VIRACEPT 250 mg film-coated tablets.

Each film-coated tablet contains nelfinavir mesilate corresponding to 250 mg of nelfinavir.

Excipients:

For a full list of excipients, see section 6.1.

Blue, oblong biconvex film-coated tablets.

VIRACEPT is indicated in antiretroviral combination treatment of human immunodeficiency virus (HIV-1) infected adults, adolescents and children of 3 years of age and older.

In protease inhibitor (PI) experienced patients the choice of nelfinavir should be based on individual viral resistance testing and treatment history.

See section 5.1.

Therapy with VIRACEPT should be initiated by a physician experienced in the management of HIV infection.

VIRACEPT is administered orally and should always be ingested with food (see section 5.2).

Patients older than 13 years: the recommended dose of VIRACEPT 250 mg film-coated tablets is 1250 mg (five tablets) twice a day (BID) or 750 mg (three tablets) three times a day (TID) by mouth.

The efficacy of the BID (twice daily) regimen has been evaluated versus the TID (three times daily) regimen primarily in patients naïve to PIs (see section 5.1).

Patients aged 3 to 13 years: for children, the recommended starting dose is 50-55 mg/kg BID or, if using a TID regimen, 25 – 30 mg/kg body weight per dose. For children unable to take tablets, VIRACEPT oral powder may be administered instead (see Summary of Product Characteristics for VIRACEPT oral powder).

The recommended dose of VIRACEPT film-coated tablets to be administered BID to children aged 3 to 13 years is as follows:

The recommended dose of VIRACEPT film-coated tablets to be administered TID to children aged 3 to 13 years is as follows:

*see Summary of Product Characteristics for VIRACEPT oral powder for patients with less than 18 kg body weight.

Renal and hepatic impairment: there are no data specific for HIV positive patients with renal impairment and therefore specific dosage recommendations cannot be made (see section 4.4). Nelfinavir is principally metabolised and eliminated by the liver. There are not sufficient data from patients with liver impairment and therefore specific dose recommendations cannot be made (see section 5.2). Caution should be used when administering VIRACEPT to patients with impaired renal or hepatic function.

Hypersensitivity to the active substance or to any of the excipients.

Co-administration with medicinal products with narrow therapeutic windows and which are substrates of CYP3A4 [e.g., terfenadine, astemizole, cisapride, amiodarone, quinidine, pimozide, triazolam, orally administered midazolam (for caution on parenterally administered midazolam, see section 4.5), ergot derivatives; see section 4.5].

Potent inducers of CYP3A (e.g., rifampicin, phenobarbital and carbamazepine) reduce nelfinavir plasma concentrations.

Co- administration with rifampicin is contra-indicated due to a reduction in exposure to nelfinavir.

Physicians should not use potent inducers of CYP 3A4 in combination with Viracept and should consider using alternatives when a patient is taking VIRACEPT (see section 4.5).

Herbal preparations containing St. John's wort (Hypericum perforatum) must not be used while taking nelfinavir due to the risk of decreased plasma concentrations and reduced clinical effects of nelfinavir (see section 4.5).

VIRACEPT should not be co-administered with omeprazole due to a reduction in exposure to nelfinavir and its active metabolite M8 (Tert-butyl hydroxy nelfinavir). This may lead to a loss of virologic response and possible resistance to VIRACEPT (see section 4.5).

Patients should be instructed that VIRACEPT is not a cure for HIV infection, that they may continue to develop infections or other illnesses associated with HIV disease, and that VIRACEPT has not been shown to reduce the risk of transmission of HIV disease through sexual contact or blood contamination.

Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterium infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Liver Disease: The safety and efficacy of nelfinavir has not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. The use of nelfinavir in patients with moderate hepatic impairment has not been studied. In the absence of such studies, caution should be exercised, as increases in nelfinavir levels and/or increases in liver enzymes may occur.

Osteonecrosis: Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Renal Impairment: Since nelfinavir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodiaylisis or peritoneal dialysis. Therefore, no special precautions or dose adjustments are required in these patients.

Diabetes mellitus and hyperglycaemia: New onset diabetes mellitus, hyperglycaemia or exacerbation of existing diabetes mellitus has been reported in patients receiving PIs. In some of these the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many patients had confounding medical conditions, some of which required therapy with agents that have been associated with the development of diabetes or hyperglycaemia.

Patients with haemophilia: There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophiliac patients type A and B treated with PIs. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship has been evoked, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Lipodystrophy:Combination antiretroviral therapy has been associated with the redistribution of body fat (acquired lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and nucleoside analogue reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

Nelfinavir is primarily metabolised via the cytochrome P450 isoenzymes CYP3A4 and CYP2C19 (see section 5.2). Nelfinavir is also an inhibitor of CYP 3A4. Based on in vitro data, nelfinavir is unlikely to inhibit other cytochrome P450 isoforms at concentrations in the therapeutic range.

Combination with other medicinal products : Caution is advised whenever VIRACEPT is co-administered with agents that are inducers or inhibitors and/or substrates of CYP3A4; such combinations may require dose adjustment (see also sections 4.3 and 4.8).

Substrates for CYP3A: Co-administration is contraindicated with the following agents that are substrates for CYP3A4 and that have narrow therapeutic windows: terfenadine, astemizole, cisapride, amiodarone, quinidine, ergot derivatives, pimozide, oral midazolam and triazolam (see section 4.3).

Co-administration of a PI with sildenafil is expected to substantially increase sildenafil concentration and may result in an increase in sildenafil associated adverse events, including hypotension, visual changes, and priapism.

For other substrates of CYP3A4 a dose reduction or consideration of an alternative may be required (Table 1).

Co-administration of nelfinavir with fluticasone proprionate may increase plasma concentrations of fluticasone propionate. Consider alternatives that are not metabolised by CYP3A4 such as beclomethasone.

Concomitant use of trazodone and nelfinavir may increase plasma concentrations of trazodone and a lower dose of trazodone should be considered.

Co-administration of nelfinavir with simvastatin or lovastatin may result in significant increases in simvastatin and lovastatin plasma concentrations. Consider alternatives that are not substrates of CYP3A4 such as pravastatin or fluvastatin.

Metabolic enzyme inducers: Potent inducers of CYP3A4 (e.g., rifampicin, phenobarbital and carbamazepine) may reduce nelfinavir plasma concentrations and their co-administration is contraindicated (see section 4.3). Caution should be used when coadministering other agents that induce CYP3A4.

Plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally and should therefore not be co-administered with nelfinavir. Parenteral midazolam should be co-administered with nelfinavir in an intensive care unit to ensure close clinical monitoring. Dose adjustment for midazolam should be considered if more than a single dose is administered (Table 1).

Metabolic enzyme inhibitors: Co-administration of nelfinavir with inhibitors of CYP2C19 (e.g., fluconazole, fluoxetine, paroxetine, lansoprazole, imipramine, amitriptyline and diazepam) may be expected to reduce the conversion of nelfinavir to its major active metabolite M8 (tert-butyl hydroxy nelfinavir) with a concomitant increase in plasma nelfinavir levels (see section 5.2). Limited clinical trial data from patients receiving one or more of these medicinal products with nelfinavir indicated that a clinically significant effect on safety and efficacy is not expected. However, such an effect cannot be ruled out.

Interactions of nelfinavir with selected agents that describe the impact of nelfinavir on the pharmacokinetics of the co-administered compound and the impact of other drugs on pharmacokinetics of nelfinavir are listed in Table 1.

Table 1: Interactions and dose recommendations with other medical products

↑ Indicates increase, indicates decrease, ↔ indicates minimal change (< 10 %)

No treatment-related adverse reactions were seen in animal reproductive toxicity studies in rats at doses providing systemic exposure comparable to that observed with the clinical dose. Clinical experience in pregnant women is limited. VIRACEPT should be given during pregnancy only if the expected benefit justifies the possible risk to the foetus.

It is recommended that HIV-infected women must not breast-feed their infants under any circumstances in order to avoid transmission of HIV. Studies in lactating rats showed that nelfinavir is excreted in breast milk. There is no data available on nelfinavir excretion into human breast milk. Mothers must be instructed to discontinue breast-feeding if they are receiving VIRACEPT.

VIRACEPT has no or negligible influence on the ability to drive and use machines.

The safety of the VIRACEPT 250 mg tablet was studied in controlled clinical trials with over 1300 patients. The majority of patients in these studies received either 750 mg TID either alone or in combination with nucleoside analogues or 1250 mg BID in combination with nucleoside analogues. The following adverse events with an at least possible relationship to nelfinavir (i.e. adverse reactions) were reported most frequently: diarrhoea, nausea, and rash. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions from clinical trials with nelfinavir

Adverse reactions in clinical studies are summarised in Table 2. The list also includes marked laboratory abnormalities that have been observed with nelfinavir (at 48 weeks).

Table 2: Incidences of Adverse Reactions and marked laboratory abnormalities from the phase II and phase III studies. (Very common ( 10 %); common ( 1 % and < 10 %)

Children and neonates:

A total of approximately 400 patients received nelfinavir in paediatric treatment trials (Studies 524, 556, PACTG 377/725, and PENTA-7) for up to 96 weeks. The adverse reaction profile seen during paediatric clinical trials was similar to that for adults. Diarrhoea was the most commonly reported adverse event in children. Neutropenia/leucopenia was the most frequently observed laboratory abnormality. During these trials less than 13% of patients in total discontinued treatment due to adverse events.

Post-marketing experience with nelfinavir

Serious and non-serious adverse reactions from post-marketing spontaneous reports (where nelfinavir was taken as the sole protease inhibitor or in combination with other antiretroviral therapy), not mentioned previously in section 4.8, for which a causal relationship to nelfinavir cannot be excluded, are summarised below. As these data come from the spontaneous reporting system, the frequency of the adverse reactions is not confirmed.

Immune system disorders:

Uncommon ( 0.1 % - 1 %): hypersensitivity including bronchospasm, pyrexia, pruritus, facial oedema and rash maculo-papular or dermatitis bullous.

Metabolism and nutrition disorders:

Uncommon - rare ( 0.01 % - 1 %): Combination antiretroviral therapy has been associated with redistribution of body fat (Lipodystrophy acquired) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (lypohypertrophy buffalo hump).

Rare ( 0.01 % - 0.1 %): new onset diabetes mellitus, or exacerbation of existing diabetes mellitus.

Gastrointestinal disorders:

Uncommon ( 0.1 % - 1 %): vomiting, pancreatitis/blood amylase increased.

Rare ( 0.01 % - 0.1 %): abdominal distension,

Hepatobiliary disorders:

Rare ( 0.01 % - 0.1 %): hepatitis, hepatic enzymes increased and jaundice when nelfinavir is used in combination with other antiretroviral agents.

Musculoskeletal and connective tissue disorders:

Rare ( 0.01 % - 0.1 %): Blood creatine phosphokinase increased, myalgia, myositis and rhabdomyolysis have been reported with PIs, particularly in combination with nucleoside analogues.

Vascular disorders:

Rare ( 0.01 % - 0.1 %): increased spontaneous haemorrhage bleeding in patients with haemophilia.

Skin and subcutaneous tissue disorders:

Very rare ( 0.01 % ), including isolated reports: Erythema multiforme.

Paediatric population:

Additional adverse reactions have been reported in the post-marketing experience and are listed below. As these data come from the spontaneous reporting system, the frequency of the adverse reactions is unknown: hypertriglyceridaemia, anaemia, blood lactic acid increased, and pneumonia.

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as blood triglycerides increased, blood cholesterol increased, insulin resistance, hyperglycaemia and hyperlactaemia. The frequency of this is unknown (see section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. The frequency of this is unknown (see section 4.4).

Human experience of acute overdose with VIRACEPT is limited. There is no specific antidote for overdose with nelfinavir. If indicated, elimination of unabsorbed nelfinavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed nelfinavir. Since nelfinavir is highly protein bound, dialysis is unlikely to significantly remove it from blood.

Overdoses of nelfinavir could theoretically be associated with prolongation of the QT-interval of the ECG (see also section 5.3). Monitoring of overdosed patients is warranted.

Pharmacotherapeutic group: direct acting antivirals, ATC code: J05AE04

Mechanism of action: HIV protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors to the individual proteins found in infectious HIV. The cleavage of these viral polyproteins is essential for the maturation of infectious virus. Nelfinavir reversibly binds to the active site of HIV protease and prevents cleavage of the polyproteins resulting in the formation of immature non-infectious viral particles.

Antiviral activity in vitro: the antiviral activity of nelfinavir in vitro has been demonstrated in both HIV acute and chronic infections in lymphoblastoid cell lines, peripheral blood lymphocytes and monocytes/macrophages. Nelfinavir was found to be active against a broad range of laboratory strains and clinical isolates of HIV-1 and the HIV-2 strain ROD. The EC₉₅ (95 % effective concentration) of nelfinavir ranged from 7 to 111 nM (mean of 58 nM). Nelfinavir demonstrated additive to synergistic effects against HIV in combination with reverse transcriptase inhibitors zidovudine (ZDV), lamivudine (3TC), didanosine (ddI), zalcitabine (ddC) and stavudine (d4T) without enhanced cytotoxicity.

Resistance: Viral escape from nelfinavir can occur via viral protease mutations at amino acid positions 30, 88 and 90.

In vitro: HIV isolates with reduced susceptibility to nelfinavir have been selected in vitro. HIV isolates from selected patients treated with nelfinavir alone or in combination with reverse transcriptase inhibitors were monitored for phenotypic (n=19) and genotypic (n=195, 157 of which were assessable) changes in clinical trials over a period of 2 to 82 weeks. One or more viral protease mutations at amino acid positions 30, 35, 36, 46, 71, 77 and 88 were detected in> 10 % of patients with assessable isolates. Of 19 patients for whom both phenotypic and genotypic analyses were performed on clinical isolates, 9 patients isolates showed reduced susceptibility (5- to 93-fold) to nelfinavir in vitro. Isolates from all 9 patients possessed one or more mutations in the viral protease gene. Amino acid position 30 appeared to be the most frequent mutation site.

Cross resistance in vitro: HIV isolates obtained from 5 patients during nelfinavir therapy showed a 5 to 93fold decrease in nelfinavir susceptibility in vitro when compared to matched baseline isolates but did not demonstrate a concordant decrease in susceptibility to indinavir, ritonavir, saquinavir or amprenavir in vitro. Conversely, following ritonavir therapy, 6 of 7 clinical isolates with decreased ritonavir susceptibility (8- to 113-fold) in vitro compared to baseline also exhibited decreased susceptibility to nelfinavir in vitro (5- to 40 fold). An HIV isolate obtained from a patient receiving saquinavir therapy showed decreased susceptibility to saquinavir (7- fold) but did not demonstrate a concordant decrease in susceptibility to nelfinavir. Cross-resistance between nelfinavir and reverse transcriptase inhibitors is unlikely because different enzyme targets are involved. Clinical isolates (n=5) with decreased susceptibility to zidovudine, lamivudine, or nevirapine remain fully susceptible to nelfinavir in vitro.

In vivo: The overall incidence of the D30N mutation in the viral protease of assessable isolates (n=157) from patients receiving nelfinavir monotherapy or nelfinavir in combination with zidovudine and lamivudine or stavudine was 54.8 %. The overall incidence of other mutations associated with primary PI resistance was 9.6 % for the L90M substitution where as substitutions at 48, 82 and 84 were not observed.

Clinical pharmacodynamic data: treatment with nelfinavir alone or in combination with other antiretroviral agents has been documented to reduce viral load and increase CD4 cell counts in HIV-1 seropositive patients. Decreases in HIV RNA observed with nelfinavir monotherapy were less pronounced and of shorter duration. The effects of nelfinavir (alone or combined with other antiretroviral agents) on biological markers of disease activity, CD4 cell count and viral RNA, were evaluated in several studies involving HIV-1 infected patients.

The efficacy of the BID regimen has been evaluated versus the TID regimen with VIRACEPT 250 mg tablets primarily in patients naïve to PIs. A randomised open-label study compared the HIV RNA suppression of nelfinavir 1250 mg BID versus nelfinavir 750 mg TID in PI naïve patients also receiving stavudine (30-40 mg BID) and lamivudine (150 mg BID).

LOCF= Last observation carried forward

ITT = Intention to Treat

NC = F: non-completers = failures

The BID regimen produced statistically significantly higher peak nelfinavir plasma levels versus the TID regimen. Small, non-statistically significant differences were observed in other pharmacokinetic parameters with no trend favouring one regimen over the other. Although study 542 showed no statistically significant differences between the two regimens in efficacy in a predominantly antiretroviral naïve patient population, the significance of these findings for antiretroviral experienced patients is unknown.

In a study of 297 HIV-1 seropositive patients receiving zidovudine and lamivudine plus nelfinavir (2 different doses) or zidovudine and lamivudine alone, the mean baseline CD4 cell count was 288 cells/mm³ and the mean baseline plasma HIV RNA was 5.21 log¹⁰ copies/ml (160,394 copies/ml). The mean decrease in plasma HIV RNA using a PCR assay (< 400 copies/ml) at 24 weeks was 2.33 log¹⁰ in patients receiving combination therapy with nelfinavir 750 mg TID, compared to 1.34 log¹⁰ in patients receiving zidovudine and lamivudine alone. At 24 weeks, the percentage of patients whose plasma HIV RNA levels had decreased to below the limit of detection of the assay (< 400 copies/ml) were 81 % and 8 % for the groups treated with nelfinavir 750 mg TID plus zidovudine and lamivudine or zidovudine and lamivudine, respectively. Mean CD4 cell counts at 24 weeks were increased by 150 and 95 cells/mm³ for the groups treated with nelfinavir 750 mg TID plus zidovudine and lamivudine or zidovudine and lamivudine, respectively. At 48 weeks, approximately 75 % of the patients treated with nelfinavir 750 mg TID plus zidovudine and lamivudine remained below the level of detection of the assay (< 400 copies/ml); mean increase in CD4 cell counts was 198 cells/mm³ at 48 weeks in this group.

No important differences in safety or tolerability were observed between the BID and TID dosing groups, with the same proportion of patients in each arm experiencing adverse events of any intensity, irrespective of relationship to trial medication.

Plasma levels of certain HIV-1 protease inhibitors, which are metabolised predominantly by CYP3A4, can be increased by the co-administration of low-dose ritonavir, which is an inhibitor of this metabolism. Treatment paradigms for several protease inhibitors, which are subject to this interaction, require the co-administration of low-dose ritonavir ('boosting') in order to enhance plasma levels and optimise antiviral efficacy. Plasma levels of nelfinavir, which is metabolised predominantly by CYP2C19 and only partially by CYP3A4, are not greatly increased by co-administration with ritonavir, and therefore nelfinavir does not require co-administration with low-dose ritonavir . Two studies have compared the safety and efficacy of nelfinavir (unboosted) with ritonavir- boosted protease inhibitors, each in combination with other antiretroviral agents.

Study M98-863 is a randomised, double blind trial of 653 antiretroviral-naïve patients investigating lopinavir/ritonavir (400/100 mg BID n=326) compared to nelfinavir (750 mg TID n=327), each in combination with lamivudine (150 mg twice daily) and stavudine (40 mg twice daily). Median baseline HIV-1 RNA was 4.98 log¹⁰ copies/ml and 5.01 log¹⁰ copies/ml in the nelfinavir and lopinavir/ritonavir treatment groups respectively. Median baseline CD4+ cell count was 232 cells/mm³ in both groups. At week 48, 63 % nelfinavir and 75 % lopinavir/ritonavir patients had HIV-1 RNA < 400 copies/ml, whereas 52 % nelfinavir and 67 % lopinavir/ritonavir patients had HIV-1 RNA <50 copies/ml (intent-to-treat, missing = failure). The mean increase from baseline in CD4+ cell count at week 48 was 195 cells/mm³ and 207 cells/mm³ in the nelfinavir and lopinavir/ritonavir groups respectively. Through 48 weeks of therapy, a statistically significantly higher proportion of patients in the lopinavir/ritonavir arm had HIV-1 RNA < 50 copies/ml compared to the nelfinavir arm.

Study APV30002 is a randomised, open-label trial of 649 antiretroviral treatment naïve patients with advanced HIV-disease, investigating fosamprenavir/ritonavir (1400 mg/200 mg QD n=322) compared to nelfinavir (1250 mg BID n=327), each in combination with lamivudine (150 mg twice daily) and abacavir (300 mg twice daily). Median baseline HIV-1 RNA was 4.8 log¹⁰ copies/ml in both treatment groups. Median baseline CD4+ cell counts were 177 and 166 x10⁶ cells/l for the nelfinavir and fosamprenavir/ritonavir groups respectively. At week 48, non-inferiority was shown with 68 % of patients in the group treated with nelfinavir and 69 % patients treated with fosamprenavir/ritonavir having plasma HIV-1 RNA <400 copies/ml whereas 53 % in the nelfinavir and 55 % in the fosamprenavir/ritonavir patients had HIV-1 RNA <50 copies/ml (intent-to-treat, rebound/discontinuation = failure). The median increase from baseline in CD4+ cell count over 48 weeks was 207 cells/mm³ and 203 cells/mm³ in the nelfinavir and fosamprenavir/ritonavir groups respectively. The virological failure was greater in the nelfinavir group (17 %) than in the fosamprenavir/ritonavir group (7 %). Treatment emergent NRTI resistance was significantly less frequent with fosamprenavir/ritonavir compared to nelfinavir (13 % versus 57 %; p<0.001).

The pharmacokinetic properties of nelfinavir have been evaluated in healthy volunteers and HIVinfected patients. No substantial differences have been observed between healthy volunteers and HIV-infected patients.

Absorption: after single or multiple oral doses of 500 to 750 mg (two to three 250 mg tablets) with food, peak nelfinavir plasma concentrations were typically achieved in 2 to 4 hours.

After multiple dosing with 750 mg every 8 hours for 28 days (steady-state), peak plasma concentrations (C_max) averaged 3-4 µg/ml and plasma concentrations prior to the next dose (trough) were 1-3 µg/ml. A greater than dose-proportional increase in nelfinavir plasma concentrations was observed after single doses; however, this was not observed after multiple dosing.

A pharmacokinetic study in HIV-positive patients compared multiple doses of 1250 mg twice daily (BID) with multiple doses of 750 mg three times daily (TID) for 28 days. Patients receiving VIRACEPT BID (n=10) achieved nelfinavir C_max of 4.0 ± 0.8 µg/ml and morning and evening trough concentrations of 2.2 ± 1.3 µg/ml and 0.7 ± 0.4 µg/ml, respectively. Patients receiving VIRACEPT TID (n=11) achieved nelfinavir peak plasma concentrations (C_max) of 3.0 ± 1.6 µg/ml and morning and evening trough concentrations of 1.4 ± 0.6 µg/ml and 1.0 ± 0.5 µg/ml, respectively. The difference between morning and afternoon or evening trough concentrations for the TID and BID regimens was also observed in healthy volunteers who were dosed at precise 8- or 12-hour intervals.

The pharmacokinetics of nelfinavir are similar during BID and TID administration. In patients, the nelfinavir AUC_0-24 with 1250 mg BID administration was 52.8 ± 15.7 µgh/ml (n=10) and with 750 mg TID administration was 43.6 ± 17.8 µgh/ml (n=11). Trough drug exposures remain at least twenty fold greater than the mean IC₉₅ throughout the dosing interval for both regimens. The clinical relevance of relating in vitro measures to drug potency and clinical outcome has not been established. A greater than dose-proportional increase in nelfinavir plasma concentrations was observed after single doses; however, this was not observed after multiple dosing.

The absolute bioavailability of VIRACEPT has not been determined.

Effect of Food on Oral Absorption

Food increases nelfinavir exposure and decreases nelfinavir pharmacokinetic variability relative to the fasted state. In one study, healthy volunteers received a single dose of 1250 mg of VIRACEPT (5x 250 mg tablets) under fasted or fed conditions (three meals with different caloric and fat contents). In a second study, healthy volunteers received single doses of 1250 mg VIRACEPT (5 x 250 mg tablets) under fasted or fed conditions (two meals with different fat content). The results from the two studies are summarised below.

Increase in AUC, C_max and T_max for Nelfinavir in Fed State Relative to Fasted State Following 1250 mg VIRACEPT (5 x 250 mg tablets)

Increase in Nelfinavir AUC, C_max and T_max in Fed Low Fat (20%) versus High fat (50%) State Relative to Fasted State Following 1250 mg VIRACEPT (5 x 250 mg tablets)

Nelfinavir exposure increases with increasing calorie or fat content of meals taken with VIRACEPT.

Distribution: Nelfinavir in serum is extensively protein-bound ( 98 %). The estimated volumes of distribution in both animals and humans is 2-7 l/kg which exceeded total body water and suggests extensive penetration of nelfinavir into tissues.

Metabolism:In vitro studies demonstrated that multiple cytochrome P-450 isoforms including CYP3A, CYP2C19/C9 and CYP2D6 are responsible for the metabolism of nelfinavir. One major and several minor oxidative metabolites were found in plasma. The major oxidative metabolite, M8 (tert-butyl hydroxy nelfinavir), has in vitro antiviral activity equal to the parent drug and its formation is catalysed by the polymorphic cytochrome CYP2C19. The further degradation of M8 appears to be catalysed by CYP3A4. In subjects with normal CYP2C19 activity, plasma levels of this metabolite are approximately 25 % of the total plasma nelfinavir-related concentration. It is expected that in CYP2C19 poor metabolisers or in patients receiving concomitantly strong CYP2C19 inhibitors (see section 4.5), nelfinavir plasma levels would be elevated whereas levels of tert-butyl hydroxy nelfinavir would be negligible or non-measurable.

Elimination: oral clearance estimates after single doses (24-33 l/h) and multiple doses (26-61 l/h) indicate that nelfinavir exhibits medium to high hepatic bioavailability. The terminal half-life in plasma was typically 3.5 to 5 hours. The majority (87 %) of an oral 750 mg dose containing ¹⁴Cnelfinavir was recovered in the faeces; total faecal radioactivity consisted of nelfinavir (22 %) and numerous oxidative metabolites (78 %). Only 1-2 % of the dose was recovered in urine, of which unchanged nelfinavir was the major component.

Pharmacokinetics in special populations:

Children:

In children between the ages of 2 and 13 years, the clearance of orally administered nelfinavir is approximately 2 to 3 times higher than in adults, with large intersubject variability. Administration of VIRACEPT oral powder or tablets at a dose of approximately 25-30 mg/kg TID with food achieves steady-state plasma concentrations that are similar to those achieved in adult patients receiving 750 mg TID.

The pharmacokinetics of nelfinavir have been investigated in 5 studies in paediatric patients from birth to 13 years of age. Patients received VIRACEPT either three times daily or twice daily with food or with meals. The dosing regimens and associated AUC₂₄ values are summarised below.

Summary of Steady-state AUC ₂₄ of nelfinavir in Paediatric Studies

¹ Protocol specified dose (actual dose range)

² N: number of subjects with evaluable pharmacokinetic results

C_trough values are not presented in the table because they are not available from all studies

Pharmacokinetic data are also available for 86 patients (age 2 to 12 years) who received VIRACEPT 25-35 mg/kg TID in Study AG1343-556. The pharmacokinetic data from Study AG1343-556 were more variable than data from other studies conducted in the paediatric population; the 95% confidence interval for AUC₂₄ was 9 to 121 mg.hr/L.

Overall, use of VIRACEPT in the paediatric population is associated with highly variable drug exposure. The reason for this high variability is not known but may be due to inconsistent food intake in paediatric patients.

Elderly:

There are no data available in the elderly.

Hepatic impairment:

The multi-dose pharmacokinetics of nelfinavir have not been studied in HIV-positive patients with hepatic insufficiency.

Pharmacokinetics of nelfinavir after a single dose of 750 mg was studied in patients with liver impairment and healthy volunteers. A 49 %-69 % increase was observed in AUC of nelfinavir in the hepatically impaired group (Child-Turcotte Classes A to C) compared to the healthy group. Specific dose recommendations for nelfinavir cannot be made based on the results of this study.

A second study evaluated the steady state pharmacokinetics of nelfinavir (1250 mg twice daily for 2 weeks) in adult HIV-seronegative subjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B; n=6) hepatic impairment. Compared to control subjects with normal hepatic function, the AUC and C_max of nelfinavir were not significantly different in subjects with mild impairment but were increased by 62% and 22%, respectively in subjects with moderate hepatic impairment.

During in vitro studies, cloned human cardiac potassium channels (hERG) were inhibited by high concentrations of nelfinavir and its active metabolite M8. hERG potassium channels were inhibited by 20 % at nelfinavir and M8 concentrations that are about four- to five-fold and seventy-fold, respectively, above the average free therapeutic levels in humans. By contrast, no effects suggesting prolongation of the QT-interval of the ECG were observed at similar doses in dogs or in isolated cardiac tissue. The clinical relevance of these in vitro data is unknown. However, based on data from products known to prolong the QT-interval, a block of hERG potassium channels of> 20 % may be clinically relevant. Therefore the potential for QT prolongation should be considered in cases of overdose (see section 4.9).

Acute and chronic toxicity: oral acute and chronic toxicity studies were conducted in the mouse (500 mg/kg/day), rat (up to 1,000 mg/kg/day) and monkey (up to 800 mg/kg/day). There were increased liver weights and dose-related thyroid follicular cell hypertrophy in rats. Weight loss and general physical decline was observed in monkeys together with general evidence of gastrointestinal toxicity.

Mutagenicity:in vitro and in vivo studies with and without metabolic activation have shown that nelfinavir has no mutagenic or genotoxic activity.

Carcinogenicity: Two year oral carcinogenicity studies with nelfinavir mesilate were conducted in mice and rats. In mice, administration of up to 1000 mg/kg/day did not result in any evidence for an oncogenic effect. In rats administration of 1000 mg/kg/day resulted in increased incidences of thyroid follicular cell adenoma and carcinoma, relative to those for controls. Systemic exposures were 3 to 4 times those for humans given therapeutic doses. Administration of 300 mg/kg/day resulted in an increased incidence of thyroid follicular cell adenoma. Chronic nelfinavir treatment of rats has been demonstrated to produce effects consistent with enzyme induction, which predisposed rats, but not humans, to thyroid neoplasms. The weight of evidence indicates that nelfinavir is unlikely to be a carcinogen in humans.

Each tablet contains the following excipients:

Tablet core:

Calcium silicate,

Crospovidone,

Magnesium stearate,

Indigo carmine (E132) as powder.

Tablet coat:

Hypromellose,

Glycerol triacetate.

Not applicable.

3 years.

Store in the original container. Do not store above 30°C.

VIRACEPT film-coated tablets are provided in HDPE plastic bottles containing either 270 or 300 tablets, fitted with HDPE child resistant closures with polyethylene liners. Not all pack sizes may be marketed.

No special requirements.

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

EU/1/97/054/004 - EU/1/97/054/005

Date of first authorisation: 22 January 1998

Date of latest renewal: 23 January 2008

January 2010