NELFINAVIR: 1,164 Adverse Event Reports & Safety Profile

VIRACEPT ® (nelfinavir mesylate) is an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease.

Viracept

Tablets are available for oral administration as a light-blue, capsule-shaped tablet with a clear film coating in 250 mg strength (as nelfinavir-free base) and as a white oval tablet with a clear film coating in 625 mg strength (as nelfinavir-free base). Each tablet contains the following common inactive ingredients: calcium silicate, crospovidone, magnesium stearate, hypromellose, and triacetin. In addition, the 250 mg tablet contains FD&C blue #2 powder and the 625 mg tablet contains colloidal silicon dioxide.

Viracept

Oral Powder is available for oral administration in a 50 mg/g strength (as nelfinavir-free base) in bottles. The oral powder also contains the following inactive ingredients: microcrystalline cellulose, maltodextrin, dibasic potassium phosphate, crospovidone, hypromellose, aspartame, sucrose palmitate, and natural and artificial flavor. The chemical name for nelfinavir mesylate is [3 S -[2(2 S* , 3 S* ), 3α,4aβ,8aβ]]- N -(1,1-dimethylethyl)decahydro-2-[2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinoline carboxamide mono-methanesulfonate (salt) and the molecular weight is 663.90 (567.79 as the free base). Nelfinavir mesylate has the following structural formula: Nelfinavir mesylate is a white to off-white amorphous powder, slightly soluble in water at pH ≤4 and freely soluble in methanol, ethanol, 2-propanol and propylene glycol.

Chemical

Structure

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 )

AND ADMINISTRATION

• See full prescribing information for administration instructions ( 2 )
• Adults and adolescents 13 years and older (tablets): 1250 mg twice daily or 750 mg three times daily with a meal ( 2.1 )
• Children 2 to less than 13 years (oral powder or 250 mg tablets): 45 to 55 mg/kg twice daily or 25 to 35 mg/kg three times daily with a meal. Refer to Tables 1 and 2 of the full prescribing information for specific dosing guidelines based on age and body weight ( 2.2 )

2.1 Adults and Adolescents (13 years and older) The recommended dose is 1250 mg (five 250 mg tablets or two 625 mg tablets) twice daily or 750 mg (three 250 mg tablets) three times daily. VIRACEPT should be taken with a meal. Patients unable to swallow the 250 or 625 mg tablets may dissolve the tablets in a small amount of water <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

2.2 Pediatric Patients (2 to less than 13 years) In children 2 years of age and older, the recommended oral dose of VIRACEPT Oral Powder or 250 mg tablets is 45 to 55 mg/kg twice daily or 25 to 35 mg/kg three times daily. All doses should be taken with a meal . Doses higher than the adult maximum dose of 2500 mg per day have not been studied in children. For children unable to swallow tablets, VIRACEPT 250 mg tablet(s) may be dissolved in a small amount of water or, VIRACEPT Oral Powder may be administered <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . The healthcare provider should assess appropriate formulation and dosage for each patient.

Tables

1 and 2 provide dosing guidelines for VIRACEPT tablets and powder based on age and body weight.

Table

1: Dosing Table for Children 2 to less than 13 years of age (tablets) Body weight Twice daily (BID) 45 – 55 mg/kg ≥2 years Three times daily (TID) 25 – 35 mg/kg ≥2 years Number of tablets (250 mg) Number of tablets (250 mg)

Kg

10 – 12 2 1 13 – 18 3 2 19 – 20 4 2 ≥21 4 – 5 For BID dosing, the maximum dose per day is 5 tablets BID 3 For TID dosing, the maximum dose per day is 3 tablets TID Table 2: Dosing Table for Children 2 to less than 13 years of age (powder) Body weight Twice daily (BID) 45 – 55 mg/kg Three times daily (TID) 25 – 35 mg/kg Kg Scoops of powder (50 mg/1 g) Teaspoons If a teaspoon is used to measure VIRACEPT oral powder, 1 level teaspoon contains 200 mg of VIRACEPT (4 level scoops equals 1 level teaspoon) of powder Scoops of powder (50 mg/1 g) Teaspoons of powder 9.0 to <10.5 10 2½ 6 1½ 10.5 to <12 11 2¾ 7 1¾ 12 to <14 13 3¼ 8 2 14 to <16 15 3¾ 9 2¼ 16 to <18 Not recommended Use VIRACEPT 250 mg tablet Not recommended 10 2½ 18 to <23 Not recommended Not recommended 12 3 ≥23 Not recommended Not recommended 15 3¾

2.3 Method of Administration For Patients Unable to Swallow Viracept Tablets

• Place VIRACEPT tablet(s) in small amount of water.
• Once dissolved, mix the cloudy liquid well, and consume it immediately.
• The glass should be rinsed with water and the rinse swallowed to ensure the entire dose is consumed.

Viracept Oral

Powder

• Mix VIRACEPT Oral Powder with a small amount of water, milk, formula, soy formula, soy milk, or dietary supplements
• Once mixed, the entire contents must be consumed in order to obtain the full dose.
• If the mixture is not consumed immediately, it must be stored under refrigeration, but storage must not exceed 6 hours.
• Acidic food or juice (e.g., orange juice, apple juice, or apple sauce) are not recommended for mixing VIRACEPT Oral Powder because the combination may result in a bitter taste.
• VIRACEPT Oral Powder should not be reconstituted with water in its original container.

2.4 Hepatic Impairment VIRACEPT can be used in patients with mild hepatic impairment without any dose adjustment. VIRACEPT should not be used in patients with either moderate or severe hepatic impairment <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ]</span> .

Coadministration of VIRACEPT is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of nelfinavir) are listed in Table 3 [also see Drug Interactions (7) , Table 6 ] .

Table

3: Drugs That Are Contraindicated With VIRACEPT Drug Class Drugs Within Class That Are Contraindicated With VIRACEPT Clinical Comment Alpha 1-adrenoreceptor antagonist Alfuzosin Potentially increased alfuzosin concentrations can result in hypotension.

Antiarrhythmics

Amiodarone, quinidine Potential for serious and/or life-threatening cardiac arrhythmia.

Antimycobacterial Agents Rifampin

Plasma concentrations of nelfinavir can be reduced by concomitant use of rifampin. This may lead to loss of therapeutic effect and possible development of resistance to VIRACEPT or other coadministered antiretroviral agents.

Antipsychotics Lurasidone Pimozide

Potential for serious and/or life-threatening reactions. Potential for serious and/or life threatening reactions such as cardiac arrhythmias.

Ergot Derivatives

Dihydroergotamine, ergotamine, methylergonovine Potential for serious and/or life threatening reactions such as ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. GI Motility Agent Cisapride Potential for serious and/or life threatening reactions such as cardiac arrhythmias. Herbal products St. John's wort ( Hypericum perforatum ) Plasma concentrations of nelfinavir can be reduced by concomitant use of the herbal preparation St. John's wort. This may lead to loss of therapeutic effect and possible development of resistance to VIRACEPT or other coadministered antiretroviral agents. HMG-CoA Reductase Inhibitors Lovastatin, Simvastatin Potential for serious reactions such as myopathy including rhabdomyolysis. PDE5 Inhibitors Sildenafil (Revatio ® ) [for treatment of pulmonary arterial hypertension]

See Drug

Interactions , Table 6 for coadministration of sildenafil and tadalafil when dosed for erectile dysfunction. A safe and effective dose has not been established when used with nelfinavir. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).

Sedative/Hypnotics

Triazolam, oral midazolam Potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression.

• Coadministration with drugs that are highly dependent on CYP3A for clearance and which elevated concentrations are associated with serious and/or life-threatening events ( 4 )

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.

AND PRECAUTIONS ALERT: Find out about medicines that should not be taken with VIRACEPT. This statement is included on the product's bottle label. ALERT: Find out about medicines that should not be taken with VIRACEPT.

• The concomitant use of VIRACEPT and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions ( 5.1 , 7.3 )
• Hepatic impairment: should not be used in patients with either moderate or severe hepatic impairment ( 2.4 , 5.2 )
• Phenylketonuria: the oral powder contains 11.2 mg phenylalanine per gram of powder ( 5.3 )
• Diabetes mellitus/hyperglycemia: new onset or exacerbation of pre-existing diabetes mellitus and hyperglycemia reported with protease inhibitors. In some cases after treatment discontinuation, hyperglycemia persisted ( 5.4 )
• Hemophilia: increased bleeding, including spontaneous skin hematomas and hemarthrosis reported with protease inhibitors. In more than half of the cases, protease inhibitors was continued or reintroduced ( 5.5 )
• Fat redistribution: observed with antiretroviral therapy ( 5.6 )
• Immune reconstitution syndrome: reported with combination antiretroviral therapy, including VIRACEPT. Patients may develop an inflammatory response to indolent or residual opportunistic infections ( 5.7 )

5.1 Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of VIRACEPT, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving VIRACEPT, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of VIRACEPT, respectively. These interactions may lead to:

• Clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications.
• Clinically significant adverse reactions from greater exposures of VIRACEPT.
• Loss of therapeutic effect of VIRACEPT and possible development of resistance.

See Table

6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7) ] . Consider the potential for drug interactions prior to and during VIRACEPT therapy; review concomitant medications during VIRACEPT therapy; and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7) ] .

5.2 Hepatic Impairment VIRACEPT should not be used in patients with either moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ]</span>.

5.3 Phenylketonurics Viracept Oral Powder contains phenylalanine, a component of aspartame. Each gram of VIRACEPT powder contains 11.2 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.

5.4 Diabetes Mellitus/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing 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 a causal relationship between protease inhibitor therapy and these events has not been established.

5.5 Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship has not been established.

5.6 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (&quot;buffalo hump&quot;), peripheral wasting, facial wasting, breast enlargement, and &quot;cushingoid appearance&quot; have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.7 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIRACEPT. 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 jiroveci pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves&apos; 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.

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.