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Lexiva Side Effects, and Drug Interactions - Fosamprenavir Calcium

SIDE EFFECTS

LEXIVA was studied in 700 patients in Phase III controlled clinical studies. The most common treatment-emergent adverse events in clinical studies of LEXIVA were diarrhea, nausea, vomiting, headache, and rash and were generally mild to moderate in severity. Treatment discontinuation due to adverse events occurred in 6.4% of patients receiving LEXIVA and in 5.9% of patients receiving comparator treatments.

Severe or life-threatening skin reactions, including 1 case of Stevens-Johnson syndrome among 700 patients treated with LEXIVA, were reported in <1% of patients treated with LEXIVA in the clinical studies. Treatment with LEXIVA should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms.

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.

Selected adverse events reported during the clinical efficacy studies of LEXIVA are shown in Tables 14 and 15. Each table presents drug-related adverse events of moderate or severe intensity and adverse events of all grades regardless of causality in patients treated with combination therapy for up to 48 weeks.

Table 14. Selected Clinical Adverse Events Reported in Antiretroviral-Naive Patients
	APV30001^*				APV30002^*
	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)
Adverse Event	Moderate/ Severe Drug-Related	All Grades^†	Moderate/ Severe Drug- Related	All Grades^†	Moderate/ Severe Drug- Related	All Grades^†	Moderate/ Severe Drug- Related	All Grades^†
Gastrointestinal
Diarrhea	5%	34%	18%	63%	10%	52%	18%	72%
Nausea	7%	39%	4%	24%	7%	37%	5%	27%
Vomiting	2%	16%	4%	17%	6%	20%	4%	13%
Abdominalpain	1%	5%	0%	8%	2%	11%	2%	11%
Skin
Pruritus	0%	7%	0%	11%	<1%	7%	1%	9%
Rash	8%	35%	2%	19%	3%	17%	2%	21%
General disorders
Fatigue	2%	10%	1%	7%	4%	18%	2%	13%
Nervous system
Depressive/ mood disorders	1%	8%	0%	8%	<1%	8%	0%	6%
Headache	2%	19%	4%	20%	3%	21%	3%	27%
Paresthesia, oral	0%	2%	0%	0%	<1%	10%	0%	<1%
^*All patients also received abacavir and lamivudine twice daily.
^†Includes adverse events of all grades regardless of causality reported in >5% of patients.

Table 15. Selected Clinical Adverse Events Reported in Protease Inhibitor-Experienced Patients (Study APV30003)
Adverse Event	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)


	Moderate/Severe Drug-Related	All rades^†	Moderate/Severe Drug-Related	All Grades^†
	Moderate/Severe Drug-Related	All rades^†	Moderate/Severe Drug-Related	All Grades^†
Gastrointestinal
Diarrhea	13%	38%	11%	47%
Nausea	3%	20%	9%	31%
Vomiting	3%	10%	5%	17%
Abdominal pain	<1%	11%	2%	9%
Skin
Pruritus	<1%	8%	0%	3%
Rash	3%	9%	0%	22%
General disorders
Fatigue	<1%	9%	<1%	14%
Nervous system
Depressive/mood disorders	<1%	11%	<1%	10%
Headache	4%	27%	2%	20%
Paresthesia, oral	0%	<1%	0%	0%
^*All patients also received 2 reverse transcriptase inhibitors.
^†Includes adverse events of all grades regardless of causality in >5% of patients.

The percentages of patients with Grade 3 or 4 laboratory abnormalities in the clinical efficacy studies of LEXIVA are presented in Tables 16 and 17.

Table 16. Grade 3/4 Laboratory Abnormalities Reported in 2% of Antiretroviral-Naïve Adult Patients in Studies APV30001 and APV30002
	APV30001^*		APV30002^*LEXIVA
Laboratory Abnormality	LEXIVA 1,400 mg b.i.d. (n = 166)	Nelfinavir 1,250 mg b.i.d. (n = 83)	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%
Hypertriglyceridemia^† (>750 mg/dL)	0%	1%	6%	2%
Neutropenia (<750 cells/mm³)	3%	6%	3%	4%
^*All patients also received abacavir and lamivudine twice daily.
^†Fasting 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 <1%.

Table 17. Grade 3/4 Laboratory Abnormalities Reported in 2% of Protease Inhibitor-Experienced Adult Patients in Study APV30003
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)
Hypertriglyceridemia^† (>750 mg/dL)	11%‡	6%^‡
Serum lipase (>2 x ULN)	5%	12%
ALT (>5 x ULN)	4%	4%
AST (>5 x ULN)	4%	2%
Hyperglycemia (>251 mg/dL)	2%‡	2%^‡
^*All patients also received 2 reverse transcriptase inhibitors.
^†Fasting specimens.
^‡n = 100 for LEXIVA/ritonavir, n = 98 for lopinavir/ritonavir.
ULN = Upper limit of normal.

DRUG INTERACTIONS

See also CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Drug Interactions.

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 and WARNINGS).

Table 12. Drugs That Should Not Be Coadministered with LEXIVA
Drug Class/Drug Name Antiarrhythmics: Flecainide, propafenone	Clinical Comment CONTRAINDICATED if LEXIVA is co-prescribed with ritonavir due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics.
Antimycobacterials: Rifampin^*	May lead to loss of virologic response and possible resistance to LEXIVA or to the class of protease inhibitors.
Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to 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.
GI motility agents: Cisapride	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
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.
HMG co-reductase inhibitors: Lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: Pimozide	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Non-nucleoside reverse transcriptase inhibitor: Delavirdine*	May lead to loss of virologic response and possible resistance to delavirdine.
Sedative/hypnotics: Midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
^See CLINICAL PHARMACOLOGY* Tables 3, 4, 5, or 6 for magnitude of interaction.

Table 13. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction (Information in the table applies to LEXIVA with or without ritonavir, unless otherwise indicated.)
Concomitant Drug Class: Drug Name	Effect on Concentration of Amprenavir or Concomitant Drug	Clinical Comment
*HIV-Antiviral Agents*
Non-nucleoside reverse transcriptase inhibitor: Efavirenz	LEXIVA: ¯ Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
Non-nucleoside reverse transcriptase inhibitor: Efavirenz	LEXIVA/ritonavir: ¯ Amprenavir	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: Nevirapine	¯ Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
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.
HIV protease inhibitors: Lopinavir/ritonavir^*	¯ Amprenavir ¯ Lopinavir	An increased rate of adverse events has been observed with coadministration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
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.
*Other Agents*
Antiarrhythmics: Amiodarone, lidocaine (systemic), and quinidine	Antiarrhythmics	Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with LEXIVA.
Antiarrhythmic: Bepridil	Bepridil	Use with caution. Increased bepridil exposure may be associated with life-threatening reactions such as cardiac arrhythmias.
Anticoagulant: Warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin	¯ Amprenavir	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly.
Antifungals: Ketoconazole, itraconazole	Ketoconazole Itraconazole	Increase monitoring for adverse events due to ketoconazole or itraconazole. 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: Rifabutin^*	Rifabutin and rifabutin metabolite	A complete blood count should be performed weekly and as clinically indicated in order to monitor for neutropenia in patients receiving LEXIVA and rifabutin. 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; however, a decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	Calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	¯ Amprenavir	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly.
Histamine H₂-receptor antagonists and proton- pump inhibitors	LEXIVA: EAmprenavir LEXIVA/ritonavir: Interaction not evaluated	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly.
HMG-CoA reductase inhibitor: Atorvastatin^*	Atorvastatin	Use 20 mg/day of atorvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin, pravastatin, or rosuvastatin in combination with LEXIVA.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin	Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with LEXIVA.
Narcotic analgesic: Methadone	¯ Methadone	Dosage of methadone may need to be increased when coadministered with LEXIVA.
Oral contraceptives: Ethinyl estradiol/ norethindrone	LEXIVA: Ethinyl estradiol/ norethindrone LEXIVA/ritonavir: Interaction not evaluated	Because hormonal levels may be altered, alternative methods of non-hormonal contraception are recommended.
PDE5 inhibitors: Sildenafil, vardenafil	Sildenafil Vardenafil	Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. LEXIVA: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse events. LEXIVA/ritonavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events.
Tricyclic antidepressants: Amitriptyline, imipramine	Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with LEXIVA.
^See CLINICAL PHARMACOLOGY* Tables 3, 4, 5, or 6 for magnitude of interaction.

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