NELFINAVIR Drug Interactions: What You Need to Know

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.

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 )

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.