VIRACEPT

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer orally. For pediatric patients, administer all doses with a meal.
Oral Solid Formulations
Tablets:
-Patients unable to swallow the tablets may place whole or crushed tablets in a small amount of water to disperse before ingestion. Once dispersed in water, the entire contents must be consumed immediately to obtain the full dose. The drinking glass should be rinsed and the rinse swallowed to insure the med.

Oral Liquid Formulations
Oral powder:
NOTE: The oral powder contains 50 mg nelfinavir as free-base in each level scoopful (1 g).
-After measuring the proper dose, mix with milk, formula, soy formula, or soy milk.
-Do not use with acidic food or juice (e.g., orange juice, apple juice, or apple sauce) because the combination may result in a bitter taste.
-If the measuring scoop that comes with the powder is lost, a level measuring teaspoon may be used. One level measuring teaspoon is equal to 4 scoops (200 mg nelfinavir).
-Use a separate container for reconstitution; do not reconstitute in the original container.
-Once mixed, the entire contents must be administered in order to receive the proper dose.
-If it is not consumed immediately, the solution may be stored for up to 6 hours under refrigeration. Do not heat.

Urogenital adverse events reported in < 2% of adult and adolescent patients during nelfinavir clinical trials include kidney calculus and urine abnormality. In general, the adverse event profile for pediatrics was similar to adults in clinical trials.

Diarrhea is the most common adverse reaction (14-20%) noted in adults and adolescents taking nelfinavir and may be seen with more frequency in patients taking the 625 mg tablets than those taking either the 250 mg tablets or the oral powder formulation. Pediatric patients experience diarrhea at a rate of 39-47%. Other gastrointestinal adverse events reported in adults and adolescent include nausea (3-7%) and flatulence (1-5%). Adverse events noted in < 2% of adult/adolescent patients include abdominal pain, anorexia, dyspepsia, epigastric pain, oral ulceration, pancreatitis, and vomiting. Anorexia and abdominal pain were also reported in pediatric patients. In general, the adverse event profile for pediatrics was similar to adults in clinical trials.

Hematologic abnormalities have been reported during nelfinavir therapy in adults and adolescent trials in combination with other antiretrovirals and include anemia (< 2%), leukopenia (< 2%), thrombocytopenia (< 2%), decreased hemoglobin (2-3%), neutropenia (2-5%), lymphopenia (1-6%). Leukopenia/neutropenia was the most commonly reported laboratory abnormality in pediatric patients. In general, the adverse event profile for pediatrics was similar to adults in clinical trials.

Nervous system adverse reactions occurring in < 2% of adult and adolescent patients in all phase II/III clinical trials and considered at least possibly related or of unknown relationship to nelfinavir therapy included anxiety, depression, dizziness, emotional lability, hyperkinesis, insomnia, migraine, paresthesias, seizures, sleep disorder, drowsiness, and suicidal ideation. In general, the adverse event profile for pediatrics was similar to adults in clinical trials.

General adverse events reported in < 2% of adult and adolescent patients receiving nelfinavir therapy include accidental injury, asthenia, fever, headache, malaise, and pain. In general, the adverse event profile for pediatrics was similar to adults in clinical trials.

There have been reports of increased spontaneous bleeding in patients with hemophilia type A and B who were treated with protease inhibitors like nelfinavir. The cases of spontaneous bleeding have primarily consisted of hematoma and hemarthroses, but more serious bleeding episodes such as GI bleeding (< 2%) have been reported. The bleeding episodes occurred a median of 22 days after initiation of protease inhibitor therapy. In more than half of the cases, treatment with protease inhibitors was continued or reintroduced. Some patients received additional coagulation factor while continuing protease inhibitor therapy.

New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia (< 2% adults/adolescents) due to insulin resistance have been reported with use of protease inhibitors including nelfinavir. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment; however, the baseline status of these patients was not well characterized. Initiation or adjustment of hypoglycemic therapy was required in some patients after beginning protease inhibitor treatment and on average, 50% of patients discontinued their protease inhibitor therapy as a result of this adverse reaction. In some patients, hyperglycemia persisted following discontinuation of protease inhibitor therapy including those not known to be diabetic at baseline. However, a causal relationship has not been established. It should also be noted that many of these patients have confounding medical conditions that require therapy with drugs that have been associated with the development of diabetes mellitus or hyperglycemia. Hypoglycemia has also been reported in < 2% of adult and adolescent patients.

A lipodystrophy syndrome consisting of redistribution/accumulation of body fat (< 2%) including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, accumulation of facial fat, lipomas, gynecomastia and other cushingoid features has been reported in patients receiving long-term highly active antiretroviral therapy (HAART) that includes protease inhibitors such as nelfinavir. This syndrome may be associated with metabolic complications such as insulin resistance, hyperglycemia, and dyslipidemia, but not always. Some studies indicate that up to 5-30% of patients receiving protease inhibitors may develop lipodystrophy. The mechanism and long-term consequences are not known. A casual relationship has not been established. Changes in HAART to reverse lipodystrophy should probably be avoided unless the patient finds the changes in body fat intolerable and more conservative interventions fail.

Hyperlipidemia (< 2% adults/adolescents) including hypertriglyceridemia and hypercholesterolemia have been reported in patients receiving protease inhibitor-containing regimens like nelfinavir. Abnormalities in lipid profiles may develop soon after starting protease inhibitor therapy. Both VLDL and LDL have been reported to increase without a significant rise in HDL. Concern has been raised about the risk of coronary artery disease in patients receiving protease inhibitors; however, other factors such as family history of heart disease, may contribute to the elevated cholesterol and triglyceride levels as well as increased risk for coronary artery disease. The benefit of highly active antiretroviral therapy (HAART) in the treatment of HIV disease may outweigh the risk of coronary artery disease.

Rash (unspecified) was reported in 1-3% of adult and adolescent patients receiving nelfinavir as part of combination antiretroviral therapy. Rash was also noted in pediatric patients. Other dermatologic or hypersensitivity-based reactions reported in < 2% of adult and adolescent patients include allergic reaction, dermatitis, folliculitis, fungal dermatitis, maculopapular rash, pruritus, sweating/hyperhidrosis, and urticaria. Other hypersensitivity reactions noted in post-marketing reports include bronchospasm, moderate to severe rash, fever, and edema. In general, the adverse event profile for pediatrics was similar to adults in clinical trials.

In clinical trials with nelfinavir, elevated hepatic enzymes (AST, ALT, GGT, alkaline phosphatase) have been reported in <= 2% of adult and adolescent patients and hepatitis was noted in < 2% of patients. In general, the adverse event profile for pediatrics was similar to adults in clinical trials. Jaundice and hyperbilirubinemia were reported during post-marketing surveillance.

Laboratory or metabolic adverse events reported in < 2% of adult and adolescent patients with the use of nelfinavir in clinical trials include hyperamylasemia, elevated lactic dehydrogenase, hyperuricemia, and dehydration. Elevated creatine phosphokinase occurred in <= 2% of adult and adolescent patients. In general, the adverse event profile for pediatrics was similar to adults in clinical trials. Metabolic acidosis was noted in post-marketing reports.

Musculoskeletal adverse events reported in < 2% of adult and adolescent patients during nelfinavir clinical trials include back pain, arthralgia, arthritis, muscle cramps, myalgia, myasthenia, and myopathy. In general, the adverse event profile for pediatrics was similar to adults in clinical trials.

Dyspnea, pharyngitis, rhinitis, and sinusitis were all reported in < 2% of adult and adolescent patients during nelfinavir clinical trials. In general, the adverse event profile for pediatrics was similar to adults in clinical trials.

Acute iritis and eye disorder (unspecified) were reported in < 2% of patients during nelfinavir clinical trials.

QT prolongation and torsade de pointes have been noted during post-marketing reports with nelfinavir.

Unplanned antiretroviral therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis), or drug non-availability. If short-term treatment interruption of nelfinavir is necessary (i.e., less than 1 to 2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable serum concentrations of efavirenz and nevirapine ranges from less than 1 week to more than 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Viracept (nelfinavir) powder should be used cautiously in patients with phenylketonuria. Patients with phenylketonuria should be warned that the powder for oral solution contains 11.2 mg phenylalanine per gram of powder.

Nelfinavir should be used cautiously in patients with hemophilia type A and B. 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. Some patients required additional factor VIII. However, the manufacturer states that in more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A cause and effect relationship has not been determined.

Nelfinavir is primarily metabolized by the liver. Use cautiously in patients with hepatic disease. Nelfinavir should not be used in patients with either moderate or severe hepatic impairment (Child-Pugh B or C, sore greater than or equal to 7).

Prior to prescribing nelfinavir, perform hepatitis B virus (HBV) screening in any patient who presents with HIV-infection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection who require treatment for either infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients 2 years and older receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, use another agent with anti-HBV activity in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Continue management of HIV with the goal of maximal suppression.

Patients with diabetes mellitus or hyperglycemia may experience an exacerbation of their condition during nelfinavir treatment. Some patients may require either initiation or dose adjustments of insulin or oral hyperglycemic agents. Patients should be monitored closely for new onset diabetes mellitus, diabetic ketoacidosis, or hyperglycemia.

Patients with advanced acquired immunodeficiency syndrome (AIDS) may be at increased risk for developing hypertriglyceridemia and pancreatitis. Patients who exhibit signs or symptoms of pancreatitis should discontinue treatment with nelfinavir. Fat redistribution and hyperlipidemia have become increasingly recognized side effects with the use of protease inhibitors. According to CDC guidelines, patients with hypertriglyceridemia or hypercholesterolemia should be evaluated for risks for cardiovascular events and pancreatitis. If a patient develops hyperlipidemia during treatment with a protease inhibitor, possible interventions include dietary modification, use of lipid lowering agents, or discontinuation of the protease inhibitor like nelfinavir.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. As with all other antiretroviral agents, resistance can develop when nelfinavir is used either alone or in combination. Monotherapy with nelfinavir is not recommended.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to antiretroviral therapy, including nelfinavir, may develop an inflammatory response to indolent or residual opportunistic infections (such as mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis carinii pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.

Description: Nelfinavir is an oral antiretroviral protease inhibitor (PI). Among drugs available for treating human immunodeficiency virus (HIV) infection, nelfinavir has one of the best side effect profiles. Diarrhea is the most common adverse event reported in pediatric patients. Nelfinavir inhibits the hepatic isoenzyme CYP3A4 giving it the potential for significant drug interactions. Nelfinavir is FDA-approved in pediatric patients as young as 2 years of age.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-Nelfinavir is NOT recommended as part of an initial protease inhibitor (PI)-based treatment regimen in pediatric patients due to inferior virologic efficacy. For a PI-based regimen in infants and children, preferred PIs are lopinavir/ritonavir, darunavir/ritonavir, or atazanavir/ritonavir. For adolescents, the preferred PI is darunavir/ritonavir.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
Oral dosage:
Neonates, Infants, and Children younger than 2 years: Efficacy has not been established. HIV guidelines state that nelfinavir should not be used in these populations.
Children 2 to 12 years: 45 to 55 mg/kg/dose PO twice daily or 25 to 35 mg/kg/dose PO three times daily with a meal (Max: 2,500 mg/day). HIV guidelines recommend the twice daily dosing. Some older children may require higher doses than adults to achieve equivalent drug exposures. Monitor for efficacy and toxicity. Consider using therapeutic drug monitoring.
Adolescents: 1,250 mg PO twice daily or 750 mg PO three times daily with a meal. HIV guidelines recommend the twice daily dosing. The HIV guidelines recommend that adolescents in early puberty (i.e., Sexual Maturity Rating (SMR) Stages 1 to 3) be administered doses based on pediatric schedules, whereas those in late puberty (i.e., SMR Stage 4 or 5) should use adult dosing schedules. Monitor patients for efficacy and toxicity. Some adolescents may require higher doses than adults to achieve equivalent drug exposures; consider using therapeutic drug monitoring.

Therapeutic Drug Monitoring:
Suggested target trough concentration: 700 ng/mL
-Routine monitoring of plasma concentrations of antiretroviral (ARV) drugs is generally not recommended in HIV-infected pediatric patients. However, therapeutic drug monitoring may be considered in the following situations :-use of drugs with limited pharmacokinetic data and/or therapeutic experience in pediatric patients
-use of drugs with significant food and/or drug interactions
-suboptimal treatment response
-suspected suboptimal absorption, distribution, metabolism, or elimination of the drug
-suspected concentration-dependent drug-associated toxicity
-use of alternative dosing regimens and ARV combinations for which safety and efficacy have not been established in clinical trials
-heavily pretreated patients experiencing virologic failure and who may have viral isolates with reduced susceptibility to ARVs

-Due to a higher variability of nelfinavir plasma concentrations in pediatric patients as compared to adults, the benefits of therapeutic drug monitoring and appropriate dose adjustment may be even greater for pediatric patients.

Maximum Dosage Limits:
-Neonates
Efficacy has not been established.
-Infants
Efficacy has not been established.
-Children
< 2 years: Efficacy has not been established.
>= 2 years: 110 mg/kg/day PO (Max: 2500 mg/day).
-Adolescents
2500 mg/day PO.

Patients with Hepatic Impairment Dosing
Nelfinavir 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). No dosage adjustments are necessary in patients with mild hepatic impairment (Child-Pugh A, score 5 to 6).

Patients with Renal Impairment Dosing
Dosing in patients with renal impairment has not been studied. Less than 2% of nelfinavir is excreted in the urine.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Nelfinavir is a competitive inhibitor of HIV protease, an enzyme involved in the replication of HIV. During the later stages of the HIV growth cycle, the gag and gag-pol gene products are first translated into polyproteins and become immature budding particles. Protease is responsible for cleaving these precursor molecules to produce the final structural proteins of a mature virion core and to activate reverse transcriptase for a new round of infection. Thus, protease is necessary for the production of mature virions. Protease inhibition renders the virus noninfectious. Because they inhibit the HIV replication cycle after translation and before assembly, HIV protease inhibitors are active in acutely and chronically infected cells, as well as in cells (e.g., monocytes and macrophages) not normally affected by dideoxynucleoside reverse transcriptase inhibitors. Nelfinavir has acitivity against clinical isolates of HIV-1 and the HIV-2 strain ROD. The EC95 (95% effective concentration) ranged from 7-196 nM. In combination with reverse transcriptase inhibitors, it demonstrated additive (didanosine or stavudine) or synergistic (zidovudine, lamivudine, or zalcitabine) antiviral activity in vitro without enhance cytotoxicity. Drug combination studies with protease inhibitors (ritonavir, saquinavir, or indinavir) show variable results ranging from antagonistic to synergistic.

Pharmacokinetics: Nelfinavir is administered orally. Plasma protein-binding is greater than 98%. Nelfinavir is metabolized by multiple hepatic cytochrome P450 (CYP) enzymes. One major and several minor oxidative metabolites have been found in plasma. The major oxidative metabolite has in vitro antiviral activity that is comparable to the parent drug. In radiolabeled studies, the majority (87%) of an oral dose was excreted in the feces as oxidative metabolites (78%) and unchanged drug (22%). Less than 2% of the drug is excreted in the urine, primarily as unchanged drug.

Affected cytochrome P450 isoenzymes: CYP3A4, CYP2C19, p-glycoprotein (P-gp)
Nelfinavir is a substrate and inhibitor of both CYP3A4 and p-glycoprotein and is a substrate of CYP2C19. CYP2C19 polymorphism may play a role in nelfinavir pharmacokinetics and clinical response. There may be an association with a poor metabolizer phenotype with an alteration in the CYP2C19-681G>A genotype that is associated with increased plasma nelfinavir exposure and possible a more favorable virologic response.


-Route-Specific Pharmacokinetics
Oral Route
Administration of the 250 mg tablets and the oral powder of nelfinavir with food increases the area-under-the-curve (AUC) 2- to 5-fold and the Cmax was increased 2- to 3-fold. A food effect study has not been conducted with the 625 mg tablet; however, based on a cross-study comparison following a single dose of nelfinavir 1250 mg, the magnitude of the food effect for the 625 mg tablets appear comparable to that of the 250 mg tablets. Peak plasma concentrations were usually achieved in 3.5 hours. Multiple dosing of nelfinavir 1250 mg (two 625 mg tablets) twice daily achieved a steady state AUC of 35.3 +/- 16.4 mg x h/L, peak plasma concentrations (Cmax) of 4.7 +/- 1.9 mg/ml, and trough concentrations (Cmin) of 1.5 +/- 1 mg/ml. In healthy volunteers receiving a single 1250 mg dose, the 625 mg tablet formulation is not bioequivalent to the 250 mg tablet formulation; under fasted conditions, the AUC and Cmax are 34% and 24% higher, respectively, for the 625 mg tablets. In a relative bioavailability assessment under fed conditions, the AUC was 24% higher for the 625 mg tablet and the Cmax was comparable for both formulations. In healthy volunteers receiving a single 750 mg dose under fed conditions, nelfinavir concentrations were similar following administration of the 250 mg tablet and oral powder.


-Special Populations
Pediatrics
Neonates, Infants, and Children < 2 years
Nelfinavir has been found to be safe in patients less than 2 years; however, concentrations are highly variable and lower than those reported with adults and older children. A reliably effective dose has not been established. Unpredictable drug exposure in this population may be exacerbated by increased drug clearance compared to adults and difficulties with compliance and adequate food intake with dosing.

Children >= 2 years and Adolescents
In the pediatric population, the use of nelfinavir, overall, is associated with highly variable drug exposure. In 5 nelfinavir pediatric pharmacokinetic protocols, 46 patients, from birth to 13 years of age, received daily doses ranging from 60-150 mg/kg/day (given in 2 to 3 divided doses). While the mean steady state AUC in these protocols was highly variable (ranging from 33.8 mg x hr/L to 101.8 mg x hr/L), there was no correlation between the dose given and the mean AUC to explain this variation. Safety and efficacy have been established in patients from 2-13 years of age, with recommended doses available. However, while nelfinavir was found to be safe at the doses studied in patients less than 2 years of age, a reliably effective dose could not be established. Unpredictable drug exposure in this population may be exacerbated by increased drug clearance compared to adults and difficulties with compliance and adequate food intake with dosing. In addition, children < 25 kg may tend to have lower trough values as compared with larger and older children.

Hepatic Impairment
The steady-state pharmacokinetics of nelfinavir (1250 mg twice daily for 2 weeks) was studied in HIV-negative patients with mild (Child-Pugh Class A, n = 6) and moderate (Child-Pugh Class B, n = 6) hepatic impairment. The Cmax and AUC were not significantly different in patients with mild hepatic impairment as compared to patients with normal hepatic function. In patients with moderate hepatic impairment, the Cmax was increased by 22% and the AUC was increased by 62% when compared to patients with normal hepatic function. Steady-state pharmacokinetics have not been studied in patients with severe hepatic impairment or in HIV-positive patients.

Renal Impairment
The pharmacokinetic parameters of nelfinavir have not been studied in patients with renal insufficiency; however, less than 2% is excreted in the urine, so the impact of renal impairment on elimination should be minimal.