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warnings and cautions
• 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 2 for listings of drugs that are contraindicated due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity [see Contraindications (4), Drug Interactions (7.2)] . See Table 7 for a listing of established and other potentially significant drug interactions [see Drug Interactions (7.3)]. 5.2 Skin Reactions Severe and life-threatening skin reactions, including 1 case of Stevens-Johnson syndrome among 700 subjects treated with LEXIVA in clinical trials. 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 trial of LEXIVA used as the sole protease inhibitor, rash occurred in 2 of 10 subjects (20%) with a history of sulfonamide allergy compared with 42 of 126 subjects (33%) with no history of sulfonamide allergy. In 2 clinical trials of LEXIVA plus low-dose ritonavir, rash occurred in 8 of 50 subjects (16%) with a history of sulfonamide allergy compared with 50 of 412 subjects (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-1-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 systems respond 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. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of 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-1-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)] .
6 ADVERSE REACTIONS • Severe or life-threatening skin reactions have been reported with the use of LEXIVA [see Warnings and Precautions (5.2)] . • The most common moderate to severe adverse reactions in clinical trials of LEXIVA were diarrhea, rash, nausea, vomiting, and headache. • Treatment discontinuation due to adverse events occurred in 6.4% of subjects receiving LEXIVA and in 5.9% of subjects receiving comparator treatments. The most common adverse reactions leading to discontinuation of LEXIVA (incidence less than or equal to 1% of subjects) included diarrhea, nausea, vomiting, AST increased, ALT increased, and rash. • In adults the most common adverse reactions (incidence greater than or equal to 4%) are diarrhea, rash, nausea, vomiting, headache. (6.1) • Vomiting and neutropenia were more frequent in pediatrics than in adults. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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. Adult Trials: The data for the 3 active-controlled clinical trials described below reflect exposure of 700 HIV-1–infected subjects to LEXIVA Tablets, including 599 subjects exposed to LEXIVA for greater than 24 weeks, and 409 subjects exposed for greater than 48 weeks. The population age ranged from 17 to 72 years. Of these subjects, 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. Selected adverse reactions reported during the clinical efficacy trials of LEXIVA are shown in Tables 3 and 4. Each table presents adverse reactions of moderate or severe intensity in subjects treated with combination therapy for up to 48 weeks. Table 3. Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater Than or Equal to 2% of Antiretroviral-Naive Adult Subjects Adverse Reaction APV30001 a APV30002 a 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 subjects also received abacavir and lamivudine twice daily. Table 4. Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater Than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects (Trial 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 subjects also received 2 reverse transcriptase inhibitors. Skin rash (without regard to causality) occurred in approximately 19% of subjects treated with LEXIVA in the pivotal efficacy trials. 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 subjects. In some subjects 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 subjects with Grade 3 or 4 laboratory abnormalities in the clinical efficacy trials of LEXIVA are presented in Tables 5 and 6. Table 5. Grade 3/4 Laboratory Abnormalities Reported in Greater Than or Equal to 2% of Antiretroviral-Naive Adult Subjects in Trials APV30001 and APV30002 Laboratory Abnormality APV30001 a APV30002 a 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% Triglycerides b (>750 mg/dL) 0% 1% 6% 2% Neutrophil count, absolute (<750 cells/mm 3 ) 3% 6% 3% 4% a All subjects also received abacavir and lamivudine twice daily. b Fasting specimens. ULN = Upper limit of normal. The incidence of Grade 3 or 4 hyperglycemia in antiretroviral-naive subjects who received LEXIVA in the pivotal trials was less than 1%. Table 6. Grade 3/4 Laboratory Abnormalities Reported in Greater Than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects in Trial 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) Triglycerides b (>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 subjects also received 2 reverse transcriptase inhibitors. b Fasting specimens. c n = 100 for LEXIVA plus ritonavir, n = 98 for lopinavir plus ritonavir. ULN = Upper limit of normal. Pediatric Trials: LEXIVA with and without ritonavir was studied in 237 HIV-1–infected pediatric subjects aged at least 4 weeks to 18 years in 3 open‑label trials, APV20002, APV20003, and APV29005 [see Clinical Studies (14.3)] . Vomiting and neutropenia occurred more frequently in pediatric subjects compared to adults. Other adverse events occurred with similar frequency in pediatric subjects compared with adults. The frequency of vomiting among pediatric subjects receiving LEXIVA twice daily with ritonavir was 20% in subjects aged at least 4 weeks to less than 2 years and 36% in subjects aged 2 to 18 years compared with 10% in adults. The frequency of vomiting among pediatric subjects receiving LEXIVA twice daily without ritonavir was 60% in subjects aged 2 to 5 years compared with 16% in adults. The median duration of drug‑related vomiting episodes in APV29005 was 1 day (range: 1 to 3 days), in APV20003 was 16 days (range: 1 to 38 days), and in APV20002 was 9 days (range: 4 to 13 days). Vomiting was treatment limiting in 4 pediatric subjects across all 3 trials. The incidence of Grade 3 or 4 neutropenia (neutrophils less than 750 cells per mm 3 ) seen in pediatric subjects treated with LEXIVA with and without ritonavir was higher (15%) than the incidence seen in adult subjects (3%). Grade 3/4 neutropenia occurred in 10% (5/51) of subjects aged at least 4 weeks to less than 2 years and 16% (28/170) of subjects aged 2 to 18 years. 6.2 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 : Hypercholesterolemia. Nervous System Disorders: Oral paresthesia. Skin and Subcutaneous Tissue Disorders: Angioedema. Urogenital: Nephrolithiasis.