fosamprenavir 700 MG Oral Tablet
Generic Name: FOSAMPRENAVIR CALCIUM
Brand Name: LEXIVA
- Substance Name(s):
- FOSAMPRENAVIR CALCIUM
DRUG INTERACTIONS
7 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.
Coadministration of LEXIVA with drugs that induce CYP3A4 may decrease amprenavir (active metabolite) concentrations leading to potential loss of virologic activity.
(7, 12.3) Coadministration with drugs that inhibit CYP3A4 may increase amprenavir concentrations.
(7, 12.3) Coadministration of LEXIVA and ritonavir may result in clinically significant interactions with drugs metabolized by CYP2D6.
(7) 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.
Table 6.
Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Amprenavir or Concomitant Drug Clinical Comment HIV-Antiviral Agents Non-nucleoside reverse transcriptase inhibitor: Efavirenza 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.
Non-nucleoside reverse transcriptase inhibitor: Nevirapinea 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.
HIV protease inhibitor: Atazanavira 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.
HIV protease inhibitors: Indinavira, nelfinavira 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.
HIV protease inhibitors: Lopinavir/ritonavira ↓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.
HIV protease inhibitor: Saquinavira 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.
Other Agents 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.
Anticoagulant: Warfarin Concentrations of warfarin may be affected.
It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoina 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.
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.
Antifungals: Ketoconazolea, 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.
Antimycobacterial: Rifabutina ↑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).
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam ↑Benzodiazepines Clinical significance is unknown.
A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine ↑Calcium channel blockers Use with caution.
Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ↓Amprenavir Use with caution.
LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidinea LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated Use with caution.
LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitor: Atorvastatina, 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.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin ↑Immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents.
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 and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone ↓Methadone Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethin-dronea 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 hormone replacement therapy (HRT) for postmenopausal women.
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.
Proton pump inhibitors: Esomeprazolea, 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.
Tricyclic antidepressants: Amitriptyline, imipramine ↑Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants.
a See Clinical Pharmacology (12.3) Tables 10, 11, 12, or 13 for magnitude of interaction.
OVERDOSAGE
10 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.
DESCRIPTION
11 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.
fosamprenavir calcium chemical structure
CLINICAL STUDIES
14 14.1 Therapy-Naive Adult Patients Study APV30001 APV30001 was a randomized, open-label study, comparing treatment with LEXIVA Tablets (1,400 mg twice daily) versus nelfinavir (1,250 mg twice daily) in 249 antiretroviral treatment-naive patients.
Both groups of patients also received abacavir (300 mg twice daily) and lamivudine (150 mg twice daily).
The mean age of the patients in this study was 37 years (range: 17 to 70 years), 69% of the patients were males, 20% were CDC Class C (AIDS), 24% were Caucasian, 32% were black, and 44% were Hispanic.
At baseline, the median CD4+ cell count was 212 cells/mm3 (range: 2 to 1,136 cells/mm3; 18% of patients had a CD4+ cell count of <50 cells/mm3 and 30% were in the range of 50 to <200 cells/mm3).
Baseline median HIV-1 RNA was 4.83 log10 copies/mL (range: 1.69 to 7.41 log10 copies/mL; 45% of patients had >100,000 copies/mL).
The outcomes of randomized treatment are provided in Table 15.
Table 15.
Outcomes of Randomized Treatment Through Week 48 (APV30001) a Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48 (Roche AMPLICOR HIV-1 MONITOR Assay Version 1.5).
b Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, and other reasons.
Outcome (Rebound or discontinuation = failure) LEXIVA 1,400 mg b.i.d.
(n = 166) Nelfinavir 1,250 mg b.i.d.
(n = 83) Respondera 66% (57%) 52% (42%) Virologic failure 19% 32% Rebound 16% 19% Never suppressed through Week 48 3% 13% Clinical progression 1% 1% Death 0% 1% Discontinued due to adverse reactions 4% 2% Discontinued due to other reasonsb 10% 10% Treatment response by viral load strata is shown in Table 16.
Table 16.
Proportions of Responders Through Week 48 by Screening Viral Load (APV30001) Screening Viral Load HIV-1 RNA (copies/mL) LEXIVA 1,400 mg b.i.d.
Nelfinavir 1,250 mg b.i.d.
<400 copies/mL n 100,000 67% 73 36% 37 Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 201 cells/mm3 in the group receiving LEXIVA and 216 cells/mm3 in the nelfinavir group.
Study APV30002 APV30002 was a randomized, open-label study, comparing treatment with LEXIVA Tablets (1,400 mg once daily) plus ritonavir (200 mg once daily) versus nelfinavir (1,250 mg twice daily) in 649 treatment-naive patients.
Both treatment groups also received abacavir (300 mg twice daily) and lamivudine (150 mg twice daily).
The mean age of the patients in this study was 37 years (range: 18 to 69 years), 73% of the patients were males, 22% were CDC Class C, 53% were Caucasian, 36% were black, and 8% were Hispanic.
At baseline, the median CD4+ cell count was 170 cells/mm3 (range: 1 to 1,055 cells/mm3; 20% of patients had a CD4+ cell count of <50 cells/mm3 and 35% were in the range of 50 to <200 cells/mm3).
Baseline median HIV-1 RNA was 4.81 log10 copies/mL (range: 2.65 to 7.29 log10 copies/mL; 43% of patients had >100,000 copies/mL).
The outcomes of randomized treatment are provided in Table 17.
Table 17.
Outcomes of Randomized Treatment Through Week 48 (APV30002) a Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48 (Roche AMPLICOR HIV-1 MONITOR Assay Version 1.5).
b Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, and other reasons.
Outcome (Rebound or discontinuation = failure) LEXIVA 1,400 mg q.d./ Ritonavir 200 mg q.d.
(n = 322) Nelfinavir 1,250 mg b.i.d.
(n = 327) Respondera 69% (58%) 68% (55%) Virologic failure 6% 16% Rebound 5% 8% Never suppressed through Week 48 1% 8% Death 1% 0% Discontinued due to adverse reactions 9% 6% Discontinued due to other reasonsb 15% 10% Treatment response by viral load strata is shown in Table 18.
Table 18.
Proportions of Responders Through Week 48 by Screening Viral Load (APV30002) Screening Viral Load HIV-1 RNA LEXIVA 1,400 mg q.d./Ritonavir 200 mg q.d.
Nelfinavir 1,250 mg b.i.d.
(copies/mL) <400 copies/mL n 100,000 66% 125 64% 133 Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 203 cells/mm3 in the group receiving LEXIVA and 207 cells/mm3 in the nelfinavir group.
14.2 Protease Inhibitor-Experienced Adult Patients Study APV30003 APV30003 was a randomized, open-label, multicenter study comparing 2 different regimens of LEXIVA plus ritonavir (LEXIVA Tablets 700 mg twice daily plus ritonavir 100 mg twice daily or LEXIVA Tablets 1,400 mg once daily plus ritonavir 200 mg once daily) versus lopinavir/ritonavir (400 mg/100 mg twice daily) in 315 patients who had experienced virologic failure to 1 or 2 prior protease inhibitor-containing regimens.
The mean age of the patients in this study was 42 years (range: 24 to 72 years), 85% were male, 33% were CDC Class C, 67% were Caucasian, 24% were black, and 9% were Hispanic.
The median CD4+ cell count at baseline was 263 cells/mm3 (range: 2 to 1,171 cells/mm3).
Baseline median plasma HIV-1 RNA level was 4.14 log10 copies/mL (range: 1.69 to 6.41 log10 copies/mL).
The median durations of prior exposure to NRTIs were 257 weeks for patients receiving LEXIVA/ritonavir twice daily (79% had ≥3 prior NRTIs) and 210 weeks for patients receiving lopinavir/ritonavir (64% had ≥3 prior NRTIs).
The median durations of prior exposure to protease inhibitors were 149 weeks for patients receiving LEXIVA/ritonavir twice daily (49% received ≥2 prior protease inhibitors) and 130 weeks for patients receiving lopinavir/ritonavir (40% received ≥2 prior protease inhibitors).
The time-averaged changes in plasma HIV-1 RNA from baseline (AAUCMB) at 48 weeks (the endpoint on which the study was powered) were -1.4 log10 copies/mL for twice-daily LEXIVA/ritonavir and -1.67 log10 copies/mL for the lopinavir/ritonavir group.
The proportions of patients who achieved and maintained confirmed HIV-1 RNA <400 copies/mL (secondary efficacy endpoint) were 58% with twice-daily LEXIVA/ritonavir and 61% with lopinavir/ritonavir (95% CI for the difference: -16.6, 10.1).
The proportions of patients with HIV-1 RNA <50 copies/mL with twice-daily LEXIVA/ritonavir and with lopinavir/ritonavir were 46% and 50%, respectively (95% CI for the difference: -18.3, 8.9).
The proportions of patients who were virologic failures were 29% with twice-daily LEXIVA/ritonavir and 27% with lopinavir/ritonavir.
The frequency of discontinuations due to adverse events and other reasons, and deaths were similar between treatment arms.
Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 81 cells/mm3 with twice-daily LEXIVA/ritonavir and 91 cells/mm3 with lopinavir/ritonavir.
This study was not large enough to reach a definitive conclusion that LEXIVA/ritonavir and lopinavir/ritonavir are clinically equivalent.
Once-daily administration of LEXIVA plus ritonavir is not recommended for protease inhibitor-experienced patients.
Through Week 48, 50% and 37% of patients receiving LEXIVA 1,400 mg plus ritonavir 200 mg once daily had plasma HIV-1 RNA <400 copies/mL and <50 copies/mL, respectively.
14.3 Pediatric Patients Two open-label studies in pediatric patients 2 to 18 years of age were conducted.
In one study, twice-daily dosing regimens (LEXIVA with or without ritonavir) were evaluated in combination with other antiretroviral agents.
A second study evaluated once-daily dosing of LEXIVA with ritonavir; the data from this study were insufficient to support a once-daily dosing regimen in any pediatric patient population.
LEXIVA: Eighteen (16 therapy-naive and 2 therapy-experienced) pediatric patients received LEXIVA Oral Suspension without ritonavir twice daily.
At Week 24, 67% (12/18) achieved HIV-1 RNA <400 copies/mL, and the median increase from baseline in CD4+ cell count was 353 cells/mm3.
LEXIVA plus ritonavir: Twenty-seven protease inhibitor-naive and 30 protease inhibitor-experienced pediatric patients received LEXIVA Oral Suspension or Tablets with ritonavir twice daily.
At Week 24, 70% of protease inhibitor-naive (19/27) and 57% of protease inhibitor-experienced (17/30) patients achieved HIV-1 RNA <400 copies/mL; median increases from baseline in CD4+ cell counts were 131 cells/mm3 and 149 cells/mm3 in protease inhibitor-naive and experienced patients, respectively.
HOW SUPPLIED
16 /STORAGE AND HANDLING LEXIVA Tablets, 700 mg, are pink, film-coated, capsule-shaped, biconvex tablets, with “GX LL7” debossed on one face.
Store at controlled room temperature of 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature).
Keep container tightly closed.
LEXIVA Oral Suspension, a white to off-white grape-bubblegum-peppermint-flavored suspension, contains 50 mg of fosamprenavir as fosamprenavir calcium equivalent to approximately 43 mg of amprenavir in each 1 mL.
This product does not require reconstitution.
Store at 5° to 30°C (41° to 86°F).
Shake vigorously before using.
Do not freeze.
This product is supplied by State of Florida DOH Central Pharmacy as follows: NDC Strength Quantity/Form Color Source Prod.
Code 53808-0281-1 700 mg 30 Tablets in a Blister Pack PINK 0173-0721
RECENT MAJOR CHANGES
Dosage and Administration, Patients With Hepatic Impairment (2.3) 4/2009 Warnings and Precautions (5.8) 9/2009 Warnings and Precautions, Nephrolithiasis (5.11) 9/2009
GERIATRIC USE
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.
DOSAGE FORMS AND STRENGTHS
3 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.
700 mg tablets and 50 mg/mL oral suspension (3)
MECHANISM OF ACTION
12.1 Mechanism of Action Fosamprenavir is an antiviral agent [see Clinical Pharmacology (12.4)].
INDICATIONS AND USAGE
1 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: 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)].
Once-daily administration of LEXIVA plus ritonavir is not recommended for adult protease inhibitor-experienced patients or any pediatric patients.
LEXIVA is an HIV protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
(1)
PEDIATRIC USE
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 (6.1)].
PREGNANCY
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.
NUSRING MOTHERS
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.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Certain drugs should not be coadministered with LEXIVA due to risk of serious or life-threatening adverse reactions.
(5.1) LEXIVA should be discontinued for severe skin reactions including Stevens-Johnson syndrome.
(5.2) LEXIVA should be used with caution in patients with a known sulfonamide allergy.
(5.3) Use of higher than approved doses may lead to transaminase elevations.
Patients with hepatitis B or C are at increased risk of transaminase elevations.
(5.4) Patients receiving LEXIVA may develop new onset or exacerbations of diabetes mellitus, hyperglycemia (5.5), immune reconstitution syndrome (5.6), redistribution/accumulation of body fat (5.7), and elevated triglyceride and cholesterol concentrations (5.8).
Monitor cholesterol and triglycerides prior to therapy and periodically thereafter.
Acute hemolytic anemia has been reported with amprenavir.
(5.9) Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required.
(5.10) Nephrolithiasis: Cases of nephrolithiasis have been reported with fosamprenavir.
(5.11) 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 and cholesterol [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 Nephrolithiasis Cases of nephrolithiasis were reported during postmarketing surveillance in HIV-infected patients receiving LEXIVA.Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made.
If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered.
5.12 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)].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling 17.1 Drug Interactions 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 LEXIVA.
LEXIVA may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, particularly St.
John’s wort.
Patients receiving PDE5 inhibitors should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism, and should promptly report any symptoms to their healthcare provider.
Patients receiving hormonal contraceptives should be instructed to use alternate contraceptive measures during therapy with LEXIVA because hormonal levels may be altered, and if used in combination with LEXIVA and ritonavir, liver enzyme elevations may occur.
17.2 Sulfa Allergy Patients should inform their healthcare provider if they have a sulfa allergy.
The potential for cross-sensitivity between drugs in the sulfonamide class and fosamprenavir is unknown.
17.3 Redistribution/Accumulation of Body Fat Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including LEXIVA, and that the cause and long-term health effects of these conditions are not known at this time.
17.4 Information About Therapy With LEXIVA Patients should be informed that LEXIVA 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 LEXIVA are unknown at this time.
Patients should be told that there are currently no data demonstrating that therapy with LEXIVA can reduce the risk of transmitting HIV to others.
Patients should be told that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death.
Patients should remain under the care of a physician while using LEXIVA.
Patients should be advised to take LEXIVA every day as prescribed.
LEXIVA 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.
17.5 Oral Suspension Patients should be instructed to shake the bottle vigorously before each use and that refrigeration of the oral suspension may improve the taste for some patients.
LEXIVA and AGENERASE are registered trademarks of GlaxoSmithKline.
GlaxoSmithKline Vertex Pharmaceuticals Incorporated Research Triangle Park, NC 27709 Cambridge, MA 02139 ©2009, GlaxoSmithKline.
All rights reserved.
PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _
DOSAGE AND ADMINISTRATION
2 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.
Therapy-Naive Adults: LEXIVA 1,400 mg twice daily; LEXIVA 1,400 mg once daily plus ritonavir 200 mg once daily; LEXIVA 1,400 mg once daily plus ritonavir 100 mg once daily; LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily.
(2.1) Protease Inhibitor-Experienced Adults: LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily.
(2.1) Pediatric Patients (2 to 18 years of age): Dosage should be calculated based on body weight (kg) and should not exceed adult dose.
(2.2) Hepatic Impairment: Recommended adjustments for patients with mild, moderate, or severe hepatic impairment.
(2.3) Dosing Considerations LEXIVA Tablets may be taken with or without food.
(2) LEXIVA Suspension: Adults should take without food; pediatric patients should take with food.
(2) 2.1 Adults Therapy-Naive Adults LEXIVA 1,400 mg twice daily (without ritonavir).
LEXIVA 1,400 mg once daily plus ritonavir 200 mg once daily.
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)].
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 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 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 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 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.
Other Dosing Considerations 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 without ritonavir (therapy-naive), 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 15): LEXIVA should be used with caution at a reduced dosage of 350 mg twice daily without ritonavir (therapy-naive) or 300 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced).