approximately 14% and
75% of an administered single dose ofC-amprenavir can be accounted
for as radiocarbon in urine and feces, respectively. Two metabolites accounted
for>90% of the radiocarbon in fecal samples. The plasma elimination half-life
of amprenavir ranged from 7.1 to 10.6 hours.<br/>Special Populations: Hepatic Insufficiency: AGENERASE has been studied in adult patients with impaired hepatic
function using a single 600-mg oral dose. The AUC���was
significantly greater in patients with moderate cirrhosis (25.76��14.68 mcg���hr/mL)
compared with healthy volunteers (12.00��4.38 mcg���hr/mL).
The AUC���and Cwere significantly greater
in patients with severe cirrhosis (AUC���: 38.66��16.08 mcg���hr/mL;
C: 9.43��2.61 mcg/mL) compared with healthy
volunteers (AUC���: 12.00��4.38 mcg���hr/mL;
C: 4.90��1.39 mcg/mL). Patients with impaired
hepatic function require dosage adjustment (see DOSAGE AND ADMINISTRATION). Renal Insufficiency: The impact of renal
impairment on amprenavir elimination in adult patients has not been studied.
The renal elimination of unchanged amprenavir represents<3% of the administered
dose. Pediatric Patients: The pharmacokinetics
of amprenavir have been studied after either single or repeat doses of AGENERASE
Capsules or Oral Solution in 84 pediatric patients. Twenty HIV���1-infected
children ranging in age from 4 to 12 years received single doses from
5 mg/kg to 20 mg/kg using 25-mg or 150-mg capsules. The Cof
amprenavir increased less than proportionally with dose. The AUC���increased proportionally at doses between 5 and 20 mg/kg. Amprenavir
is 14% less bioavailable from the liquid formulation than from the capsules;
therefore AGENERASE Capsules and AGENERASE Oral
Solution are not interchangeable on a milligram-per-milligram basis. AGENERASE Oral Solution is contraindicated in
infants and children below the age of 4 years due to the potential risk
of toxicity from the large amount of the excipient, propylene glycol. Please
see the complete prescribing information for AGENERASE
Oral Solution for full information. AUC is 0 to 12 hours for b.i.d. and 0
to 8 hours for t.i.d., therefore the Cis a better comparison
of the exposures. Geriatric
Patients: The pharmacokinetics of amprenavir have not been studied
in patients over 65 years of age. Gender: The pharmacokinetics of amprenavir do not differ between males
and females. Race: The pharmacokinetics of amprenavir do not differ between blacks
and non-blacks.<br/>Drug Interactions: See also CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug
Interactions. Amprenavir is metabolized in the liver
by the cytochrome P450 enzyme system. Amprenavir inhibits CYP3A4. Caution
should be used when coadministering medications that are substrates, inhibitors,
or inducers of CYP3A4, or potentially toxic medications that are metabolized
by CYP3A4. Amprenavir does not inhibit CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2E1,
or uridine glucuronosyltransferase (UDPGT). Drug interaction
studies were performed with amprenavir capsules and other drugs likely to
be coadministered or drugs commonly used as probes for pharmacokinetic interactions.
The effects of coadministration of amprenavir on the AUC, C,
and Care summarized in Table 3 (effect of other drugs on amprenavir)
and Table 4 (effect of amprenavir on other drugs). For information regarding
clinical recommendations, see PRECAUTIONS. Based on total-drug concentrations. Compared
to amprenavir 1,200 mg b.i.d. in the same patients. Median
percent change; confidence interval not reported. ���=
Increase;���= Decrease;���= No change (���or���<10%);
NA = Cnot calculated for single-dose study. Median percent change; confidence interval
not reported. ���= Increase;���= Decrease;���= No change (���or���<10%); NA = Cnot
calculated for single-dose study; ND = Interaction cannot be determined
as Cwas below the lower limit of quantitation.<br/>Nucleoside Reverse Transcriptase Inhibitors (NRTIs): There was no effect of amprenavir on abacavir in subjects
receiving both agents based on historical data.<br/>HIV Protease Inhibitors: The effect of
amprenavir on total drug concentrations of other HIV protease inhibitors in
subjects receiving both agents was evaluated using comparisons to historical
data. Indinavir steady-state C, AUC, and Cwere
decreased by 22%, 38%, and 27%, respectively, by concomitant amprenavir. Similar
decreases in Cand AUC were seen after the first dose. Saquinavir
steady-state C, AUC, and Cwere increased 21%,
decreased 19%, and decreased 48%, respectively, by concomitant amprenavir.
Nelfinavir steady-state C, AUC, and Cwere increased
by 12%, 15%, and 14%, respectively, by concomitant amprenavir.<br/>Methadone: Coadministration
of amprenavir and methadone can decrease plasma levels of methadone. Coadministration
of amprenavir and methadone as compared to a non-matched historical control
group resulted in a 30%, 27%, and 25% decrease in serum amprenavir AUC, C,
and C, respectively. For information
regarding clinical recommendations, see PRECAUTIONS: Drug Interactions.
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Coadministration of AGENERASE
is contraindicated with drugs that are highly dependent on CYP3A4 for clearance
and for which elevated plasma concentrations are associated with serious and/or
life-threatening events. These drugs are listed in Table 6. If AGENERASE is coadministered with ritonavir, the antiarrhythmic
agents flecainide and propafenone are also contraindicated. Because
of the potential toxicity from the large amount of the excipient, propylene
glycol, contained in AGENERASE Oral Solution,
that formulation is contraindicated in certain patient populations and should
be used with caution in others. Consult the complete prescribing information
for AGENERASE Oral Solution for full information. AGENERASEis contraindicated in patients with previously
demonstrated clinically significant hypersensitivity to any of the components
of this product.
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AGENERASE Capsules, 50 mg,
are oblong, opaque, off-white to cream-colored soft gelatin capsules printed
with���GX CC1���on one side. Bottles
of 480 with child-resistant closures (NDC 0173-0679-00). Store at controlled room temperature of 25��C (77��F)
(see USP). AGENERASE Capsules are manufactured
by R.P. Scherer Beinheim, France for Licensed from GlaxoSmithKline
Vertex Pharmaceuticals Incorporated Research Triangle
Park, NC 27709 Cambridge, MA 02139 AGENERASE is a
registered trademark of GlaxoSmithKline. ��2005,
GlaxoSmithKline. All rights reserved. May 2005 RL-2194 PHARMACIST���DETACH
HERE AND GIVE INSTRUCTIONS TO PATIENT _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _
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Because of the potential risk of toxicity from the large
amount of the excipient, propylene glycol, contained in AGENERASE
Oral Solution, that formulation is contraindicated in infants and
children below the age of 4 years and certain other patient populations
and should be used with caution in others. Consult the complete prescribing
information for AGENERASE Oral Solution for
full information.
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| dailymed-instance:inactiveI... |
dailymed-ingredient:d-alpha_tocopheryl_polyethylene_glycol_1000_succinate_(TPGS),
dailymed-ingredient:d-sorbitol_and_sorbitans_solution,
dailymed-ingredient:edible_red_ink,
dailymed-ingredient:gelatin,
dailymed-ingredient:glycerin,
dailymed-ingredient:polyethylene_glycol_400,
dailymed-ingredient:propylene_glycol,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:vitamin_E_in_form_of_TPGS
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General: AGENERASE Capsules and AGENERASE
Oral Solution are not interchangeable on a milligram-per-milligram basis(see CLINICAL PHARMACOLOGY: Pediatric Patients). Amprenavir
is a sulfonamide. The potential for cross-sensitivity between drugs in the
sulfonamide class and amprenavir is unknown. AGENERASE should be used with
caution in patients with a known sulfonamide allergy. AGENERASE
is principally metabolized by the liver. AGENERASE, when used alone and in
combination with low-dose ritonavir, has been associated with elevations of
SGOT (AST) and SGPT (ALT) in some patients. Caution should be exercised when
administering AGENERASE to patients with hepatic impairment (see DOSAGE AND
ADMINISTRATION). Appropriate laboratory testing should be conducted prior
to initiating therapy with AGENERASE and at periodic intervals during treatment. Formulations
of AGENERASE provide high daily doses of vitamin E (see Information for Patients,
DESCRIPTION, and DOSAGE AND ADMINISTRATION). The effects of long-term, high-dose
vitamin E administration in humans is not well characterized and has not been
specifically studied in HIV-infected individuals. High vitamin E doses may
exacerbate the blood coagulation defect of vitamin K deficiency caused by
anticoagulant therapy or malabsorption.<br/>Patients with Hemophilia: There have been reports of spontaneous bleeding in patients
with hemophilia A and B treated with protease inhibitors. In some patients,
additional factor VIII was required. In many of the reported cases, treatment
with protease inhibitors was continued or restarted. A causal relationship
between protease inhibitor therapy and these episodes has not been established. Immune Reconstitution Syndrome: Immune reconstitution
syndrome has been reported in patients treated with combination antiretroviral
therapy, including AGENERASE. During the initial phase of combination antiretroviral
treatment, patients whose immune system responds may develop an inflammatory
response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis),
which may necessitate further evaluation and treatment.<br/>Fat Redistribution: Redistribution/accumulation of body fat, including central
obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting,
facial wasting, breast enlargement, and���cushingoid appearance,���have been observed in patients receiving antiretroviral therapy. The mechanism
and long-term consequences of these events are currently unknown. A causal
relationship has not been established.<br/>Lipid Elevations: Treatment with AGENERASE alone or in combination with ritonavir
has resulted in increases in the concentration of total cholesterol and triglycerides.
Triglyceride and cholesterol testing should be performed prior to initiation
of therapy with AGENERASE and at periodic intervals during treatment. Lipid
disorders should be managed as clinically appropriate. See PRECAUTIONS Table
8: Established and Other Potentially Significant Drug Interactions for additional
informationon potential drug interactions with AGENERASE and HMG-CoA reductase
inhibitors.<br/>Resistance/Cross-Resistance: Because the potential for HIV cross-resistance among protease
inhibitors has not been fully explored, it is unknown what effect amprenavir
therapy will have on the activity of subsequently administered protease inhibitors.
It is also unknown what effect previous treatment with other protease inhibitors
will have on the activity of amprenavir (see MICROBIOLOGY).<br/>Information for Patients: A statement to patients and healthcare providers is included
on the product's bottle label: ALERT: Find
out about medicines that should NOT be taken with AGENERASE. A Patient
Package Insert (PPI) for AGENERASE Capsules is available for patient information. Patients
treated with AGENERASE Capsules should be cautioned against switching to AGENERASE Oral Solution because of the increased
risk of adverse events from the large amount of propylene glycol in AGENERASE Oral Solution. Please see the complete
prescribing information for AGENERASE Oral Solution for full information. Patients should be
informed that AGENERASE is not a cure for HIV infection and that they may
continue to develop opportunistic infections and other complications associated
with HIV disease. The long-term effects of AGENERASE (amprenavir) are unknown
at this time. Patients should be told that there are currently no data demonstrating
that therapy with AGENERASE can reduce the risk of transmitting HIV to others
through sexual contact. Patients should remain under
the care of a physician while using AGENERASE. Patients should be advised
to take AGENERASE every day as prescribed. AGENERASE must always be used in
combination with other antiretroviral drugs. Patients should not alter the
dose or discontinue therapy without consulting their physician. If a dose
is missed, patients should take the dose as soon aspossible and then return
to their normal schedule. However, if a dose is skipped, the patient should
not double the next dose. Patients should inform their
doctor if they have a sulfa allergy. The potential for cross-sensitivity between
drugs in the sulfonamide class and amprenavir is unknown. AGENERASE
may interact with many drugs; therefore, patients should be advised to report
to their doctor the use of any other prescription or nonprescription medication
or herbal products, particularly St. John's wort. Patients
taking antacids (or the buffered formulation of didanosine) should take AGENERASE
at least 1 hour before or after antacid (or the buffered formulation
of didanosine) use. Patients receiving sildenafil
should be advised that they may be at an increased risk of sildenafil-associated
adverse events, including hypotension, visual changes, and priapism, and should
promptly report any symptoms to their doctor. Patients
taking AGENERASE should be instructed not to
use hormonal contraceptives because some birth control pills (those containing
ethinyl estradiol/norethindrone) have been found to decrease the concentration
of amprenavir. Therefore, patients receiving hormonal contraceptives should
be instructed to use alternate contraceptive measures during therapy with
AGENERASE. High-fat meals may decrease the absorption
of AGENERASE and should be avoided. AGENERASE may be taken with meals of normal
fat content. Patients should be informed that redistributionor accumulation of body fat may occur in patients receiving antiretroviral
therapy and that the cause and long-term health effects of these conditions
are not known at this time. Adult and pediatric patients
should be advised not to take supplemental vitamin E since the vitamin E content
of AGENERASE Capsules and Oral Solution exceeds the Reference Daily Intake
(adults 30 IU, pediatrics approximately 10 IU).<br/>Laboratory Tests: The combination of AGENERASE and low-dose ritonavir has
been associated with elevations of cholesterol and triglycerides, SGOT (AST),
and SGPT (ALT) in some patients. Appropriate laboratory testing should be
considered prior to initiating combination therapy with AGENERASE and ritonavir
and at periodic intervals or if any clinical signs or symptoms of hyperlipidemia
or elevated liver function tests occur during therapy. For comprehensive information
concerning laboratory test alterations associated with ritonavir, physicians
should refer to the complete prescribing information for NORVIR (ritonavir).<br/>Drug Interactions: See also CONTRAINDICATIONS, WARNINGS,
and CLINICAL PHARMACOLOGY: Drug Interactions. AGENERASE
is an inhibitor of cytochrome P450 3A4 metabolism and therefore should not
be administered concurrently with medications with narrow therapeutic windows
that are substrates of CYP3A4. There are other agents that may result in serious
and/or life-threatening drug interactions (see CONTRAINDICATIONS and WARNINGS). See CLINICAL PHARMACOLOGY for magnitude of
interaction, Tables 3 and 4. See CLINICAL PHARMACOLOGY for magnitude of
interaction, Tables 3 and 4.<br/>Carcinogenesis and Mutagenesis: Amprenavir was evaluated for carcinogenic potential by oral
gavage administration to mice and rats for up to 104 weeks. Daily doses
of 50, 275 to 300, and 500 to 600 mg/kg/day were administered to mice
and doses of 50, 190, and 750 mg/kg/day were administered to rats. Results
showed an increase in the incidence of benign hepatocellular adenomas and
an increase in the combined incidence of hepatocellular adenomas plus carcinoma
in malesof both species at the highest doses tested. Female mice and rats
were not affected. These observations were made at systemic exposures equivalent
to approximately 2 times (mice) and 4 times (rats) the human exposure
(based on AUCmeasurement) at the recommended dose of 1,200 mg
twice daily. Administration of amprenavir did not cause a statistically significant
increase in the incidence of any other benign or malignant neoplasm in mice
or rats. It is not known how predictive the results of rodent carcinogenicity
studies may be for humans. However, amprenavir was not mutagenic or genotoxic
in a battery of in vitro and in vivo assays including bacterial reverse mutation
(Ames), mouse lymphoma, rat micronucleus, and chromosome aberrations in human
lymphocytes.<br/>Fertility: : The effects of amprenavir on fertility and general reproductive
performance were investigated in male rats (treated for 28 days before
mating at doses producing up to twice the expected clinical exposure based
on AUC comparisons) and female rats (treated for 15 days before mating
through day 17 of gestation at doses producing up to 2 times the
expected clinical exposure). Amprenavir did not impair mating or fertility
of male or female rats and did not affect the development and maturation of
sperm from treated rats. The reproductive performance of the F1 generation
born to female rats given amprenavir was not different from control animals.<br/>Pregnancy and Reproduction: Pregnancy Category C. Embryo/fetal development studies were
conducted in rats (dosed from 15 days before pairing to day 17 of
gestation) and rabbits (dosed from day 8 to day 20 of gestation).
In pregnant rabbits, amprenavir administration was associated with abortions
and an increased incidence of 3 minor skeletal variations resulting from deficient
ossification of the femur, humerus trochlea, and humerus. Systemic exposure
at the highest tested dose was approximately one twentieth of the exposure
seen atthe recommended human dose. In rat fetuses, thymic elongation and
incomplete ossification of bones were attributed to amprenavir. Both findings
were seen at systemic exposures that were one half of that associated with
the recommended human dose. Pre- and post-natal developmental
studies were performed in rats dosed from day 7 of gestation to day 22
of lactation. Reduced body weights (10% to 20%) were observed in the offspring.
The systemic exposure associated with this finding was approximately twice
the exposure in humans following administration of the recommended human dose.
The subsequent development of these offspring, including fertility and reproductive
performance, was not affected by the maternal administration of amprenavir. There
are no adequate and well-controlled studies in pregnant women. AGENERASE should
be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus. AGENERASE
Oral Solution is contraindicated during pregnancy due to the potential
risk of toxicity to the fetus from the high propylene glycol content.<br/>Antiretroviral Pregnancy Registry: To monitor maternal-fetal
outcomes of pregnant women exposed to AGENERASE, an Antiretroviral Pregnancy
Registry has been established. Physicians are encouraged to register patients
by calling 1-800-258-4263.<br/>Nursing Mothers: The Centers for Disease Control
and Prevention recommend that HIV-infected mothers not breastfeed their infants
to avoid risking postnatal transmission of HIV. Although it is not
known if amprenavir is excreted in human milk, amprenavir is secreted into
the milk of lactating rats. Because of both the potential for HIV transmission
and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are
receiving AGENERASE.<br/>Pediatric Use: Two hundred fifty-one patients aged 4 and above have received
amprenavir as single or multiple doses in studies. An adverse event profile
similar to that seen in adults was seen in pediatric patients. AGENERASE Capsules have not been evaluated in pediatric
patients below the age of 4 years (see CLINICAL PHARMACOLOGY and DOSAGE
AND ADMINISTRATION). AGENERASE
Oral Solution is contraindicated in infants and children below the
age of 4 years due to the potential risk of toxicity from the large amount
of the excipient, propylene glycol. Please see the complete prescribing informationfor AGENERASE Oral Solution for full information.<br/>Geriatric Use: Clinical studies of AGENERASE did not include sufficient
numbers of patients aged 65 and over to determine whether they respond differently
from younger adults. In general, dose selection for an elderly patient should
be cautious, reflecting the greater frequency of decreased hepatic, renal,
or cardiac function, and of concomitant disease or other drug therapy.
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There is no known antidote
for AGENERASE. It is not known whether amprenavir can be removed by peritoneal
dialysis or hemodialysis. If overdosage occurs, the patient should be monitored
for evidence of toxicity and standard supportive treatment applied as necessary.
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amprenavir
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AGENERASE (Capsule)
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In clinical studies,
adverse events leading to amprenavir discontinuation occurred primarily during
the first 12 weeks of therapy, and were mostly due to gastrointestinal
events (nausea, vomiting, diarrhea, and abdominal pain/discomfort), which
were mild to moderate in severity. Skin rash occurred
in 22% of patients treated with amprenavir in studies PROAB3001 and PROAB3006.
Rashes were usually maculopapular and of mild or moderate intensity, some
with pruritus. Rashes had a median onset of 11 days after amprenavir
initiation and a median duration of 10 days. Skin rashes led to amprenavir
discontinuation in approximately 3% of patients. In some patients with mild
or moderate rash, amprenavir dosing was often continued without interruption;
if interrupted, reintroduction of amprenavir generally did not result in rash
recurrence. Severe or life-threatening
rash (Grade 3 or 4), including cases of Stevens-Johnson syndrome, occurred
in approximately 1% of recipients of AGENERASE (see WARNINGS). Amprenavir
therapy should be discontinued for severe or life-threatening rashes and for
moderate rashes accompanied by systemic symptoms. Among amprenavir-treated patients in Phase 3 studies,
2 patients developed de novo diabetes mellitus, 1 patient developed a dorsocervical
fat enlargement (buffalo hump), and 9 patients developed fat redistribution. In
studies PROAB3001 and PROAB3006, no increased frequency of Grade 3 or 4 AST,
ALT, amylase, or bilirubin elevations was seen compared to controls.<br/>Pediatric Patients: An adverse event profile similar to that seen in adults
was seen in pediatric patients.<br/>Concomitant Therapy with Ritonavir: Tables 10 and 11 present adverse clinical events and laboratory
abnormalities observed in subjects who received AGENERASE plus ritonavir.
Since the trials were small, open-label, of varying duration, and often included
different patient populations, direct comparisons to the frequency of events
with AGENERASE alone (see Table 9) cannot be made. Data from 2 open-label studies in treatment-naive
patients also receiving abacavir/lamivudine. Data
from 3 open-label studies in treatment-naive and treatment-experienced
patients receiving combination antiretroviral therapy. Data from 2 open-label studies in treatment-naive
patients also receiving abacavir/lamivudine. Data
from 3 open-label studies in treatment-naive and treatment-experienced
patients receiving combination antiretroviral therapy.
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ALERT: Find out about medicines that should
not be taken with AGENERASE. Serious
and/or life-threatening drug interactions could occur between amprenavir and
amiodarone, lidocaine (systemic), tricyclic antidepressants, and quinidine.
Concentration monitoring of these agents is recommended if these agents are
used concomitantly with AGENERASE (see CONTRAINDICATIONS). Rifampin
should not be used in combination with amprenavir because it reduces plasma
concentrations and AUC of amprenavir by about 90%. A
drug interaction study in healthy subjects has shown that ritonavir significantly
increases plasma fluticasone propionate exposures, resulting in significantly
decreased serum cortisol concentrations. Concomitant use of AGENERASE with
ritonavir and fluticasone propionate is expected to produce the same effects.
Systemic corticosteroid effects including Cushing's syndrome and adrenalsuppression have been reported during postmarketing use in patients receiving
ritonavir andinhaled or intranasally administered fluticasone propionate.
Therefore, coadministration of fluticasone propionate and AGENERASE/ritonavir
is not recommended unless the potential benefit to the patient outweighs the
risk of systemic corticosteroid side effects (see PRECAUTIONS: Drug Interactions). Concomitant
use of AGENERASE and St. John's wort (hypericum perforatum) or products containing
St. John's wort is not recommended. Coadministration of protease inhibitors,
including AGENERASE, with St. John's wort is expected to substantially decrease
protease inhibitor concentrations and may result in suboptimal levels of amprenavir
and lead to loss of virologic response and possible resistance to AGENERASE
or to the class of protease inhibitors. Concomitant
use of AGENERASE with lovastatin or simvastatin is not recommended. Caution
should be exercised if HIV protease inhibitors, including AGENERASE, are used
concurrently with other HMG-CoA reductase inhibitors that are also metabolized
by the CYP3A4 pathway (e.g., atorvastatin). The risk of myopathy, including
rhabdomyolysis, may be increased when HIV protease inhibitors, including amprenavir,
are used in combination with these drugs. Particular
caution should be used when prescribing sildenafil in patients receiving amprenavir.
Coadministration of AGENERASE with sildenafil is expected to substantially
increase sildenafil concentrations and may result in an increase in sildenafil-associated
adverse events, including hypotension, visual changes, and priapism (see PRECAUTIONS:
Drug Interactions and Information for Patients, and the complete prescribing
information for sildenafil). Because of the potential
toxicity from the large amount of the excipient, propylene glycol, contained
in AGENERASE Oral Solution, that formulation
is contraindicated in certain patient populations and should be used with
caution in others. Consult the complete prescribing information for AGENERASE OralSolution for full information. Severe and life-threatening skin reactions, including Stevens-Johnson
syndrome, have occurred in patients treated with AGENERASE (see ADVERSE REACTIONS). Acute hemolytic anemia has been reported in a patient treated
with AGENERASE. 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 causal relationships between protease inhibitor therapy
and these events have not been established.
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| dailymed-instance:indicatio... |
AGENERASE (amprenavir) is indicated
in combination with other antiretroviral agents for the treatment of HIV-1
infection. The
following points should be considered when initiating therapy with AGENERASE: In a study of
NRTI-experienced, protease inhibitor-naive patients, AGENERASE was found to
be significantly less effective than indinavir (see Description of Clinical
Studies). Mild
to moderate gastrointestinal adverse events led to discontinuation of AGENERASE
primarily during the first 12 weeks of therapy (see ADVERSE REACTIONS). There are no data on response to therapy with AGENERASE in
protease inhibitor-experienced patients.<br/>Description of Clinical Studies:<br/>Therapy-Naive Adults: PROAB3001, a
randomized, double-blind, placebo-controlled, multicenter study, compared
treatment with AGENERASE Capsules (1,200 mg twice daily) plus lamivudine (150 mg
twice daily) plus zidovudine (300 mg twice daily) versus lamivudine (150 mg
twice daily) plus zidovudine (300 mg twice daily) in 232 patients.
Through 24 weeks of therapy, 53% of patients assigned to AGENERASE/zidovudine/lamivudine
achieved HIV-1 RNA<400 copies/mL. Through week 48, the antiviral
response was 41%. Through 24 weeks of therapy, 11% of patients assigned
to zidovudine/lamivudine achieved HIV-1 RNA<400 copies/mL. Antiviral
response beyond week 24 is not interpretable because the majority of
patients discontinued or changed their antiretroviral therapy.<br/>NRTI-Experienced Adults: PROAB3006, a randomized, open-label multicenter study, compared
treatment with AGENERASE Capsules (1,200 mg twice daily) plus NRTIs versus
indinavir (800 mg every 8 hours) plus NRTIs in 504 NRTI-experienced,
protease inhibitor-naive patients, median age 37 years (range 20 to
71 years), 72% Caucasian, 80% male, with a median CD4 cell count of 404 cells/mm(range
9 to 1,706 cells/mm) and a median plasma HIV-1 RNA level
of 3.93 logcopies/mL (range 2.60 to 7.01 logcopies/mL)
at baseline. Through 48 weeks of therapy, the median CD4 cell count increase
from baseline in the amprenavir group was significantly lower than in the
indinavir group, 97 cells/mmversus 144 cells/mm,
respectively. There was also a significant difference in the proportions of
patients with plasma HIV-1 RNA levels<400 copies/mL through 48 weeks
(see Figure 1 and Table 5). HIV-1 RNA status and reasons for
discontinuation of randomized treatment at 48 weeks are summarized (Table 5). Corresponds to rates at Week 48 in Figure
1. Virological failures at or before
Week 48. Considered to be treatment
failure in the analysis. Includes
discontinuations due to consent withdrawn, loss to follow-up, protocol violations,
non-compliance, pregnancy, never treated, and other reasons.
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| dailymed-instance:name |
AGENERASE
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