nelfinavir mesylate

7 DRUG INTERACTIONS • Coadministration of VIRACEPT with other drugs ( CYP3A substrates) can alter the concentration of these other drugs , and other drugs (inhibitors and/or inducers of CYP3A or CYP2C19) may alter the concentrations of nelfinavir. The potential drug-drug concentrations must be considered prior to and during therapy ( 4 , 7 , 12.3 ) • VIRACEPT should be given with food one hour after or more than 2 hours before didanosine ( 7 ) 7.1 Potential for VIRACEPT to Affect Other Drugs Nelfinavir is an inhibitor of CYP3A. Coadministration of VIRACEPT and drugs primarily metabolized by CYP3A (e.g., dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and PDE5 inhibitors) may result in increased plasma concentrations of such drugs that could increase or prolong both its therapeutic and adverse effects (see Tables 3 and 6 ). 7.2 Potential for Other Drugs to Affect VIRACEPT Nelfinavir is metabolized by CYP3A and CYP2C19. Coadministration of VIRACEPT and drugs that induce CYP3A or CYP2C19, such as rifampin, may decrease nelfinavir plasma concentrations and reduce its therapeutic effect. Coadministration of VIRACEPT and drugs that inhibit CYP3A or CYP2C19 may increase nelfinavir plasma concentrations. 7.3 Established and Other Potentially Significant Drug Interactions Table 6 provides the effect on concentrations of VIRACEPT or concomitant drug as a result of coadministration with VIRACEPT. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. Table 6: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies [see Clinical Pharmacology (12.3) ( Tables 12 and 13 ) for magnitude of interaction] Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment HIV Antiviral Agents: Reverse Transcriptase Inhibitors Delavirdine ↑ nelfinavir (C min ) ↓ delavirdine Concentrations of nelfinavir were increased while concentrations of delavirdine were decreased when the two agents were coadministered. Appropriate doses of the combination, with respect to safety and efficacy, have not been established. Nevirapine ↓ nelfinavir (C min ) Concentrations of nelfinavir were decreased when coadministered with nevirapine. An appropriate dose of nelfinavir with respect to safety and efficacy has not been established. Didanosine ↔ nelfinavir There was no change in nelfinavir concentration when coadministered with didanosine. However, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food). HIV Antiviral Agents: Protease Inhibitors Indinavir ↑ nelfinavir ↑ indinavir Concentrations of both indinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. Ritonavir ↑ nelfinavir ↔ ritonavir Concentrations of nelfinavir were increased when coadministered with ritonavir. An appropriate dose of nelfinavir for this combination, with respect to safety and efficacy, has not been established. Saquinavir ↑ nelfinavir ↑ saquinavir Concentrations of both saquinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. ANTICOAGULANT Warfarin Warfarin Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy. ANTICONVULSANTS Carbamazepine Phenobarbital Phenytoin ↓ nelfinavir ↓ phenytoin Concentrations of nelfinavir may be decreased. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly. Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration. ANTIDEPRESSANT Trazodone ↑ trazodone Concomitant use of trazodone and VIRACEPT 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 VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered. ANTIGOUT Colchicine ↑ colchicines Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT due to the risk of colchicine toxicity. Treatment of gout flares – co- administration of colchicine in patients on VIRACEPT: 0.6 mg (1 tablet) × 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 – coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine 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)– coadministration of colchicine in patients on VIRACEPT: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). ANTIMYCOBACTERIAL Rifabutin ↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID) It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin. ENDOTHELIN RECEPTOR ANTAGONIST Bosentan ↑ bosentan Concentrations of bosentan may be increased when coadministered with VIRACEPT. Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability. HMG-CoA REDUCTASE INHIBITORS Atorvastatin Rosuvastatin ↑ atorvastatin ↑ rosuvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 40 mg/day. IMMUNOSUPPRESSANTS Cyclosporine Tacrolimus Sirolimus ↑ immuno-suppressants ↑ nelfinavir Concentrations of these immunosuppressants and nelfinavir may be increased by coadministration of these agents with nelfinavir. INHALED BETA AGONIST Salmeterol ↑ salmeterol Concurrent administration of salmeterol with VIRACEPT 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 ↑ fluticasone Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. MACROLIDE ANTIBIOTIC Azithromycin ↑ azithromycin Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted. NARCOTIC ANALGESIC Methadone ↓ methadone Concentrations of methadone were decreased when coadministered with VIRACEPT. Dosage of methadone may need to be increased when coadministered with VIRACEPT. HORMONAL CONTRACEPTIVES Ethinyl estradiol Norethindrone ↓ ethinyl estradiol ↓ norethindrone Concentrations of ethinyl estradiol and norethindrone were decreased when coadministered with VIRACEPT. Alternative or additional contraceptive measures should be used when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered. PDE5 INHIBITORS Sildenafil Vardenafil Tadalafil ↑ PDE5 Inhibitors Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. 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): • Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ] . • The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA: Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events. PROTON PUMP INHIBITORS Omeprazole ↓ nelfinavir Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance. ANTIPSYCHOTICS Quetiapine ↑ quetiapine Initiation of VIRACEPT in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking VIRACEPT: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

1 INDICATIONS AND USAGE VIRACEPT in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection. VIRACEPT is a protease inhibitor indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. ( 1 )

6 ADVERSE REACTIONS 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 practice. • Most common adverse reactions (≥2%) of moderate or severe intensity in adults and adolescents (13 years and older) are diarrhea, nausea, rash, and flatulence ( 6.1 ) • Most common adverse reactions in pediatric patients (2 to less than 13 years) are diarrhea, leukopenia/neutropenia, rash, anorexia, and abdominal pain. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience: Adults and Adolescents (13 years and older) The safety of VIRACEPT was studied in over 5000 patients who received drug either alone or in combination with nucleoside analogues. The majority of adverse events were of mild intensity. The most frequently reported adverse event among patients receiving VIRACEPT was diarrhea, which was generally of mild to moderate intensity. Drug-related clinical adverse experiences of moderate or severe intensity in ≥2% of patients treated with VIRACEPT coadministered with d4T and 3TC (Study 542) for up to 48 weeks, or with ZDV plus 3TC (Study 511) for up to 24 weeks are presented in Table 4. Table 4: Percentage of Patients with Treatment-Emergent Includes those adverse events at least possibly, probably or definitely related to study drug or of unknown relationship and excludes concurrent HIV conditions Adverse Events of Moderate or Severe Intensity Reported in ≥ 2% of Adult and Adolescent Patients Study 511 Study 542 24 weeks 48 weeks Adverse Events Placebo + ZDV/3TC (n=101) 500 mg TID VIRACEPT + ZDV/3TC (n=97) 750 mg TID VIRACEPT + ZDV/3TC (n=100) 1250 mg BID VIRACEPT + d4T/3TC (n=344) 750 mg TID VIRACEPT + d4T/3TC (n=210) Digestive System Diarrhea 3% 14% 20% 20% 15% Nausea 4% 3% 7% 3% 3% Flatulence 0 5% 2% 1% 1% Skin/Appendages Rash 1% 1% 3% 2% 1% Adverse events occurring in less than 2% of patients receiving VIRACEPT in all phase 2 and 3 clinical trials and considered at least possibly related or of unknown relationship to treatment and of at least moderate severity are listed below. Body as a Whole : abdominal pain, accidental injury, allergic reaction, asthenia, back pain, fever, headache, malaise, pain, and redistribution/accumulation of body fat [see Warnings and Precautions (5.7) ] . Digestive System : anorexia, dyspepsia, epigastric pain, gastrointestinal bleeding, hepatitis, mouth ulceration, pancreatitis, and vomiting. Hemic/Lymphatic System : anemia, leukopenia, and thrombocytopenia. Metabolic/Nutritional System : increases in alkaline phosphatase, amylase, creatine phosphokinase, lactic dehydrogenase, SGOT, SGPT, and gamma-glutamyl transpeptidase; hyperlipemia, hyperuricemia, hyperglycemia, hypoglycemia, dehydration, and liver function tests abnormal. Musculoskeletal System : arthralgia, arthritis, cramps, myalgia, myasthenia, and myopathy. Nervous System : anxiety, depression, dizziness, emotional lability, hyperkinesia, insomnia, migraine, paresthesia, seizures, sleep disorder, somnolence, and suicide ideation. Respiratory System : dyspnea, pharyngitis, rhinitis, and sinusitis. Skin/Appendages : dermatitis, folliculitis, fungal dermatitis, maculopapular rash, pruritus, sweating, and urticaria. Special Senses : acute iritis and eye disorder. Urogenital System : kidney calculus, sexual dysfunction, and urine abnormality. Laboratory Abnormalities The percentage of patients with marked laboratory abnormalities in Studies 542 and 511 are presented in Table 5. Marked laboratory abnormalities are defined as a Grade 3 or 4 abnormality in a patient with a normal baseline value, or a Grade 4 abnormality in a patient with a Grade 1 abnormality at baseline. Table 5: Percentage of Patients by Treatment Group with Marked Laboratory Abnormalities Marked laboratory abnormalities are defined as a shift from Grade 0 at baseline to at least Grade 3 or from Grade 1 to Grade 4 in >2% of Patients Study 511 Study 542 Placebo + ZDV/3TC (n=101) 500 mg TID VIRACEPT + ZDV/3TC (n=97) 750 mg TID VIRACEPT + ZDV/3TC (n=100) 1250 mg BID VIRACEPT + d4T/3TC (n=344) 750 mg TID VIRACEPT + d4T/3TC (n=210) Hematology Hemoglobin 6% 3% 2% 0 0 Neutrophils 4% 3% 5% 2% 1% Lymphocytes 1% 6% 1% 1% 0 Chemistry ALT (SGPT) 6% 1% 1% 2% 1% AST (SGOT) 4% 1% 0 2% 1% Creatine Kinase 7% 2% 2% NA NA 6.2 Clinical Trials Experience: Pediatrics (2 to less than 13 years of age) VIRACEPT has been studied in approximately 400 pediatric patients in clinical trials from birth to 13 years of age. The adverse event profile seen during pediatric clinical trials was similar to that for adults. The most commonly reported drug-related, treatment-emergent adverse events reported in the pediatric studies included: diarrhea, leukopenia/neutropenia, rash, anorexia, and abdominal pain. Diarrhea, regardless of assigned relationship to study drug, was reported in 39% to 47% of pediatric patients receiving VIRACEPT in 2 of the larger treatment trials. Leukopenia/neutropenia was the laboratory abnormality most commonly reported as a significant event across the pediatric studies. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of VIRACEPT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole : hypersensitivity reactions (including bronchospasm, moderate to severe rash, fever, and edema). Cardiovascular System : QTc prolongation, torsades de pointes . Digestive System : jaundice. Metabolic/Nutritional System : bilirubinemia, metabolic acidosis.