Viracept (Tablets, Powder) Instructions for Use

ATC Code

J05AE04 (Nelfinavir)

Active Substance

Nelfinavir (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

Human immunodeficiency virus (HIV) protease is an enzyme necessary for the proteolytic cleavage of viral polyprotein precursors into individual proteins that make up the infectious HIV. The cleavage of these viral polyproteins is extremely important for the maturation of the infectious virus.

Nelfinavir binds to the active site of HIV protease and inhibits the cleavage of polyproteins, leading to the formation of immature viral particles incapable of infecting other cells.

In vitro antiviral activity

The in vitro antiviral activity of nelfinavir was demonstrated in conditions of acute and chronic HIV infection in lymphoblast cell lines, peripheral blood lymphocytes, and monocytes and macrophages.

Nelfinavir is active against a wide range of laboratory strains and clinical isolates of HIV-1 and HIV-2, strain ROD. The 95% effective concentration (EC₉₅) of nelfinavir ranges from 7 to 111 nM (average, 58 nM).

Nelfinavir has an additive and synergistic effect against HIV as a component of dual and triple combination therapy regimens that include the reverse transcriptase inhibitors zidovudine (ZDV), lamivudine (3TC), didanosine (ddI), zalcitabine (ddC), and stavudine (d4T), without increasing the cytotoxicity of the latter.

Efficacy

Nelfinavir monotherapy or combination therapy with other antiretroviral drugs reduces viral load and increases the CD4 cell count in HIV-1-infected patients.

The reduction in HIV RNA concentration with Viracept monotherapy is less pronounced and of shorter duration than with combination therapy.

Potential for resistance and cross-resistance development

HIV isolates with reduced sensitivity to nelfinavir have been obtained in vitro.

Genotyping of the virus variant with a 9-fold reduced sensitivity showed a unique substitution of aspartic acid (D) for asparagine (N) in HIV protease at amino acid residue 30 (D30N).

In accordance with in vitro results, the dominant change in HIV protease genes in clinical virus isolates was the D30N substitution, which persisted in a number of patients up to week 44 of therapy.

Mutations described for other protease inhibitors were either never observed (G48V, V82F/T, I84V) or observed very rarely (L90M).

Analysis of the amino acid sequence of protease genes obtained from patients, taken by random sampling and receiving either nelfinavir monotherapy or nelfinavir in combination with zidovudine and lamivudine for up to 16 weeks in large studies, showed a significant reduction in genotypic resistance to nelfinavir when it was prescribed in combination with zidovudine and lamivudine compared to monotherapy (56% and 12%, respectively).

Cross-resistance between nelfinavir and reverse transcriptase inhibitors is unlikely because these drugs act on different target enzymes.

HIV isolates with a high degree of resistance to zidovudine, lamivudine, nevirapine, and delavirdine remain fully sensitive to nelfinavir.

In vitro, the sensitivity of six clinical virus isolates containing the D30N substitution to saquinavir, ritonavir, indinavir, and amprenavir was unchanged.

Cross-resistance between nelfinavir and other protease inhibitors was studied in those patients in whom HIV RNA levels increased during clinical trials while taking nelfinavir.

Twenty-four patients who had previously received extensive antiretroviral therapy with reverse transcriptase inhibitors (mean number of drugs = 2.9) and nelfinavir for an average of 59.7 weeks were switched to another protease inhibitor.

At the time of switching, the HIV RNA level was 4.44 log10 copies/mL. After starting therapy with the new protease inhibitor, 16 out of 24 patients (67%) achieved sustained viral load suppression over 56 weeks.

After Viracept was prescribed to 65 patients who had previously received reverse transcriptase inhibitors (on average, having changed 4.4 drugs) and protease inhibitors (2 drugs), the viral load decreased by more than 0.5 log10 in 51%.

Pharmacokinetics

The pharmacokinetic properties of nelfinavir have been studied in healthy volunteers and HIV-infected patients, with no significant differences found between them.

Absorption

After a single or multiple oral administration of 500-750 mg (2 or 3 tablets of 250 mg) of nelfinavir with food, the C_max of the drug in plasma was usually reached within 2-4 hours.

After multiple administration of 750 mg every 8 hours for 28 days (steady state), the C_max in plasma was 3-4 µg/mL, and the minimum concentrations (immediately before the next dose) were 1-3 µg/mL.

After a single administration of different doses, the plasma concentrations of nelfinavir increased faster than the corresponding doses.

The absolute bioavailability of the drug has not been determined; however, a study with a radioactive label, taking into account the large number of metabolites detected in urine, suggested that about 78% of the orally administered dose is absorbed.

When the drug is taken with food, its C_max in plasma and AUC are consistently 2-3 times higher than when taken on an empty stomach.

The increase in plasma concentrations after taking the drug with food did not depend on the fat content of the meal.

Distribution

In humans and animals, the estimated V_d (2-7 L/kg) exceeded the total body water volume, suggesting extensive penetration of nelfinavir into tissues.

Although studies in humans have not been conducted, a single administration of C-nelfinavir at a dose of 50 mg/kg to rats showed that its concentrations in the brain were lower than in other tissues, but in vitro exceeded the 95% effective antiviral concentration (EC₉₅).

In serum, Nelfinavir is highly (>98%) bound to proteins.

Metabolism

After a single oral administration of 750 mg of ¹⁴C-nelfinavir, unchanged Nelfinavir accounted for 82-86% of the radioactivity in plasma.

One major and several minor metabolites formed by oxidation were found in plasma.

The main oxymetabolite in vitro has the same antiviral activity as the parent drug.

In vitro, the metabolism of nelfinavir is carried out under the influence of numerous cytochrome P-450 isoenzymes, including CYP3A, CYP2C19/C9 and CYP2D6.

Excretion

Oral clearance values after single (24-33 L/h) and repeated administration (26-61 L/h) indicate moderate to high hepatic bioavailability of nelfinavir.

The T_1/2 of the terminal phase in plasma was generally 3.5-5 hours.

The majority (87%) of an orally administered dose of 750 mg containing ¹⁴C-Nelfinavir was found in the feces; the radioactivity of the feces was due to labeled nelfinavir (22%) and its numerous oxymetabolites.

Only 1-2% of the administered dose was found in the urine, mainly in the form of unchanged nelfinavir.

Pharmacokinetics in special clinical cases

In children aged 2 to 13 years, the oral clearance of nelfinavir is approximately 2-3 times higher than in adults.

Prescribing Viracept as an oral powder or tablets in doses of about 25-30 mg/kg 3 times/day with meals allows achieving C_ss in plasma similar to those in adult patients receiving 750 mg 3 times/day.

Indications

• Combination therapy of HIV-1-infected adults and children, together with antiretroviral drugs from the group of nucleoside analogues.

ICD codes

Dosage Regimen

Powder

Viracept tablets and powder should be taken with food.

Adults and children over 13 years: 750 mg (3 tablets of 250 mg) 3 times/day orally.

Children up to 13 years inclusive: 25-30 mg/kg 3 times/day. For children who cannot swallow tablets, Viracept can be prescribed as a powder for oral administration.

Recommended number of tablets or amount of Viracept powder for administration 3 times/day for children

The powder can be mixed with water, milk, infant formula, including soy-based, soy milk, pudding.

Viracept powder mixed with these products is recommended to be used no later than 6 hours after preparation.

It is not recommended to mix Viracept powder with acidic media (orange or apple juice, applesauce), as this results in a bitter taste.

Do not add water to the bottles with Viracept powder.

Impaired liver and kidney function

There is currently no data available for these categories of patients, so specific dosing recommendations cannot be provided.

Tablets

Individual, depending on age, therapy regimen and the dosage form used.

Adverse Reactions

The safety of Viracept was assessed in patients receiving the drug as monotherapy or in combination with nucleoside analogues.

Most of the observed adverse events were mild.

The most frequent side effect of Viracept was diarrhea.

In clinical studies with a frequency of > 2%, the following adverse events were noted (possibly or probably related to the intake of Viracept or when a causal relationship with the drug could not be assessed)

From the skin rash.

From the digestive system flatulence, nausea.

Laboratory changes decreased neutrophil count, increased creatine kinase activity.

Outside of clinical studies, during the use of the drug in everyday practice, the following adverse reactions have been rarely reported: hypersensitivity reactions, including bronchospasm, moderate or severe rash, fever and swelling; vomiting.

In some patients, combined antiretroviral therapy using protease inhibitors may be accompanied by a redistribution of fat depots, including a decrease in peripheral adipose tissue and an increase in visceral fat, breast hypertrophy, and fat deposition on the back of the neck (buffalo hump).

The use of protease inhibitors may also be accompanied by metabolic disorders in the form of hypertriglyceridemia, hypercholesterolemia, insulin resistance and hyperglycemia, as well as an increase in spontaneous bleeding in patients with hemophilia.

Contraindications

• Simultaneous use of drugs with a narrow therapeutic window that are substrates of the cytochrome P450 system (CYP3A4) (terfenadine, astemizole, cisapride, amiodarone, quinidine, triazolam, midazolam and ergot derivatives);
• Hypersensitivity to nelfinavir or any excipient included in the drug.

Use in Pregnancy and Lactation

In reproductive toxicity studies in rats, in which animals received doses providing the same systemic exposure to the drug as used in the clinic, no adverse events related to the drug were observed.

There is no clinical experience of use in pregnant women.

Until additional data are available, Viracept should be prescribed during pregnancy only in exceptional cases.

HIV-infected women are strongly advised not to breastfeed to avoid transmitting HIV to their children.

Data on the excretion of nelfinavir in human milk are lacking.

Studies in lactating rats have shown that Nelfinavir passes into breast milk.

There are no data on the excretion of nelfinavir into human breast milk.

Women are advised to discontinue breastfeeding if they are receiving Viracept.

Use in Hepatic Impairment

Nelfinavir is metabolized and excreted mainly by the liver.

Consequently, caution should be exercised when prescribing Viracept to patients with impaired liver function.

Use in Renal Impairment

Only 1-2% of the Viracept dose is excreted in the urine, so impaired renal function is unlikely to affect plasma concentrations of nelfinavir.

Pediatric Use

Children up to 13 years inclusive: 25-30 mg/kg 3 times/day. For children who cannot swallow tablets, Viracept can be prescribed as a powder for oral administration.

The safety and efficacy of nelfinavir in children under 2 years of age have not been established.

Special Precautions

Nelfinavir is metabolized and excreted mainly by the liver.

Consequently, caution should be exercised when prescribing Viracept to patients with impaired liver function.

Only 1-2% of the Viracept dose is excreted in the urine, so impaired renal function is unlikely to affect plasma concentrations of nelfinavir.

The safety and efficacy of nelfinavir in children under 2 years of age have not been established.

There have been reports of increased frequency of bleeding, including spontaneous subcutaneous hematomas and hemarthrosis in patients with hemophilia receiving protease inhibitors.

Some patients required factor VIII administration.

In more than half of the described cases, treatment with the protease inhibitor was continued or initially interrupted and then resumed.

A causal relationship between protease inhibitors and this type of adverse reaction is suspected, although its mechanism is unclear.

Therefore, patients with hemophilia should be warned about the possible increased risk of bleeding.

Cases of newly diagnosed diabetes mellitus, hyperglycemia, and worsening of pre-existing diabetes mellitus have been reported in patients receiving protease inhibitors.

Sometimes hyperglycemia was very severe, and in some cases it was accompanied by ketoacidosis.

Many of these patients had concomitant conditions and diseases that required the use of drugs that could also contribute to the development of diabetes mellitus or hyperglycemia.

A causal relationship between the use of protease inhibitors and the development of hyperglycemia and diabetes has not been established.

Physical examination of patients should pay attention to signs of fat redistribution.

It is necessary to remember to determine serum lipids and blood glucose.

The mechanism of development of these adverse events and their long-term consequences, including the increased risk of cardiovascular disease, are not yet clear.

Caution should be exercised when prescribing Viracept concomitantly with inducers, inhibitors, or substrates of the CYP3A4 isoenzyme; dose adjustment of the drugs may be required.

Overdose

Data on acute overdose of Viracept in humans are limited.

There is no specific antidote for Viracept overdose.

If indicated, the unabsorbed drug is removed by inducing vomiting or gastric lavage.

Administration of activated charcoal is advisable to remove the unabsorbed drug.

Since Nelfinavir is highly bound to proteins, dialysis is unlikely to remove significant amounts of the drug from the blood.

Drug Interactions

Nelfinavir is partially metabolized by the CYP3A system.

Caution should be exercised when co-administering CYP3A inducers or potentially toxic drugs that are themselves metabolized by CYP3A.

According to data obtained in vitro, at therapeutic concentrations, Nelfinavir is unlikely to inhibit the activity of other cytochrome P450 isoenzymes.

Other antiretroviral drugs

Nucleoside reverse transcriptase inhibitors

No clinically significant interactions between nelfinavir and nucleoside analogues (especially zidovudine + lamivudine, stavudine and stavudine + didanosine) have been observed.

Since didanosine is recommended to be taken on an empty stomach, Viracept should be taken with food either 1 hour after didanosine or more than 2 hours before taking didanosine.

Non-nucleoside reverse transcriptase inhibitors

No clinical interaction between Viracept and efavirenz has been noted.

Concomitant administration of these drugs increases the AUC of nelfinavir by 20%, while the AUC of efavirenz does not change.

Dose adjustment when taken together is not required.

Concomitant administration of delavirdine and nelfinavir was accompanied by a doubling of exposure to nelfinavir and a 40% decrease in exposure to delavirdine.

The safety of this combination has not been established.

Other protease inhibitors

Concomitant administration of ritonavir and Viracept led to an increase in the AUC of nelfinavir by 152% and a very slight change in the AUC of ritonavir.

There are currently no data on the efficacy and safety of this combination.

Concomitant administration of Viracept and indinavir led to an increase in the AUC of nelfinavir by 83% and the AUC of indinavir by 51%.

There are currently no data on the efficacy and safety of this combination.

Concomitant administration of Viracept and saquinavir in soft gelatin capsules (Fortovase) led to an increase in the AUC of nelfinavir by 18% and the AUC of saquinavir by 4 times.

If Viracept is prescribed in combination with saquinavir in hard gelatin capsules (Invirase) at the recommended doses of 600 mg 3 times/day, no dose adjustment is required.

Inducers of metabolism enzymes

Rifampin reduces the AUC of nelfinavir by 82%.

Other potent inducers of CYP3A (nevirapine, phenobarbital, phenytoin, carbamazepine) may also reduce plasma concentrations of nelfinavir.

If a patient taking Viracept requires treatment with the above drugs, the physician should seek alternatives for them.

Concomitant administration of Viracept and rifabutin leads to a 32% decrease in the AUC of nelfinavir and an approximately 200% increase in the AUC of rifabutin.

When Viracept and rifabutin are taken concomitantly, the dose of the latter should be halved.

Enzyme Metabolism Inhibitors

Concomitant administration of Viracept and a strong CYP3A inhibitor, ketoconazole, was accompanied by a 35% increase in the AUC of nelfinavir. This change is not considered clinically significant; therefore, dose adjustment during concomitant administration of these drugs is not required. Given the metabolic characteristics, clinically significant drug interactions with other specific CYP3A inhibitors (fluconazole, itraconazole, clarithromycin, erythromycin) are not expected, but this possibility cannot be ruled out.

Other Possible Interactions

Viracept increases plasma concentrations of terfenadine; therefore, they should not be administered concomitantly to avoid severe or life-threatening arrhythmias. Since similar interactions with astemizole and cisapride are likely, Viracept should not be administered concomitantly with these drugs either. Although specific studies on this topic have not been conducted, potent sedative agents metabolized by CYP3A, for example, triazolam or midazolam, should also not be used together with Viracept, as their sedative effect may be prolonged. Viracept may increase plasma concentrations of other substances that are substrates for CYP3A (e.g., calcium channel blockers); therefore, in such cases, patients should be carefully monitored for signs of toxicity of these drugs.

Oral Contraceptives

Administration of Viracept 750 mg 3 times/day and a combined oral contraceptive containing 400 mcg of norethindrone and 35 mcg of 17-α-ethinyl estradiol for 7 days was accompanied by a 47% decrease in the AUC of ethinyl estradiol and an 18% decrease in the AUC of norethindrone. The use of other contraceptive measures should be considered.

Storage Conditions

Keep out of reach of children.

Store in the original packaging at a temperature not exceeding 30°C (86°F).

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.