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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
LEXIVA is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection.
The following points should be considered when initiating therapy with LEXIVA plus ritonavir in protease inhibitor-experienced patients:
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The protease inhibitor-experienced patient study was not large enough to reach a definitive conclusion that LEXIVA plus ritonavir and lopinavir plus ritonavir are clinically equivalent [see Clinical Studies (14.2)].
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Once-daily administration of LEXIVA plus ritonavir is not recommended for adult protease inhibitor-experienced patients or any pediatric patients.
2 DOSAGE AND ADMINISTRATION
LEXIVA Tablets may be taken with or without food.
Adults should take LEXIVA Oral Suspension without food. Pediatric patients should take LEXIVA Oral Suspension with food [see Clinical Pharmacology (12.3)]. If emesis occurs within 30 minutes after dosing, re-dosing of LEXIVA Oral Suspension should occur.
Higher-than-approved dose combinations of LEXIVA plus ritonavir are not recommended due to an increased risk of transaminase elevations [see Overdosage (10)].
When LEXIVA is used in combination with ritonavir, prescribers should consult the full prescribing information for ritonavir.
2.1 Adults
Therapy-Naive Adults
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LEXIVA 1,400 mg twice daily (without ritonavir).
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LEXIVA 1,400 mg once daily plus ritonavir 200 mg once daily.
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LEXIVA 1,400 mg once daily plus ritonavir 100 mg once daily.
Dosing of LEXIVA 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data [see Clinical Pharmacology (12.3)] .
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LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily.
Dosing of LEXIVA 700 mg twice daily plus 100 mg ritonavir twice daily is supported by pharmacokinetic and safety data [see Clinical Pharmacology (12.3)].
Protease Inhibitor-Experienced Adults
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LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily
2.2 Pediatric Patients (2 to 18 years of age)
The recommended dosage of LEXIVA in patients ≥ 2 years of age should be calculated based on body weight (kg) and should not exceed the recommended adult dose. The data are insufficient to recommend: (1) once-daily dosing of LEXIVA alone or in combination with ritonavir, and (2) any dosing of LEXIVA in therapy-experienced patients 2 to 5 years of age.
Therapy-Naive 2 to 5 Years of Age
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LEXIVA Oral Suspension 30 mg/kg twice daily, not to exceed the adult dose of LEXIVA 1,400 mg twice daily.
Therapy-Naive ≥ 6 Years of Age
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Either LEXIVA Oral Suspension 30 mg/kg twice daily not to exceed the adult dose of LEXIVA 1,400 mg twice daily or LEXIVA Oral Suspension 18 mg/kg plus ritonavir 3 mg/kg twice daily not to exceed the adult dose of LEXIVA 700 mg plus ritonavir 100 mg twice daily.
Therapy-Experienced ≥ 6 Years of Age
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LEXIVA Oral Suspension 18 mg/kg plus ritonavir 3 mg/kg administered twice daily not to exceed the adult dose of LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily.
When administered without ritonavir, the adult regimen of LEXIVA Tablets 1,400 mg twice daily may be used for pediatric patients weighing at least 47 kg.
When administered in combination with ritonavir, LEXIVA Tablets may be used for pediatric patients weighing at least 39 kg; ritonavir capsules may be used for pediatric patients weighing at least 33 kg.
2.3 Patients With Hepatic Impairment
See Clinical Pharmacology (12.3) .
Mild Hepatic Impairment (Child-Pugh score ranging from 5 to 6)
LEXIVA should be used with caution at a reduced dosage of 700 mg twice daily without ritonavir (therapy-naive) or 700 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced).
Moderate Hepatic Impairment (Child-Pugh score ranging from 7 to 9)
LEXIVA should be used with caution at a reduced dosage of 700 mg twice daily (therapy-naive) without ritonavir, or 450 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced).
Severe Hepatic Impairment (Child-Pugh score ranging from 10 to 12)
LEXIVA should be used with caution at a reduced dosage of 350 mg twice daily without ritonavir (therapy-naive). There are no data on the use of LEXIVA in combination with ritonavir in patients with severe hepatic impairment.
3 DOSAGE FORMS AND STRENGTHS
LEXIVA Tablets, 700 mg, are pink, film-coated, capsule-shaped, biconvex tablets with “GX LL7” debossed on one face.
LEXIVA Oral Suspension, 50 mg/mL, is a white to off-white suspension that has a characteristic grape-bubblegum-peppermint flavor.
4 CONTRAINDICATIONS
LEXIVA is contraindicated:
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in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome) to any of the components of this product or to amprenavir.
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when coadministered 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 (Table 1).
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Drug Class/Drug Name |
Clinical Comment |
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Antiarrhythmics: Flecainide, propafenone |
POTENTIAL for serious and/or life-threatening reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics if LEXIVA is co-prescribed with ritonavir. |
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Antimycobacterials: Rifampin* |
May lead to loss of virologic response and possible resistance to LEXIVA or to the class of protease inhibitors. |
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Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine |
POTENTIAL for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
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GI motility agents: Cisapride |
POTENTIAL for serious and/or life-threatening reactions such as cardiac arrhythmias. |
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Herbal products: St. John’s wort (hypericum perforatum) |
May lead to loss of virologic response and possible resistance to LEXIVA or to the class of protease inhibitors. |
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HMG co-reductase inhibitors: Lovastatin, simvastatin |
POTENTIAL for serious reactions such as risk of myopathy including rhabdomyolysis. |
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Neuroleptic: Pimozide |
POTENTIAL for serious and/or life-threatening reactions such as cardiac arrhythmias. |
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Non-nucleoside reverse transcriptase inhibitor: Delavirdine* |
May lead to loss of virologic response and possible resistance to delavirdine. |
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Sedative/hypnotics: Midazolam, triazolam |
POTENTIAL for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. |
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*See Clinical Pharmacology (12.3) Tables 10, 11, 12, or 13 for magnitude of interaction. |
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when coadministered with ritonavir in patients receiving the antiarrhythmic agents flecainide and propafenone. If LEXIVA is coadministered with ritonavir, reference should be made to the full prescribing information for ritonavir for additional contraindications.
5 WARNINGS AND PRECAUTIONS
5.1 Drug Interactions
See Table 1 for listings of drugs that are contraindicated due to potentially life-threatening adverse events, significant drug interactions, or due to loss of virologic activity [see Contraindications (4), Drug Interactions (7.2)].
5.2 Skin Reactions
Severe and life-threatening skin reactions, including 1 case of Stevens-Johnson syndrome among 700 patients treated with LEXIVA in clinical studies. Treatment with LEXIVA should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms [see Adverse Reactions (6)].
5.3 Sulfa Allergy
LEXIVA should be used with caution in patients with a known sulfonamide allergy. Fosamprenavir contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and fosamprenavir is unknown. In a clinical study of LEXIVA used as the sole protease inhibitor, rash occurred in 2 of 10 patients (20%) with a history of sulfonamide allergy compared with 42 of 126 patients (33%) with no history of sulfonamide allergy. In 2 clinical studies of LEXIVA plus low-dose ritonavir, rash occurred in 8 of 50 patients (16%) with a history of sulfonamide allergy compared with 50 of 412 patients (12%) with no history of sulfonamide allergy.
5.4 Hepatic Toxicity
Use of LEXIVA with ritonavir at higher-than-recommended dosages may result in transaminase elevations and should not be used [see Dosage and Administration (2), Overdosage (10)]. Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing or worsening of transaminase elevations. Appropriate laboratory testing should be conducted prior to initiating therapy with LEXIVA and patients should be monitored closely during treatment.
5.5 Diabetes/Hyperglycemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing 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.
5.6 Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including LEXIVA. 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.
5.7 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, including LEXIVA. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
5.8 Lipid Elevations
Treatment with LEXIVA plus ritonavir has resulted in increases in the concentration of triglycerides [see Adverse Reactions (6)]. Triglyceride and cholesterol testing should be performed prior to initiating therapy with LEXIVA and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate [see Drug Interactions (7)].
5.9 Hemolytic Anemia
Acute hemolytic anemia has been reported in a patient treated with amprenavir.
5.10 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.
5.11 Resistance/Cross-Resistance
Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored, it is unknown what effect therapy with LEXIVA will have on the activity of subsequently administered protease inhibitors. LEXIVA has been studied in patients who have experienced treatment failure with protease inhibitors [see Clinical Studies (14.2)].
6 ADVERSE REACTIONS
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Severe or life-threatening skin reactions have been reported with the use of LEXIVA [see Warnings and Precautions (5.2)].
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The most common moderate to severe adverse reactions in clinical studies of LEXIVA were diarrhea, rash, nausea, vomiting, and headache.
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Treatment discontinuation due to adverse events occurred in 6.4% of patients receiving LEXIVA and in 5.9% of patients receiving comparator treatments. The most common adverse reactions leading to discontinuation of LEXIVA (incidence ≤1% of patients) included diarrhea, nausea, vomiting, AST increased, ALT increased, and rash.
6.1 Clinical Trials in Adults
The data for the 3 active-controlled clinical trials described below reflect exposure of 700 HIV-1 infected patients to LEXIVA Tablets, including 599 patients exposed to LEXIVA for >24 weeks, and 409 patients exposed for >48 weeks. The population age ranged from 17 to 72 years. Of these patients, 26% were female, 51% Caucasian, 31% Black, 16% American Hispanic, and 70% were antiretroviral-naive. Sixty-one percent received LEXIVA 1,400 mg once daily plus ritonavir 200 mg once daily, 24% received LEXIVA 1,400 mg twice daily, and 15% received LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Selected adverse reactions reported during the clinical efficacy studies of LEXIVA are shown in Tables 2 and 3. Each table presents adverse reactions of moderate or severe intensity in patients treated with combination therapy for up to 48 weeks.
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APV30001* |
APV30002* |
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Adverse Reaction |
LEXIVA 1,400 mg b.i.d. (n = 166) |
Nelfinavir 1,250 mg b.i.d. (n = 83) |
LEXIVA 1,400 mg q.d./ Ritonavir 200 mg q.d. (n = 322) |
Nelfinavir 1,250 mg b.i.d. (n = 327) |
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Gastrointestinal | ||||
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Diarrhea |
5% |
18% |
10% |
18% |
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Nausea |
7% |
4% |
7% |
5% |
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Vomiting |
2% |
4% |
6% |
4% |
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Abdominal pain |
1% |
0% |
2% |
2% |
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Skin | ||||
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Rash |
8% |
2% |
3% |
2% |
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General disorders | ||||
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Fatigue |
2% |
1% |
4% |
2% |
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Nervous system | ||||
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Headache |
2% |
4% |
3% |
3% |
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*All patients also received abacavir and lamivudine twice daily. |
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Adverse Reaction |
LEXIVA 700 mg b.i.d./ Ritonavir 100 mg b.i.d.* (n = 106) |
Lopinavir 400 mg b.i.d./ Ritonavir 100 mg b.i.d.* (n = 103) |
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Gastrointestinal | ||
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Diarrhea |
13% |
11% |
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Nausea |
3% |
9% |
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Vomiting |
3% |
5% |
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Abdominal pain |
<1% |
2% |
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Skin | ||
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Rash |
3% |
0% |
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Nervous system | ||
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Headache |
4% |
2% |
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*All patients also received 2 reverse transcriptase inhibitors. |
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Skin rash (without regard to causality) occurred in approximately 19% of patients treated with LEXIVA in the pivotal efficacy studies. Rashes were usually maculopapular and of mild or moderate intensity, some with pruritus. Rash had a median onset of 11 days after initiation of LEXIVA and had a median duration of 13 days. Skin rash led to discontinuation of LEXIVA in <1% of patients. In some patients with mild or moderate rash, dosing with LEXIVA was often continued without interruption; if interrupted, reintroduction of LEXIVA generally did not result in rash recurrence.
The percentages of patients with Grade 3 or 4 laboratory abnormalities in the clinical efficacy studies of LEXIVA are presented in Tables 4 and 5.
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APV30001* |
APV30002* |
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Laboratory Abnormality |
LEXIVA 1,400 mg b.i.d. (n = 166) |
Nelfinavir 1,250 mg b.i.d. (n = 83) |
LEXIVA 1,400 mg q.d./ Ritonavir 200 mg q.d. (n = 322) |
Nelfinavir 1,250 mg b.i.d. (n = 327) |
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ALT (>5 x ULN) |
6% |
5% |
8% |
8% |
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AST (>5 x ULN) |
6% |
6% |
6% |
7% |
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Serum lipase (>2 x ULN) |
8% |
4% |
6% |
4% |
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Triglycerides† (>750 mg/dL) |
0% |
1% |
6% |
2% |
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Neutrophil count, absolute (<750 cells/mm3) |
3% |
6% |
3% |
4% |
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*All patients also received abacavir and lamivudine twice daily. |
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†Fasting specimens. |
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ULN = Upper limit of normal. |
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The incidence of Grade 3 or 4 hyperglycemia in antiretroviral-naive patients who received LEXIVA in the pivotal studies was <1%.
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Laboratory Abnormality |
LEXIVA 700 mg b.i.d./ Ritonavir 100 mg b.i.d.* (n = 104) |
Lopinavir 400 mg b.i.d./ Ritonavir 100 mg b.i.d.* (n = 103) |
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Triglycerides† (>750 mg/dL) |
11%‡ |
6%‡ |
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Serum lipase (>2 x ULN) |
5% |
12% |
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ALT (>5 x ULN) |
4% |
4% |
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AST (>5 x ULN) |
4% |
2% |
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Glucose (>251 mg/dL) |
2%‡ |
2%‡ |
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*All patients also received 2 reverse transcriptase inhibitors. |
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†Fasting specimens. |
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‡n = 100 for LEXIVA plus ritonavir, n = 98 for lopinavir plus ritonavir. |
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ULN = Upper limit of normal. |
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6.2 Clinical Trials in Pediatric Patients
LEXIVA with and without ritonavir was studied in 144 pediatric patients 2 to 18 years of age in 2 open-label studies. Safety information from 75 pediatric patients receiving LEXIVA twice daily with or without ritonavir follows.
All adverse events regardless of causality, all drug-related adverse events, and all laboratory events occurred with similar frequency in pediatrics compared with adults, with the exception of vomiting. Vomiting, regardless of causality, occurred more frequently among pediatric patients receiving LEXIVA twice daily with ritonavir [(30%) all between 2 and 18 years of age] and without ritonavir [(56%) all between 2 and 5 years of age] compared with adults receiving LEXIVA twice daily with ritonavir (10%) and without ritonavir (16%). The median duration of drug-related vomiting episodes was 1 day (range 1 to 62 days). Vomiting required temporary dose interruptions in 4 pediatric patients and was treatment-limiting in 1 pediatric patient, all of whom were receiving LEXIVA twice daily with ritonavir.
7 DRUG INTERACTIONS
See also Contraindications (4), Clinical Pharmacology (12.3).
If LEXIVA is used in combination with ritonavir, see full prescribing information for ritonavir for additional information on drug interactions.
7.1 CYP Inhibitors and Inducers
Amprenavir, the active metabolite of fosamprenavir, 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. Data also suggest that amprenavir induces CYP3A4.
Amprenavir is metabolized by CYP3A4. Coadministration of LEXIVA and drugs that induce CYP3A4, such as rifampin, may decrease amprenavir concentrations and reduce its therapeutic effect. Coadministration of LEXIVA and drugs that inhibit CYP3A4 may increase amprenavir concentrations and increase the incidence of adverse effects.
The potential for drug interactions with LEXIVA changes when LEXIVA is coadministered with the potent CYP3A4 inhibitor ritonavir. The magnitude of CYP3A4-mediated drug interactions (effect on amprenavir or effect on coadministered drug) may change when LEXIVA is coadministered with ritonavir. Because ritonavir is a CYP2D6 inhibitor, clinically significant interactions with drugs metabolized by CYP2D6 are possible when coadministered with LEXIVA plus ritonavir.
There are other agents that may result in serious and/or life-threatening drug interactions [see Contraindications (4)].
7.2 Drugs That Should Not Be Coadministered With LEXIVA
See Contraindications (4).
7.3 Established and Other Potentially Significant Drug Interactions
Table 6 provides a listing of established or potentially clinically significant drug interactions. Information in the table applies to LEXIVA with or without ritonavir, unless otherwise indicated.
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Concomitant Drug Class: Drug Name |
Effect on Concentration of Amprenavir or Concomitant Drug |
Clinical Comment |
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HIV-Antiviral Agents |
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Non-nucleoside reverse transcriptase inhibitor: Efavirenz* |
LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir |
Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily. |
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Non-nucleoside reverse transcriptase inhibitor: Nevirapine* |
LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine |
Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied. |
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HIV protease inhibitor: Atazanavir* |
LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir |
Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
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HIV protease inhibitors: Indinavir*, nelfinavir* |
LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. |
Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
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HIV protease inhibitors: Lopinavir/ritonavir* |
↓Amprenavir ↓Lopinavir |
An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
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HIV protease inhibitor: Saquinavir* |
LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated. |
Appropriate doses of the combination with respect to safety and efficacy have not been established. |
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Other Agents |
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Antiarrhythmics: Amiodarone, bepridil, lidocaine (systemic), and quinidine |
↑Antiarrhythmics |
Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics. |
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Anticoagulant: Warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. |
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Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoin* |
LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin |
Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended. |
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Antidepressant: Paroxetine, trazodone |
↓Paroxetine ↑Trazodone |
Coadministration of paroxetine with LEXIVA/ritonavir significantly decreased plasma levels of paroxetine. Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Concomitant use of trazodone and LEXIVA with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered. |
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Antifungals: Ketoconazole*, itraconazole |
↑Ketoconazole ↑Itraconazole |
Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (>200 mg/day) are not recommended. |
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Antimycobacterial: Rifabutin* |
↑Rifabutin and rifabutin metabolite |
A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week). |
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Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam |
↑Benzodiazepines |
Clinical significance is unknown. A decrease in benzodiazepine dose may be needed. |
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Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine |
↑Calcium channel blockers |
Use with caution. Clinical monitoring of patients is recommended. |
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Corticosteroid: Dexamethasone |
↓Amprenavir |
Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations. |
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Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine* |
LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated |
Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations. |
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HMG-CoA reductase inhibitor: Atorvastatin*, rosuvastatin |
↑Atorvastatin ↑Rosuvastatin |
Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin or pravastatin. |
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Immunosuppressants: Cyclosporine, tacrolimus, rapamycin |
↑Immunosuppressants |
Therapeutic concentration monitoring is recommended for immunosuppressant agents. |
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Inhaled/nasal steroid: Fluticasone |
LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone |
Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushings syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone propionate and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. |
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Narcotic analgesic: Methadone |
↓Methadone |
Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms. |
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Oral contraceptives: Ethinyl estradiol/norethin-drone* |
LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol |
Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. * Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as HRT for postmenopausal women. |
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PDE5 inhibitors: Sildenafil, tadalafil, vardenafil |
↑Sildenafil ↑Tadalafil ↑Vardenafil |
May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism. LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 72 hours. |
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Proton pump inhibitors: Esomeprazole*, lansoprazole, omeprazole, pantoprazole, rabeprazole |
LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole |
Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations. |
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Tricyclic antidepressants: Amitriptyline, imipramine |
↑Tricyclics |
Therapeutic concentration monitoring is recommended for tricyclic antidepressants. |
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*See Clinical Pharmacology (12.3) Tables 10, 11, 12, or 13 for magnitude of interaction. |
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8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C. Embryo/fetal development studies were conducted in rats (dosed from day 6 to day 17 of gestation) and rabbits (dosed from day 7 to day 20 of gestation). Administration of fosamprenavir to pregnant rats and rabbits produced no major effects on embryo-fetal development; however, the incidence of abortion was increased in rabbits that were administered fosamprenavir. Systemic exposures (AUC0-24 hr) to amprenavir at these dosages were 0.8 (rabbits) to 2 (rats) times the exposures in humans following administration of the maximum recommended human dose (MRHD) of fosamprenavir alone or 0.3 (rabbits) to 0.7 (rats) times the exposures in humans following administration of the MRHD of fosamprenavir in combination with ritonavir. In contrast, administration of amprenavir was associated with abortions and an increased incidence of minor skeletal variations resulting from deficient ossification of the femur, humerus, and trochlea, in pregnant rabbits at the tested dose; approximately one twentieth the exposure seen at the recommended human dose.
The mating and fertility of the F1 generation born to female rats given fosamprenavir was not different from control animals; however, fosamprenavir did cause a reduction in both pup survival and body weights. Surviving F1 female rats showed an increased time to successful mating, an increased length of gestation, a reduced number of uterine implantation sites per litter, and reduced gestational body weights compared with control animals. Systemic exposure (AUC0-24 hr) to amprenavir in the F0 pregnant rats was approximately 2 times higher than exposures in humans following administration of the MRHD of fosamprenavir alone or approximately the same as those seen in humans following administration of the MRHD of fosamprenavir in combination with ritonavir.
There are no adequate and well-controlled studies in pregnant women. LEXIVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to LEXIVA, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
8.3 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 LEXIVA.
8.4 Pediatric Use
The safety, pharmacokinetic profile, and virologic response of LEXIVA Oral Suspension and Tablets were evaluated in pediatric patients 2 to 18 years of age in 2 open-label studies [see Clinical Studies (14.3)]. No data are available for pediatric patients <2 years of age.
The adverse reaction profile seen in pediatrics was similar to that seen in adults. Vomiting regardless of causality was more frequent in pediatrics than in adults [see Adverse Reactions (6.2)].
8.5 Geriatric Use
Clinical studies of LEXIVA 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.
8.6 Hepatic Impairment
Amprenavir is principally metabolized by the liver; therefore, caution should be exercised when administering LEXIVA to patients with hepatic impairment because amprenavir concentrations may be increased [see Clinical Pharmacology (12.3)]. Patients with impaired hepatic function receiving LEXIVA with or without concurrent ritonavir require dose reduction [see Dosage and Administration (2.3)]. There are no data on the use of LEXIVA in combination with ritonavir in patients with severe hepatic impairment.
10 OVERDOSAGE
In a healthy volunteer repeat-dose pharmacokinetic study evaluating high-dose combinations of LEXIVA plus ritonavir, an increased frequency of Grade 2/3 ALT elevations (>2.5 x ULN) was observed with LEXIVA 1,400 mg twice daily plus ritonavir 200 mg twice daily (4 of 25 subjects). Concurrent Grade 1/2 elevations in AST (>1.25 x ULN) were noted in 3 of these 4 subjects. These transaminase elevations resolved following discontinuation of dosing.
There is no known antidote for LEXIVA. 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.
11 DESCRIPTION
LEXIVA (fosamprenavir calcium) is a prodrug of amprenavir, an inhibitor of HIV protease. The chemical name of fosamprenavir calcium is (3S)-tetrahydrofuran-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt. Fosamprenavir calcium is a single stereoisomer with the (3S)(1S,2R) configuration. It has a molecular formula of C25H34CaN3O9PS and a molecular weight of 623.7. It has the following structural formula:
Fosamprenavir calcium is a white to cream-colored solid with a solubility of approximately 0.31 mg/mL in water at 25°C.
LEXIVA Tablets are available for oral administration in a strength of 700 mg of fosamprenavir as fosamprenavir calcium (equivalent to approximately 600 mg of amprenavir). Each 700-mg tablet contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and povidone K30. The tablet film-coating contains the inactive ingredients hypromellose, iron oxide red, titanium dioxide, and triacetin.
LEXIVA Oral Suspension is available in a strength of 50 mg/mL of fosamprenavir as fosamprenavir calcium equivalent to approximately 43 mg of amprenavir. LEXIVA Oral Suspension is a white to off-white suspension with a grape-bubblegum-peppermint flavor. Each one milliliter (1 mL) contains the inactive ingredients artificial grape-bubblegum flavor, calcium chloride dihydrate, hypromellose, methylparaben, natural peppermint flavor, polysorbate 80, propylene glycol, propylparaben, purified water, and sucralose.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Fosamprenavir is an antiviral agent [see Clinical Pharmacology (12.4)].
12.3 Pharmacokinetics
The pharmacokinetic properties of amprenavir after administration of LEXIVA, with or without ritonavir, have been evaluated in both healthy adult volunteers and in HIV-infected patients; no substantial differences in steady-state amprenavir concentrations were observed between the 2 populations.
The pharmacokinetic parameters of amprenavir after administration of LEXIVA (with and without concomitant ritonavir) are shown in Table 7.
|
Regimen |
Cmax (mcg/mL) |
Tmax (hours)* |
AUC24 (mcg•hr/mL) |
Cmin (mcg/mL) |
|
LEXIVA 1,400 mg b.i.d. |
4.82 (4.06-5.72) |
1.3 (0.8-4.0) |
33.0 (27.6-39.2) |
0.35 (0.27-0.46) |
|
LEXIVA 1,400 mg q.d. plus Ritonavir 200 mg q.d. |
7.24 (6.32-8.28) |
2.1 (0.8-5.0) |
69.4 (59.7-80.8) |
1.45 (1.16-1.81) |
|
LEXIVA 1,400 mg q.d. plus Ritonavir 100 mg q.d. |
7.93 (7.25-8.68) |
1.5 (0.75-5.0) |
66.4 (61.1-72.1) |
0.86 (0.74-1.01) |
|
LEXIVA 700 mg b.i.d. plus Ritonavir 100 mg b.i.d. |
6.08 (5.38-6.86) |
1.5 (0.75-5.0) |
79.2 (69.0-90.6) |
2.12 (1.77-2.54) |
|
*Data shown are median (range). |
||||
The mean plasma amprenavir concentrations of the dosing regimens over the dosing intervals are displayed in Figure 1.
Figure 1. Mean (±SD) Steady-State Plasma Amprenavir Concentrations and Mean IC50 Values Against HIV from Protease Inhibitor-Naive Patients (in the Absence of Human Serum)
Absorption and Bioavailability
After administration of a single dose of LEXIVA to HIV-1-infected patients, the time to peak amprenavir concentration (Tmax) occurred between 1.5 and 4 hours (median 2.5 hours). The absolute oral bioavailability of amprenavir after administration of LEXIVA in humans has not been established.
After administration of a single 1,400-mg dose in the fasted state, LEXIVA Oral Suspension (50 mg/mL) and LEXIVA Tablets (700 mg) provided similar amprenavir exposures (AUC), however, the Cmax of amprenavir after administration of the suspension formulation was 14.5% higher compared with the tablet.
Effects of Food on Oral Absorption
Administration of a single 1,400-mg dose of LEXIVA Tablets in the fed state (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) compared with the fasted state was associated with no significant changes in amprenavir Cmax, Tmax, or AUC0-∞ [see Dosage and Administration (2)].
Administration of a single 1,400-mg dose of LEXIVA Oral Suspension in the fed state (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) compared with the fasted state was associated with a 46% reduction in Cmax, a 0.72-hour delay in Tmax, and a 28% reduction in amprenavir AUC0-∞.
Distribution
In vitro, amprenavir is approximately 90% bound to plasma proteins, primarily to alpha1-acid glycoprotein. In vitro, concentration-dependent binding was observed over the concentration range of 1 to 10 mcg/mL, with decreased binding at higher concentrations. 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
After oral administration, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. This occurs in the gut epithelium during absorption. 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. Unchanged amprenavir in urine accounts for approximately 1% of the dose; unchanged amprenavir was not detectable in feces. Approximately 14% and 75% of an administered single dose of 14C-amprenavir can be accounted for as metabolites in urine and feces, respectively. Two metabolites accounted for >90% of the radiocarbon in fecal samples. The plasma elimination half-life of amprenavir is approximately 7.7 hours.
Special Populations
Hepatic Impairment
The pharmacokinetics of amprenavir have been studied after the administration of LEXIVA in combination with ritonavir to adult HIV-1-infected patients with mild and moderate hepatic impairment. Following 2 weeks of dosing with LEXIVA plus ritonavir, the AUC of amprenavir was increased by approximately 22% in patients with mild hepatic impairment and by approximately 70% in patients with moderate hepatic impairment compared with HIV-1-infected patients with normal hepatic function. Protein binding of amprenavir was decreased in both mild and moderate hepatic impairment, with the unbound fraction at 2 hours (approximate Cmax) increasing by 18% to 57% and the unbound fraction at the end of the dosing interval (Cmin) increasing 50% to 102% [see Dosage and Administration (2.3)]. There are no data on the use of LEXIVA in combination with ritonavir in patients with severe hepatic impairment.
The pharmacokinetics of amprenavir have been studied after administration of amprenavir given as AGENERASE® Capsules to adult patients with hepatic impairment. Following administration of a single 600-mg oral dose the AUC of amprenavir was increased by approximately 2.5 fold in patients with moderate cirrhosis and by approximately 4.5 fold in patients with severe cirrhosis compared with healthy volunteers [see Dosage and Administration (2.3)].
Renal Impairment
The impact of renal impairment on amprenavir elimination in adult patients has not been studied. The renal elimination of unchanged amprenavir represents approximately 1% of the administered dose; therefore, renal impairment is not expected to significantly impact the elimination of amprenavir.
Pediatric Patients
The pharmacokinetics of amprenavir after administration of LEXIVA Oral Suspension and LEXIVA Tablets, with or without ritonavir, have been evaluated in 124 patients 2 to 18 years of age. Pharmacokinetic parameters for LEXIVA administered with food and with or without ritonavir in this patient population are provided in Tables 8 and 9 below.
|
Parameter |
2 to 5 Years |
|
|
n |
LEXIVA 30 mg/kg b.i.d. |
|
|
AUC(24) (mcg•hr/mL) |
8 |
31.4 (13.7, 72.4) |
|
Cmax (mcg/mL) |
8 |
5.00 (1.95, 12.8) |
|
Cmin (mcg/mL) |
17 |
0.454 (0.342, 0.604) |
|
Parameter |
6 to 11 Years |
12 to 18 Years |
||
|
n |
LEXIVA 18 mg/kg plus Ritonavir 3 mg/kg b.i.d. |
n |
LEXIVA 700 mg plus Ritonavir 100 mg b.i.d. |
|
|
AUC(0-24) (mcg•hr/mL) |
9 |
93.4 (67.8, 129) |
8 |
58.8 (38.8, 89.0) |
|
Cmax (mcg/mL) |
9 |
6.07 (4.40, 8.38) |
8 |
4.33 (2.82, 6.65) |
|
Cmin (mcg/mL) |
17 |
2.69 (2.15, 3.36) |
24 |
1.61 (1.21, 2.15) |
Geriatric Patients
The pharmacokinetics of amprenavir after administration of LEXIVA to patients over 65 years of age have not been studied [see Use in Specific Populations (8.5)].
Gender
The pharmacokinetics of amprenavir after administration of LEXIVA do not differ between males and females.
Race
The pharmacokinetics of amprenavir after administration of LEXIVA do not differ between blacks and non-blacks.
Drug Interactions
[See Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7).]
Amprenavir, the active metabolite of fosamprenavir, is metabolized in the liver by the cytochrome P450 enzyme system. Amprenavir inhibits CYP3A4. Data also suggest that amprenavir induces 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 LEXIVA and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration on AUC, Cmax, and Cmin values are summarized in Table 10 (effect of other drugs on amprenavir) and Table 12 (effect of LEXIVA on other drugs). In addition, since LEXIVA delivers comparable amprenavir plasma concentrations as AGENERASE, drug interaction data derived from studies with AGENERASE are provided in Tables 11 and 13. For information regarding clinical recommendations, see Drug Interactions (7).
|
Coadministered Drug(s) and Dose(s) |
Dose of LEXIVA* |
n |
% Change in Amprenavir Pharmacokinetic Parameters (90% CI) |
||
|
Cmax |
AUC |
Cmin |
|||
|
Antacid (MAALOX TC®) 30 mL single dose |
1,400 mg single dose |
30 |
↓35 (↓24 to ↓42) |
↓18 (↓9 to ↓26) |
↑14 (↓7 to ↑39) |
|
Atazanavir 300 mg q.d. for 10 days |
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 10 days |
22 |
↔ |
↔ |
↔ |
|
Atorvastatin 10 mg q.d. for 4 days |
1,400 mg b.i.d. for 2 weeks |
16 |
↓18 (↓34 to ↑1) |
↓27 (↓41 to ↓12) |
↓12 (↓27 to ↓6) |
|
Atorvastatin 10 mg q.d. for 4 days |
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks |
16 |
↔ |
↔ |
↔ |
|
Efavirenz 600 mg q.d. for 2 weeks |
1,400 mg q.d. plus ritonavir 200 mg q.d. for 2 weeks |
16 |
↔ |
↓13 (↓30 to ↑7) |
↓36 (↓8 to ↓56) |
|
Efavirenz 600 mg q.d. plus additional ritonavir 100 mg q.d. for 2 weeks |
1,400 mg q.d. plus ritonavir 200 mg q.d. for 2 weeks |
16 |
↑18 (↑1 to ↑38) |
↑11 (0 to ↑24) |
↔ |
|
Efavirenz 600 mg q.d. for 2 weeks |
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks |
16 |
↔ |
↔ |
↓17 (↓4 to ↓29) |
|
Esomeprazole 20 mg q.d. for 2 weeks |
1,400 mg b.i.d. for 2 weeks |
25 |
↔ |
↔ |
↔ |
|
Esomeprazole 20 mg q.d. for 2 weeks |
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks |
23 |
↔ |
↔ |
↔ |
|
Ethinyl estradiol/norethindrone 0.035 mg/0.5 mg q.d. for 21 days |
700 mg b.i.d. plus ritonavir† 100 mg b.i.d. for 21 days |
25 |
↔‡ |
↔‡ |
↔‡ |
|
Ketoconazole§ 200 mg q.d. for 4 days |
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 4 days |
15 |
↔ |
↔ |
↔ |
|
Lopinavir/ritonavir 533 mg/133 mg b.i.d. |
1,400 mg b.i.d. for 2 weeks |
18 |
↓13¦ |
↓26¦ |
↓42¦ |
|
Lopinavir/ritonavir 400 mg/100 mg b.i.d. for 2 weeks |
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks |
18 |
↓58 (↓42 to ↓70) |
↓63 (↓51 to ↓72) |
↓65 (↓54 to ↓73) |
|
Methadone 70 to 120 mg q.d. for 2 weeks |
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks |
19 |
↔‡ |
↔‡ |
↔‡ |
|
Nevirapine 200 mg b.i.d. for 2 weeks¶ |
1,400 mg b.i.d. for 2 weeks |
17 |
↓25 (↓37 to ↓10) |
↓33 (↓45 to ↓20) |
↓35 (↓50 to ↓15) |
|
Nevirapine 200 mg b.i.d. for 2 weeks¶ |
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks |
17 |
↔ |
↓11 (↓23 to ↑3) |
↓19 (↓32 to ↓4) |
|
Phenytoin 300 mg q.d. for 10 days |
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 10 days |
13 |
↔ |
↑20 (↑8 to↑34) |
↑19 (↑6 to ↑33) |
|
Ranitidine 300 mg single dose (administered 1 hour before fosamprenavir) |
1,400 mg single dose |
30 |
↓51 (↓43 to ↓58) |
↓30 (↓22 to ↓37) |
↔ (↓19 to ↑21) |
|
Rifabutin 150 mg q.o.d. for 2 weeks |
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 2 weeks |
15 |
↑36‡ (↑18 to ↑55) |
↑35‡ (↑17 to ↑56) |
↑17‡ (↓1 to ↑39) |
|
Tenofovir 300 mg q.d. for 4 to 48 weeks |
700 mg b.i.d. plus ritonavir 100 mg b.i.d. for 4 to 48 weeks |
45 |
NA |
NA |
↔# |
|
Tenofovir 300 mg q.d. for 4 to 48 weeks |
1,400 mg q.d. plus ritonavir 200 mg q.d. for 4 to 48 weeks |
60 |
NA |
NA |
↔# |
|
* Concomitant medication is also shown in this column where appropriate. |
|||||
|
† Ritonavir Cmax, AUC, and Cmin increased by 63%, 45%, and 13%, respectively, compared with historical control. |
|||||
|
‡ Compared with historical control. |
|||||
|
§ Patients were receiving LEXIVA/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and LEXIVA/ritonavir. |
|||||
|
¦Compared with LEXIVA 700 mg/ritonavir 100 mg b.i.d. for 2 weeks. |
|||||
|
¶ Patients were receiving nevirapine for at least 12 weeks prior to study. |
|||||
|
# Compared with parallel control group. |
|||||
|
↑= Increase;↓= Decrease; ↔ = No change (↑or ↓≤10%), NA = Not applicable. |
|||||
|
Coadministered Drug(s) and Dose(s) |
Dose of AGENERASE* |
n |
% Change in Amprenavir Pharmacokinetic Parameters (90% CI) |
||
|
Cmax |
AUC |
Cmin |
|||
|
Abacavir 300 mg b.i.d. for 2 to 3 weeks |
900 mg b.i.d. for 2 to 3 weeks |
4 |
↔* |
↔* |
↔* |
|
Clarithromycin 500 mg b.i.d. for 4 days |
1,200 mg b.i.d. for 4 days |
12 |
↑15 (↑1 to ↑31) |
↑18 (↑8 to ↑29) |
↑39 (↑31 to ↑47) |
|
Delavirdine 600 mg b.i.d. for 10 days | |||||