Roche Products Limited

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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 35 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 shown in the table below.as follows:  Children with weights between 10.5-12 kg, 12-14 kg and 18-22 kg will receive a different number of tablets with each meal.  The table provides a schedule assuring that the appropriate total daily dose of Viracept is taken each day based on the child’s weight.

The prescriber should advise the caregiver to carefully monitor increases in weight of the child to ensure that the appropriate total daily dose is taken.  The prescriber should also advise the caregiver about the importance of adhering to the dosing instructions and that the appropriate number of tablets should be taken at each dose with a meal.

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

* Children with these weights will be given an uneven number of tablets during the
    day. The virologic and immunologic responses should be monitored to assure
    these children achieve response to therapy.

For patients unable to swallow the tablets, VIRACEPT tablets may be dispersed in a half cup of water while thoroughly stirring with a spoon. Once dispersed, the cloudy bluish liquid should be thoroughly mixed and consumed immediately. The glass should be rinsed with a half cup of water and the rinse should be swallowed to ensure that the entire dose is consumed.

Acidic food or juice (e.g. orange juice, apple juice or apple sauce) are not recommended to be used in combination with VIRACEPT, because the combination may result in a bitter taste. The VIRACEPT suspension should be taken with a meal.

The prescriber should assure that the caregiver understands the importance of monitoring adherence and the appropriate method to prepare and administer Viracept tablets to children in each weight band.

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.

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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, and 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

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

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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 dosage of VIRACEPT 250 mg film-coated tablets is 1250 mg (five 250 mg tablets) twice a day (BID) or 750 mg (three 250 mg 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.

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 cyatochrome P450 isoforms at concentrations in the therapeutic range.

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

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.

Potent inducers of CYP3A (e.g., phenobarbital and carbamazepine) may reduce nelfinavir plasma concentrations. Physicians should consider using alternatives when a patient is taking VIRACEPT (see section 4.3.)

Interactions of nelfinavir with selected compounds 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.

Substrates for CYP3A: Nelfinavir is primarily metabolised via the cytochrome P450 isoenzymes CYP3A and CYP2C19 (see section 5.2). Co-administration with is contraindicated with the following medicinal agents products that are substrates for CYP3A4 and which that have narrow therapeutic windows: is contraindicated (see section 4.3 and below):

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, phehnobarbital and carbamazepine) may reduce nelfinanvir plasma concentrations and their coradministration is contraindicated (see section 4.3). Caution should be used when co‑administering other medicinal productsagents that induce CYP3A4or potentially toxic medicinal products which are themselves metabolised by CYP3A (see section 4.3). Based on in vitro data, nelfinavir is unlikely to inhibit other cytochrome P450 isoforms at concentrations in the therapeutic range..

 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 %)

5.2     Pharmacokinetic properties

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 summarizsed 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.

Pharmacokinetics in special  clinical situationspopulations:

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 film-coated tablets with food 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.

In an open prospective study, the pharmacokinetics of BID and TID VIRACEPT regimens in 18 HIV infected children aged 2-14 years were investigated. Children weighing less than 25 kg received 30‑37 mg/kg nelfinavir TID or 45-55 mg/kg nelfinavir BID. Children over 25 kg received 750 mg TID or 1250 mg BID.

The C_min, C_max and AUC_0-24 were all significantly higher with the BID regimen compared with the TID regimen. In addition, in twice daily application, 14 out of 18 (78 %) and 11 out of 18 (61 %) reached C_min values of 1-3 µg/ml and C_max values of 3-4 µg/ml, whereas in TID application only 4 out of 18 (22 %) and 7 out of 18 (39 %) reached these values. ³

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 summarizsed below.

Summary of Steady-state AUC₂₄ 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 forfrom 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 groups with impairment (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.

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4.3       Contraindications

Potent inducers of CYP3A (e.g., rifampicin, phenobarbital and carbamazepine) may reduce nelfinavir plasma concentrations. Physicians should consider using alternatives when a patient is taking VIRACEPT (see section 4.5).

Co-administration with rifampicin is contra-indicated due to a reduction in exposure to nelfinavir. Physicians should not use potent CYP3A4 in combination with Viracept and should consider using alternatives when a patient is taking VIRACEPT (see section 4.5).

Co-administration with rifampicin (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 hydroxyl 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

Combination with other medicinal products: Caution is advised whenever VIRACEPT is co-administered with medicinal products which are inducers or inhibitors and/or substrates of CYP3A4; such combinations may require dose adjustment (see also sections 4.3, 4.5 and 4.8).

The HMG (hydroxyl-3-methyl-glutaryl)-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A4 for metabolism, thus concomitant use of VIRACEPT with simvastatin or lovastatin is not recommended due to an increased risk of myopathy including rhabdomyolysis. Caution must also be exercised if VIRACEPT is used concurrently with atorvastatin, which is metabolised to a lesser extent by CYP3A4. In this situation a reduced dose of atorvastatin should be considered. If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see section 4.5).

Particular caution should be used when prescribing sildenafil in patients receiving PIs, including nelfinavir. 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.

Potent inducers of CYP3A (e.g., phenobarbital and carbamazepine) may reduce nelfinavir plasma concentrations. Physicians should consider using alternatives when a patient is taking VIRACEPT (see sections 4.3 and 4.5).

The absorption of nelfinavir may be reduced in situations where the gastric pH is increased irrespective of cause. When nelfinavir is co-administered with omeprazole this may lead to a loss of virologic response and therefore concomitant use is contra-indicated (see section 4.3 and 4.5). Caution is recommended when nelfinavir is co-administered with other proton pump inhibitors (see section 4.5).

VIRACEPT may lead to a decreased AUC of phenytoin; therefore phenytoin concentrations should be monitored during concomitant use with VIRACEPT (see section 4.5).

Methadone AUC may be decreased when co-administered with VIRACEPT; therefore upward adjustment of methadone dose may be required during concomitant use with VIRACEPT (see section 4.5).

Oral contraceptives: Co-administration of the combination oral contraceptive containing norethindrone and 17 α-ethinylestradiol with VIRACEPT resulted in a decrease in AUC of the contraceptive drug; therefore alternative contraceptive measure should also be considered (see section 4.5).

4.5     Interaction with other medicinal products and other forms of interaction

Please refer to Table 1 and Table 2 for interactions of nelfinavir with selected compounds, Table 1 for impact on the pharmacokinetics of the co-administered compound, Table 2 for the impact of other drugs on pharmacokinetics of nelfinavir.

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

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.

Potent inducers of CYP3A (e.g., phenobarbital and carbamazepine) may reduce nelfinavir plasma concentrations. Physicians should consider using alternatives when a patient is taking VIRACEPT (see section 4.3.)

Interactions of nelfinavir with selected compounds 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.

Other antiretrovirals:

Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs):

Clinically significant interactions have not been observed between nelfinavir and nucleoside analogues (specifically zidovudine plus lamivudine, stavudine, and stavudine plus didanosine). At present, there is no evidence of inadequate efficacy of zidovudine in the CNS that could be associated with the modest reduction in plasma levels of zidovudine when co-administered with nelfinavir. Since it is recommended that didanosine be administered on an empty stomach, VIRACEPT should be administered (with food) one hour after or more than 2 hours before didanosine.

Other Protease Inhibitors (PIs):

Ritonavir: There were no significant differences between low doses of ritonavir (either 100 or 200 mg BID) for effects on AUCs of nelfinavir and M8. The clinical relevance of these findings has not been established. See Tables 1 and 2 for more information.

Indinavir: The safety of this combination has not been established. See Tables 1 and 2 for more information.

Saquinavir soft gelatin capsule: See Tables 1 and 2 for more information.

Amprenavir: No dose adjustment is necessary for either medicinal product when nelfinavir is administered in combination with amprenavir. See Tables 1 and 2 for more information.

Non-nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs):

Efavirenz: A dose adjustment is not needed when efavirenz is administered with VIRACEPT. See Tables 1 and 2 for more information.

Delavirdine: The safety of this drug combination has not been established and this combination is not recommended. See Tables 1 and 2 for more information.

Nevirapine: A dose adjustment is not needed when nevirapine is administered with VIRACEPT. See Tables 1 and 2 for more information.

Metabolic enzyme inducers: rifampicin decreases nelfinavir plasma AUC by 82 % and its concomitant use with nelfinavir is contraindicated (see section 4.3). Other potent inducers of CYP3A (e.g., phenobarbital, carbamazepine) may also reduce nelfinavir plasma concentrations. If therapy with such medicinal products is warranted, physicians should consider using alternatives when a patient is taking VIRACEPT.

Rifabutin: Dosage reduction of rifabutin to 150 mg once a day is necessary when nelfinavir 750 mg TID or 1250 mg BID and rifabutin are co-administered. See Tables 1 and 2 for more information.

Phenytoin: Co-administration of nelfinavir 1250 mg BID with phenytoin 300 mg once a day did not change the concentration of nelfinavir. However, AUC values of phenytoin and free phenytoin were reduced by 29 % and 28 % by co-administration of nelfinavir, respectively. No dose adjustment for nelfinavir is recommended. Phenytoin concentrations should be monitored during co-administration with nelfinavir.

St. John’s wort (Hypericum perforatum): Plasma levels of nelfinavir can be reduced by concomitant use of the herbal preparation St. John’s wort (Hypericum perforatum). This is due to induction of drug metabolising enzymes and/or transport proteins by St. John’s wort. Herbal preparations containing St. John’s wort must not be used concomitantly with VIRACEPT. If a patient is already taking St. John’s wort, stop St. John’s wort, check viral levels and if possible nelfinavir levels. Nelfinavir levels may increase on stopping St. John’s wort, and the dose of VIRACEPT may need adjusting. The inducing effect of St. John’s wort may persist for at least 2 weeks after cessation of treatment (see section 4.3).

Metabolic enzyme inhibitors: co-administration of nelfinavir and a strong inhibitor of CYP3A, ketoconazole, resulted in a 35 % increase in nelfinavir plasma AUC. This change is not considered clinically significant and no dose adjustment is needed when ketoconazole and VIRACEPT are co‑administered. Based on the metabolic profiles, a clinically relevant drug interaction would not be expected with other specific inhibitors of CYP3A (e.g., fluconazole, itraconazole, clarithromycin, erythromycin); however, the possibility cannot be excluded.

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.

Omeprazole: Co-administration of omeprazole (20 mg twice daily) and Viracept (1250 mg twice daily) to 19 healthy volunteers for 4 days resulted in reduced mean nelfinavir AUC by 36 %, mean C_max by 37 %, and mean C_min by 39 %. Reductions were observed in the mean M8 AUC by 92 %, mean C_max by 89 %, and mean C_min by 75 %. Therefore omeprazole should not be co-administered with VIRACEPT (see section 4.3)

The absorption of nelfinavir may be reduced in conditions where gastric pH is increased, therefore concomitant use of VIRACEPT with Proton Pump Inhibitors is not recommended (see section 4.4), except for omeprazole which is contra-indicated (see section 4.3).

HMG-CoA reductase inhibitors which are highly dependent on CYP3A4 metabolism, such as lovastatin and simvastatin, are expected to have markedly increased plasma concentrations when co‑administered with VIRACEPT. See Tables 1 and 2 for more information.

Since increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, the combination of these medicinal products with VIRACEPT is not recommended. Atorvastatin is less dependent on CYP3A4 for metabolism. When used with VIRACEPT, the lowest possible dose of atorvastatin should be administered. The metabolism of pravastatin and fluvastatin is not dependent on CYP3A4, and interactions are not expected with PIs. If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.

Methadone: Co-administration of nelfinavir 1250 mg BID with methadone 80 +/- 21 mg once a day in HIV negative methadone maintenance patients resulted in a 47 % decrease in methadone AUC. None of the subjects experienced withdrawal symptoms in this study; however, due to the pharmacokinetic changes, it should be expected that some patients who received this drug combination may experience withdrawal symptoms and require an upward adjustment of the methadone dose.

Other potential interactions (see also section 4.3): Nelfinavir increases terfenadine plasma concentrations; therefore, VIRACEPT must not be administered concurrently with terfenadine because of the potential for serious and/or life-threatening cardiac arrhythmias. Because similar interactions are likely with astemizole and cisapride, VIRACEPT must not be administered concurrently with these drugs. Midazolam is extensively metabolised by CYP3A4. Co-administration with VIRACEPT may cause a large increase in the concentration of this benzodiazepine. No drug interaction study has been performed for the co-administration of VIRACEPT with benzodiazepines. Based on data for other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally. Therefore VIRACEPT should not be co-administered with orally administered midazolam (see section 4.3), whereas caution should be used with co-administration of VIRACEPT and parenteral midazolam. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels. If VIRACEPT is co-administered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.

Similarly, concomitant administration of nelfinavir with any of amiodarone, quinidine, pimozide and ergot derivatives is contraindicated. For other compounds that are substrates for CYP3A (e.g., calcium channel blockers including bepridil, immunosuppressants including tacrolimus and ciclosporin, and sildenafil) plasma concentrations may be elevated when co-administered with VIRACEPT; therefore, patients should be monitored for toxicities associated with such medicinal products.

Oral contraceptives: administration of nelfinavir 750 mg TID and a combination oral contraceptive which included 0.4 mg of norethindrone and 35 mg of 17 a-ethinylestradiol for 7 days resulted in a 47 % decrease in ethinylestradiol and an 18 % decrease in norethindrone plasma AUC. Alternative contraceptive measures should be considered.

Table 1: Drug Interactions:  Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence of Nelfinavir

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

Table 2: Drug Interactions:  Changes in Pharmacokinetic Parameters for Nelfinavir in the Presence of the Co-administered Drug