1. Name Of The Medicinal Product
VIRACEPT 250 mg film-coated tablets.
2. Qualitative And Quantitative Composition
Each film-coated tablet contains nelfinavir mesilate corresponding to 250 mg of nelfinavir.
Excipients:
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Blue, oblong biconvex film-coated tablets.
4. Clinical Particulars
4.1 Therapeutic Indications
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.
4.2 Posology And Method Of Administration
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:
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The recommended dose of VIRACEPT film-coated tablets to be administered TID to children aged 3 to 13 years is as follows:
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*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.
4.3 Contraindications
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, alfuzosin, and sildenafil when used for treatment of pulmonary arterial hypertension hypertension (for the use of sildenafil and other PDE-5 inhibitors in patients with erectile dysfunction, 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).
4.4 Special Warnings And Precautions For Use
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.
Patients with hepatic impairment should not be given colchicine with VIRACEPT.
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.
Patients with renal impairment should not be given colchicine with VIRACEPT.
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).
PDE5 inhibitors: particular caution should be used when prescribing sildenafil, tadalafil or vardenafil for the treatment of erectile dysfunction in patients receiving Viracept. Co-administration of Viracept with these medicinal products is expected to increase their concentrations and may result in associated adverse events such as hypotension, syncope, visual changes and prolonged erection (see section 4.5). Concomitant use of sildenafil prescribed for the treatment of pulmonary arterial hypertension with Viracept is contraindicated (see section 4.3).
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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, triazolam, alfuzosin, and sildenafil when used to treat pulmonary arterial hypertension (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).
Coadministration 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.
Coadministration 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.
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.
Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the international normalized ratio (INR) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
Metabolic enzyme inducers: Potent inducers of CYP3A4 (e.g., rifampicin, pehnobarbital and carbamazepine) may reduce nelfianvir plasma concentrations and their coadministration is contraindicated (see section 4.3). Caution should be used when co-administering 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 coadministered with nelfinavir. Parenteral midazolam should be coadministered 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
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↑ Indicates increase,
4.6 Pregnancy And Lactation
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.
4.7 Effects On Ability To Drive And Use Machines
VIRACEPT has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable Effects
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 (
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Children and neonates:
A total of approximately 400 patients received nelfinavir in paediatric treatment trials (St
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