Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2306
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AGENERASE (Solution)
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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 Oral Solution exceeds the Reference Daily Intake (adults 30 IU,
pediatrics approximately 10 IU) (see DESCRIPTION). The
recommended dose of AGENERASE Oral Solution based on body weight and age is
shown in Table 12. Consideration should be given
to switching patients from AGENERASE Oral Solution to AGENERASE Capsules as
soon as they are able to take the capsule formulation (see WARNINGS). Concomitant Therapy: Concurrent use of AGENERASE Oral Solution and NORVIR (ritonavir)
Oral Solution is not recommended because the large amount of propylene glycol
in AGENERASE Oral Solution and ethanol in NORVIR Oral Solution may compete
for the same metabolic pathway for elimination.<br/>Patients with Hepatic Impairment: AGENERASE Oral Solution is contraindicated in patients with
hepatic failure (see CONTRAINDICATIONS). Patients
with hepatic impairment are at increased risk of propylene glycol-associated
adverse events (see WARNINGS). AGENERASE Oral Solution should be used with
caution in patients with hepatic impairment. Based on a study with AGENERASE
Capsules, adult patients with a Child-Pugh score ranging from 5 to 8 should
receive a reduceddose of AGENERASE Oral Solution of 513 mg (34 mL)
twice daily, and adult patients with a Child-Pugh score ranging from 9 to
12 should receive a reduced dose of AGENERASE Oral Solution of 342 mg
(23 mL) twice daily (see CLINICAL PHARMACOLOGY: Hepatic Insufficiency). AGENERASE
Oral Solution has not been studied in children with hepatic impairment.<br/>Renal Insufficiency: AGENERASE Oral
Solution is contraindicated in patients with renal failure (see CONTRAINDICATIONS). Patients
with renal impairment are at increased risk of propylene glycol-associated
adverse events. AGENERASE Oral Solution should be used with caution in patients
with renal impairment (see WARNINGS). AGENERASE
Capsules and AGENERASE Oral Solution are not interchangeable on a milligram-per-milligram
basis (see CLINICAL PHARMACOLOGY).
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| dailymed-instance:descripti... |
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
Oral Solution is for oral administration. One milliliter (1 mL)
of AGENERASE Oral Solution contains 15 mg of amprenavir in solution and
the inactive ingredients acesulfame potassium, artificial grape bubblegum
flavor, citric acid (anhydrous), d-alpha tocopheryl polyethylene glycol 1000
succinate (TPGS), menthol, natural peppermint flavor, polyethylene glycol
400 (PEG 400) (170 mg), propylene glycol (550 mg), saccharin sodium,
sodium chloride, and sodium citrate (dihydrate). Solutions of sodium hydroxide
and/or diluted hydrochloric acid may have been added to adjust pH. Each mL
of AGENERASE Oral Solution contains 46 IU vitamin E in the form
of TPGS. Propylene glycol is in the formulation to achieve adequate solubility
of amprenavir. The recommended daily dose of AGENERASE Oral Solution of 22.5 mg/kg
twice daily corresponds to a propylene glycol intake of 1,650 mg/kg/day.
Acceptable intake of propylene glycol for pharmaceuticals has not been established.
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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.<br/>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).<br/>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.<br/>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. AGENERASE
Oral Solution contains a large amount of propylene glycol, which is hepatically
metabolized by the alcohol and aldehyde dehydrogenase enzyme pathway. Alcohol
dehydrogenase (ADH) is present in the human fetal liver at 2 months of
gestational age, but at only 3% of adult activity. Although the data are limited,
it appears that by 12 to 30 months of postnatal age, ADH activity is
equal to or greater than that observed in adults. Additionally, certain patient
groups (females, Asians, Eskimos, Native Americans) may be at increased risk
of propylene glycol-associated adverse events due to diminished ability to
metabolize propylene glycol (see CLINICAL PHARMACOLOGY: Special Populations:
Gender and Race).<br/>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:<br/>Hepatic Insufficiency: AGENERASE Oral Solution is contraindicated in patients with
hepatic failure. Patients with hepatic impairment
are at increased risk of propylene glycol-associated adverse events (see WARNINGS).
AGENERASE Oral Solution should be used with caution in patients with hepatic
impairment. AGENERASE Capsules have 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).<br/>Renal Insufficiency: AGENERASE Oral Solution is contraindicated in patients with
renal failure. Patients with renal impairment are
at increased risk of propylene glycol-associated adverse events. Additionally,
because metabolites of the excipient, propylene glycol, in AGENERASE Oral
Solution may alter acid-base balance, patients with renal impairment should
be monitored for potential adverse events (see WARNINGS). AGENERASE Oral Solution
should be used with caution in patients with renal impairment. The impact
of renal impairment on amprenavir elimination has not been studied. The renal
elimination of unchanged amprenavir represents<3% of the administered
dose.<br/>Pediatric Patients: AGENERASE Oral Solution is contraindicated in infants and
children below 4 years of age (see CONTRAINDICATIONS and WARNINGS). 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. 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.<br/>Geriatric Patients: The pharmacokinetics of amprenavir have not been studied
in patients over 65 years of age.<br/>Gender: The pharmacokinetics of amprenavir do not differ between
males and females. Females may have a lower amount of alcohol dehydrogenase
compared with males and may be at increased risk of propylene glycol-associated
adverse events; no data are available on propylene glycol metabolism in females.<br/>Race: The pharmacokinetics of amprenavir do not differ between
blacks and non-blacks. Certain ethnic populations (Asians, Eskimos, and Native
Americans) may be at increased risk of propylene glycol-associated adverse
events because of alcohol dehydrogenase polymorphisms; no data are available
on propylene glycol metabolism in these groups.<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 capsules 1,200 mg
b.i.d. in the same patients. Median
percent change; confidence interval not reported. [Symbol_Wingdings_225]
= Increase; [Symbol_Wingdings_226] = Decrease;���= No change ([Symbol_Wingdings_225]
or [Symbol_Wingdings_226]<10%); NA = Cnot calculated for
single-dose study. Median percent change;
confidence interval not reported. [Symbol_Wingdings_225]
= Increase; [Symbol_Wingdings_226] = Decrease;���= No change ([Symbol_Wingdings_225]
or [Symbol_Wingdings_226]<10%); NA = Cnot calculated for
single-dose study; ND = Interaction cannot be determined as Cwas
below the lower limit of quantitation. Nucleoside
Reverse Transcriptase Inhibitors (NRTIs): There was no effect of
amprenavir on abacavir in subjects receiving both agents based on historical
data. HIV Protease
Inhibitors: Concurrent use of AGENERASE Oral Solution and NORVIR (ritonavir)
Oral Solution is not recommended because the large amount of propylene glycol
in AGENERASE Oral Solution and ethanol in NORVIR Oral Solution may compete
for the same metabolic pathway for elimination. This combination has not been studied in pediatric patients. 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. 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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Because of the potential risk
of toxicity from the large amount of the excipient, propylene glycol, AGENERASE
Oral Solution is contraindicated in infants and children below the age of
4 years, pregnant women, patients with hepatic or renal failure, and
patients treated with disulfiram or metronidazole (see WARNINGS and PRECAUTIONS). 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 Capsules are coadministered with ritonavir
capsules, the antiarrhythmic agents flecainide and propafenone are also contraindicated. AGENERASEis contraindicated in patients with previously
demonstrated clinically significant hypersensitivity to any of the components
of this product.
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AGENERASE Oral Solution, a clear, pale yellow to yellow,
grape-bubblegum-peppermint-flavored liquid, contains 15 mg of amprenavir
in each 1 mL. Bottles of 240 mL with child-resistant
closures (NDC 0173-0687-00). This product does not require reconstitution. Store at controlled room temperature of 25��C (77��F)
(see USP). 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-2195 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, AGENERASE Oral Solution is contraindicated
in infants and children below the age of 4 years, pregnant women, patients
with hepatic or renal failure, and patients treated with disulfiram or metronidazole
(see CONTRAINDICATIONS AND WARNINGS). AGENERASE Oral
Solution should be used only when AGENERASE Capsules or other protease inhibitor
formulations are not therapeutic options.
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dailymed-ingredient:acesulfame_potassium,
dailymed-ingredient:artificial_grape_bubblegum_flavor,
dailymed-ingredient:citric_acid_anhydrous,
dailymed-ingredient:d-alpha_tocopheryl_polyethylene_glycol_1000_succinate_(TPGS),
dailymed-ingredient:hydrochloric_acid,
dailymed-ingredient:menthol,
dailymed-ingredient:natural_peppermint_flavor,
dailymed-ingredient:polyethylene_glycol_400,
dailymed-ingredient:propylene_glycol,
dailymed-ingredient:saccharin_sodium,
dailymed-ingredient:sodium_chloride,
dailymed-ingredient:sodium_citrate_dihydrate,
dailymed-ingredient:sodium_hydroxide
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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 and CONTRAINDICATIONS). 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
capsules 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 information on 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 Oral Solution is available for patient
information. AGENERASE Oral Solution is contraindicated
in infants and children below the age of 4 years, pregnant women, patients
with hepatic or renal failure, and patients treated with disulfiram or metronidazole.
AGENERASE Oral Solution should be used only when AGENERASE Capsules or other
protease inhibitor formulations are not therapeutic options. 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. Women,
Asians, Eskimos, or Native Americans, as well as patients who have hepatic
or renal insufficiency, should be informed that they may be at increased risk
of adverse events from the large amount of propylene glycol in AGENERASE Oral
Solution. 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 as possible 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 should be advised that
drinking alcoholic beverages is not recommended while taking AGENERASE Oral
Solution. 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 redistribution or 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 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 capsules
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). Use
of alcoholic beverages is not recommended in patients treated with AGENERASE
Oral Solution. 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 males of 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 orgenotoxic
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: AGENERASE Oral Solution is contraindicated during pregnancy
due to the potential risk of toxicity to the fetus from the high propylene
glycol content. Therefore, if AGENERASE is used in pregnant women, the AGENERASE
Capsules formulation should be used (see complete prescribing information
for AGENERASE Capsules). 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: AGENERASE Oral Solution is contraindicated
in infants and children below the age of 4 years due to the potential
risk of toxicity from the excipient, propylene glycol (see CONTRAINDICATIONS
and WARNINGS). Alcohol dehydrogenase (ADH), which metabolizes propylene
glycol, is present in the human fetal liver at 2 months of gestational
age, but at only 3% of adult activity. Although the data are limited, it appears
that by 12 to 30 months of postnatal age, ADH activity is equal to or
greater than that observed in adults. 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. Concurrent use of AGENERASE
Oral Solution and NORVIR (ritonavir) Oral Solution is not recommended because
the large amount of propylene glycol in AGENERASE Oral Solution and ethanol
in NORVIR Oral Solution may compete for the same metabolic pathway for elimination. This combination has not been studied in pediatric
patients.<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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| dailymed-instance:overdosag... |
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. AGENERASE
Oral Solution contains large amounts of propylene glycol. In the event of
overdosage, monitoring and management of acid-base abnormalities is recommended.
Propylene glycol can be removed by hemodialysis.
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amprenavir
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AGENERASE (Solution)
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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. AGENERASE Capsules. 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 Capsules 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. Because of the potential risk of toxicity from the large
amount of the excipient, propylene glycol, AGENERASE Oral Solution is contraindicated
in infants and children below the age of 4 years, pregnant women, patients
with hepatic or renal failure, and patients treated with disulfiram or metronidazole
(see CLINICAL PHARMACOLOGY, CONTRAINDICATIONS, and PRECAUTIONS). Because of the possible toxicity associated with the large
amount of propylene glycol and the lack of information on chronic exposure
to large amounts of propylene glycol, AGENERASE Oral Solution should be used
only when AGENERASE Capsules or other protease inhibitor formulations are
not therapeutic options. Certain ethnic populations (Asians, Eskimos, Native
Americans) and women may be at increased risk of propylene glycol-associated
adverse events due to diminished ability to metabolize propylene glycol; no
data are available on propylene glycol metabolism in these groups (see CLINICAL
PHARMACOLOGY: Special Populations: Gender and Race). If patients require treatment with AGENERASE Oral Solution,
they should bemonitored closely for propylene
glycol-associated adverse events, including seizures, stupor, tachycardia,
hyperosmolality, lactic acidosis, renal toxicity, and hemolysis. Patients
should be switched from AGENERASE Oral Solution to AGENERASE Capsules as soon
as they are able to take the capsule formulation. Concurrent use of AGENERASE Oral Solution and NORVIR (ritonavir)
Oral Solution is not recommended because the large amount of propylene glycol
in AGENERASE Oral Solution and ethanol in NORVIR Oral Solution may compete
for the same metabolic pathway for elimination. Use of alcoholic beverages is not recommended in patients
treated with AGENERASE Oral Solution. 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 adrenal suppression have been reported during
postmarketing use in patients receiving ritonavir and inhaled 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). 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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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. AGENERASE Oral Solution should be used only when AGENERASE
Capsules or other protease inhibitor formulations are not therapeutic options.<br/>Description of Clinical Studies: 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. 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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