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Lexiva
SIDE EFFECTS
- Severe or life-threatening skin reactions have been reported with the use of LEXIVA [see WARNINGS AND PRECAUTIONS ].
- The most common moderate to severe adverse reactions in clinical studies of LEXIVA were diarrhea, rash, nausea, vomiting, and headache.
- 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 less than or equal to 1% of patients) included diarrhea, nausea, vomiting, AST increased, ALT increased, and rash.
Clinical Trials
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 greater than 24 weeks, and 409 patients exposed for greater than 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.
Table 2: Selected Moderate/Severe Clinical Adverse
Reactions Reported in Greater Than or Equal to 2% of Antiretroviral-Naive Adult
Patients
| APV30001a | APV30002a | |||
| 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) |
|
| Gastrointestinal | ||||
| Diarrhea | 5% | 18% | 10% | 18% |
| Nausea | 7% | 4% | 7% | 5% |
| Vomiting | 2% | 4% | 6% | 4% |
| Abdominal pain | 1% | 0% | 2% | 2% |
| Skin | ||||
| Rash | 8% | 2% | 3% | 2% |
| General disorders | ||||
| Fatigue | 2% | 1% | 4% | 2% |
| Nervous system | ||||
| Headache | 2% | 4% | 3% | 3% |
| a All patients also received abacavir and lamivudine twice daily. | ||||
Table 3: Selected
Moderate/Severe Clinical Adverse Reactions Reported in Greater Than or Equal to
2% of Protease Inhibitor-Experienced Adult Patients (Study APV30003)
| Adverse Reaction | LEXIVA 700 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 106) |
Lopinavir 400 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 103) |
| Gastrointestinal | ||
| Diarrhea | 13% | 11% |
| Nausea | 3% | 9% |
| Vomiting | 3% | 5% |
| Abdominal pain | < 1% | 2% |
| Skin | ||
| Rash | 3% | 0% |
| Nervous system | ||
| Headache | 4% | 2% |
| a All patients also received 2 reverse transcriptase inhibitors. | ||
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 less than 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.
Table 4: Grade 3/4 Laboratory Abnormalities Reported in
Greater Than or Equal to 2% of Antiretroviral-Naive Adult Patients in Studies
APV30001 and APV30002
| Laboratory Abnormality | APV30001a | APV30002a | ||
| 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) |
|
| ALT ( > 5 x ULN) | 6% | 5% | 8% | 8% |
| AST ( > 5 x ULN) | 6% | 6% | 6% | 7% |
| Serum lipase ( > 2 x ULN) | 8% | 4% | 6% | 4% |
| Triglyceridesb ( > 750 mg/dL) | 0% | 1% | 6% | 2% |
| Neutrophil count, absolute ( < 750 cells/mm³) | 3% | 6% | 3% | 4% |
| a All patients also received abacavir and lamivudine twice
daily. bFasting specimens. ULN = Upper limit of normal. |
||||
The incidence of Grade 3 or 4 hyperglycemia in antiretroviral-naive patients who received LEXIVA in the pivotal studies was less than 1%.
Table 5: Grade 3/4 Laboratory
Abnormalities Reported in Greater Than or Equal to 2% of Protease
Inhibitor-Experienced Adult Patients in Study APV30003
| Laboratory Abnormality | LEXIVA 700 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 104) |
Lopinavir 400 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 103) |
| Triglyceridesb ( > 750 mg/dL) | 11%c | 6%c |
| Serum lipase ( > 2 x ULN) | 5% | 12% |
| ALT ( > 5 x ULN) | 4% | 4% |
| AST ( > 5 x ULN) | 4% | 2% |
| Glucose ( > 251 mg/dL) | 2%c | 2%c |
| a All patients also received 2 reverse transcriptase
inhibitors. bFasting specimens. cn = 100 for LEXIVA plus ritonavir, n = 98 for lopinavir plus ritonavir. ULN = Upper limit of normal. |
||
Pediatric Patients
LEXIVA with and without ritonavir was studied in 144 pediatric patients aged 2 to 18 years 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 aged between 2 and 18 years) and without ritonavir ([56%] all aged between 2 and 5 years) 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.
Postmarketing Experience
In addition to adverse reactions reported from clinical trials, the following reactions have been identified during post-approval use of LEXIVA. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to LEXIVA.
Cardiac Disorders
Myocardial infarction.
Metabolism and Nutrition Disorders
Nervous System Disorders
Oral paresthesia.
Skin and Subcutaneous Tissue Disorders
Urogenital
Read the Lexiva (fosamprenavir calcium) Side Effects Center for a complete guide to possible side effects »
DRUG INTERACTIONS
See also CONTRAINDICATIONS, CLINICAL PHARMACOLOGY.
If LEXIVA is used in combination with ritonavir, see full prescribing information for ritonavir for additional information on drug interactions.
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].
Drugs That Should Not Be Coadministered With LEXIVA
See CONTRAINDICATIONS.
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. |
| HIV integrase inhibitor: Raltegravira | LEXIVA: ↓Amprenavir ↓Raltegravir LEXIVA/ritonavir: ↓Amprenavir ↓Raltegravir |
Appropriate doses of the combination with respect to safety and efficacy have not been established [see CLINICAL PHARMACOLOGY]. |
| 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 (greater than 200 mg/day) are not recommended. |
| Anti-gout: Colchicine | ↑Colchicine | Patients with renal or hepatic impairment should not be given colchicine with LEXIVA/ritonavir. LEXIVA/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). LEXIVA and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day). |
| 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. |
| Endothelin receptor antagonists: Bosentan | ↑Bosentan | Coadministration of bosentan in patients on LEXIVA: In patients who have been receiving LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of LEXIVA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of LEXIVA. After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| Histamine H2-recepto rantagonists: 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 inhibitors: Atorvastatina | ↑Atorvastatin | Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day. |
| Immunosuppressants: Cyclosporine, tacrolimus, rapamycin | ↑Immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents. |
| Inhaled beta agonist: Salmeterol | ↑Salmeterol | Concurrent administration of salmeterol with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
| 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/norethindronea | LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol |
Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response.a 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, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
In patients receiving LEXIVA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of LEXIVA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of LEXIVA. Stop ADCIRCA at least 24 hours prior to starting LEXIVA. After at least one week following the initiation of LEXIVA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: 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. Use with increased monitoring for adverse events. |
| 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 Tables 10, 11, 12, or 13 for magnitude of interaction. | ||
Last reviewed on RxList: 3/1/2013
This monograph has been modified to include the generic and brand name in many instances.
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