Busvir

Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infected patients (adults and children of 2 years of age and older).

Busvir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infected patients (adults and children of 2 years of age and older).

Ritonavir should be administered by physicians who are experienced in the treatment of HIV infection.

Ritonavir film-coated tablets are administered orally and should be ingested with food.

Busvir film-coated tablets should be swallowed whole and not chewed, broken or crushed.

Posology

Ritonavir dosed as a pharmacokinetic enhancer

When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors the Summary of Product Characteristics for the particular protease inhibitor must be consulted.

The following HIV-1 protease inhibitors have been approved for use with ritonavir as a pharmacokinetic enhancer at the noted doses.

Adults

Amprenavir 600 mg twice daily with ritonavir 100 mg twice daily.

Atazanavir 300 mg once daily with ritonavir 100 mg once daily.

Fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily.

Lopinavir co-formulated with ritonavir (lopinavir/ritonavir) 400 mg/100 mg or 800 mg/200 mg.

Saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily in ART experienced patients. Initiate treatment with saquinavir 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days, then saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily in ART-naïve patients.

Tipranavir 500 mg twice daily with ritonavir 200 mg twice daily. Tipranavir with ritonavir should not be used in treatment-naïve patients.

Darunavir 600 mg twice daily with ritonavir 100 mg twice daily in antiretroviral treatment. (ART) experienced patients. Darunavir 800 mg once daily with ritonavir 100 mg once daily may be used in some ART experienced patients. Refer to the darunavir Summary of Product Characteristics for further information on once daily dosing in ART experienced patients.

Darunavir 800 mg once daily with ritonavir 100 mg once daily in ART-naïve patients.

Children and adolescents

Ritonavir is recommended for children 2 years of age and older. For further dosage recommendations, refer to the product information of other Protease Inhibitors approved for co-administration with ritonavir.

Special populations

Renal impairment

As ritonavir is primarily metabolised by the liver, ritonavir may be appropriate for use with caution as a pharmacokinetic enhancer in patients with renal insufficiency depending on the specific protease inhibitor with which it is co-administered. However, since the renal clearance of ritonavir is negligible, the decrease in the total body clearance is not expected in patients with renal impairment. For specific dosing information in patients with renal impairment, refer to the Summary of Product Characteristics (SPC) of the co-administered protease inhibitor.

Hepatic impairment

Ritonavir should not be given as a pharmacokinetic enhancer to patients with decompensated liver disease,. In the absence of pharmacokinetic studies in patients with stable severe hepatic impairment (Child Pugh Grade C) without decompensation, caution should be exercised when ritonavir is used as a pharmacokinetic enhancer as increased levels of the co-administered PI may occur. Specific recommendations for use of ritonavir as a pharmacokinetic enhancer in patients with hepatic impairment are dependent on the protease inhibitor with which it is co-administered. The SPC of the co-administered PI should be reviewed for specific dosing information in this patient population.

Ritonavir dosed as an antiretroviral agent

Adults

The recommended dose of Busvir film-coated tablets is 600 mg (6 tablets) twice daily (total of 1200 mg per day) by mouth.

Gradually increasing the dose of ritonavir when initiating therapy may help to improve tolerance. Treatment should be initiated at 300 mg (3 tablets) twice daily for a period of three days and increased by 100 mg (1 tablet) twice daily increments up to 600 mg twice daily over a period of no longer than 14 days. Patients should not remain on 300 mg twice daily for more than 3 days.

Children and adolescents (2 years of age and above)

The recommended dosage of Busvir in children is 350 mg/m² by mouth twice daily and should not exceed 600 mg twice daily. Busvir should be started at 250 mg/m² and increased at 2 to 3 day intervals by 50 mg/m² twice daily (please refer to the Busvir 80 mg/ml oral solution Summary of Product Characteristics).

For older children it may be feasible to substitute tablets for the maintenance dose of the oral solution.

Dosage conversion from oral solution to tablets for children

Busvir is not recommended in children below 2 years of age due to lack of data on safety and efficacy.

Special populations

Elderly

Pharmacokinetic data indicated that no dose adjustment is necessary for elderly patients.

Renal impairment

Currently, there are no data specific to this patient population and therefore specific dosage recommendations cannot be made. The renal clearance of ritonavir is negligible therefore; a decrease in the total body clearance is not expected in patients with renal impairment. Because ritonavir is highly protein bound it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis.

Hepatic impairment

Ritonavir is principally metabolised and eliminated by the liver. Pharmacokinetic data indicate that no dose adjustment is necessary in patients with mild to moderate hepatic impairment. Ritonavir must not be given to patients with severe hepatic impairment.

Paediatric population

The safety and efficacy of Busvir in childred aged below 2 years has not been established.2 but no recommendation on a posology can be made.

Busvir should be administered by physicians who are experienced in the treatment of HIV infection.

Busvir film-coated tablets are administered orally and should be ingested with food.

Busvir film-coated tablets should be swallowed whole and not chewed, broken or crushed.

Posology

Busvir dosed as a pharmacokinetic enhancer

When Busvir is used as a pharmacokinetic enhancer with other protease inhibitors (PI) the Summary of Product Characteristics (SmPC) for the particular protease inhibitor must be consulted.

The following HIV-1 protease inhibitors have been approved for use with Busvir as a pharmacokinetic enhancer at the noted doses.

Adults:

Amprenavir 600 mg twice daily with Busvir 100 mg twice daily

Atazanavir 300 mg once daily with Busvir 100 mg once daily

Fosamprenavir 700 mg twice daily with Busvir 100 mg twice daily

Lopinavir co-formulated with Busvir (lopinavir/Busvir) 400 mg/100 mg or 800 mg/200 mg

Saquinavir 1000 mg twice daily with Busvir 100 mg twice daily in ART experienced patients. Initiate treatment with saquinavir 500 mg twice daily with Busvir 100 mg twice daily for the first 7 days, then saquinavir 1000 mg twice daily with Busvir 100 mg twice daily in ART-naïve patients.

Tipranavir 500 mg twice daily with Busvir 200 mg twice daily. (Tipranavir with Busvir should not be used in treatment-naïve patients).

Darunavir 600 mg twice daily with Busvir 100 mg twice daily in antiretroviral treatment (ART) experienced patients. Darunavir 800 mg once daily with Busvir 100 mg once daily may be used in some ART experienced patients. Refer to the darunavir Summary of Product Characteristics for further information on once daily dosing in ART experienced patients.

Darunavir 800 mg once daily with Busvir 100 mg once daily in ART-naïve patients

Children and adolescents

Busvir is recommended for children 2 years of age and older. For further dosage recommendations, refer to the product information of other Protease Inhibitors approved for co-administration with Busvir.

Special populations

Renal impairment: As Busvir is primarily metabolised by the liver, Busvir may be appropriate for use with caution as a pharmacokinetic enhancer in patients with renal insufficiency depending on the specific protease inhibitorwith which it is co-administered. However, since the renal clearance of Busvir is negligible, the decrease in the total body clearance is not expected in patients with renal impairment. For specific dosing information in patients with renal impairment, refer to the Summary of Product Characteristics (SPC) of the co- administered protease inhibitor.

Hepatic impairment: Busvir should not be given as a pharmacokinetic enhancer to patients with decompensated liver disease. In the absence of pharmacokinetic studies in patients with stable severe hepatic impairment (Child Pugh Grade C) without decompensation, caution should be exercised when Busvir is used as a pharmacokinetic enhancer as increased levels of the co-administered protease inhibitor may occur. Specific recommendations for use of Busvir as a pharmacokinetic enhancer in patients with hepatic impairment are dependent on the protease inhibitor with which it is co-administered. The Summary of Product Characteristics of the co-administered protease inhibitor should be reviewed for specific dosing information in this patient population.

Busvir dosed as an antiretroviral agent

Adults

The recommended dose of Busvir film-coated tablets is 600 mg (6 tablets) twice daily (total of 1200 mg per day) by mouth.

Gradually increasing the dose of Busvir when initiating therapy may help to improve tolerance. Treatment should be initiated at 300 mg (3 tablets) twice daily for a period of three days and increased by 100 mg (1 tablet) twice daily increments up to 600 mg twice daily over a period of no longer than 14 days. Patients should not remain on 300 mg twice daily for more than 3 days.

Children and adolscents (2 years of age and above)

The recommended dosage of Busvir in children is 350 mg/m² by mouth twice daily and should not exceed 600 mg twice daily. Busvir should be started at 250 mg/m² and increased at 2 to 3 day intervals by 50 mg/m² twice daily (Other pharmaceutical forms/strengths may be more appropriate for administration to this population).

For older children it may be feasible to substitute tablets for the maintenance dose of the oral solution.

Dosage conversion from oral solution to tablets for children

Busvir is not recommended in children below 2 years of age due to lack of data on safety and efficacy.

Special populations

Elderly

Pharmacokinetic data indicated that no dose adjustment is necessary for elderly patients.

Renal impairment

Currently, there are no data specific to this patient population and therefore specific dosage recommendations cannot be made. The renal clearance of Busvir is negligible, therefore, a decrease in the total body clearance is not expected in patients with renal impairment. Because Busvir is highly protein bound it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis.

Hepatic impairment

Busvir is principally metabolised and eliminated by the liver. Pharmacokinetic data indicate that no dose adjustment is necessary in patients with mild to moderate hepatic impairment. Busvir must not be given to patients with severe hepatic impairment.

Paediatric population

The safety and efficacy of Busvir in childred aged below 2 years has not been established.2 but no recommendation on a posology can be made.

When ritonavir is used as a pharmacokinetic enhancer of other PIs, consult the Summary of Product Characteristics of the co-administered protease inhibitor for contraindications.

Ritonavir should not be given as a pharmacokinetic enhancer or as an antiretroviral agent to patients with decompensated liver disease.

In vitro and in vivo studies have demonstrated that ritonavir is a potent inhibitor of CYP3A- and CYP2D6- mediated biotransformations. The following medicines are contraindicated when used with ritonavir and unless otherwise noted, the contraindication is based on the potential for ritonavir to inhibit metabolism of the co-administered medicinal product, resulting in increased exposure to the co-administered medicinal product and risk of clinically significant adverse effects.

The enzyme-modulating effect of ritonavir may be dose dependent. For some products, contraindications may be more relevant when ritonavir is used as an antiretroviral agent than when ritonavir is used as a pharmacokinetic enhancer (e.g. rifabutin and voriconazole):

When Busvir is used as a pharmacokinetic enhancer of other Protease inhibitors, consult the Summary of Product Characteristics of the co- administered protease inhibitor for contraindications.

Busvir should not be given as a pharmacokinetic enhancer or as an antiretroviral agent to patients with decompensated liver disease.

In vitro and in vivo studies have demonstrated that Busvir is a potent inhibitor of CYP3A- and CYP2D6- mediated biotransformations. The following medicines are contraindicated when used with Busvir and, unless otherwise noted, the contraindication is based on the potential for Busvir to inhibit metabolism of the co-administered medicinal product, resulting in increased exposure to the co- administered medicinal product and risk of clinically significant adverse effects.

The enzyme-modulating effect of Busvir may be dose dependent. For some products, contraindications may be more relevant when Busvir is used as an antiretroviral agent than when Busvir is used as a pharmacokinetic enhancer (e.g. rifabutin and voriconazole):

Ritonavir is not a cure for HIV-1 infection or AIDS. Patients receiving Ritonavir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 infection.

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

When ritonavir is used as a pharmacokinetic enhancer with other PIs, full details on the warnings and precautions relevant to that particular PI should be considered, therefore the Summary of Product Characteristics for the particular PI must be consulted.

Ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer

Patients with chronic diarrhoea or malabsorption

Extra monitoring is recommended when diarrhoea occurs. The relatively high frequency of diarrhoea during treatment with ritonavir may compromise the absorption and efficacy (due to decreased compliance) of ritonavir or other concurrent medicinal products. Serious persistent vomiting and/or diarrhoea associated with ritonavir use might also compromise renal function. It is advisable to monitor renal function in patients with renal function impairment.

Haemophilia

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than a half of the reported cases, treatment with protease inhibitors 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.

Weight and metabolic parameters:

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose, reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Pancreatitis

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and Busvir therapy should be discontinued if a diagnosis of pancreatitis is made.

Immune Reconstitution Inflammatory Syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymtomatic 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 mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

Liver disease

Ritonavir should not be given to patients with decompensated liver disease. 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 reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer 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.

Renal disease

Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice.

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 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.

PR interval prolongation

Ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some healthy adult subjects. Rare reports of 2^nd or 3^rd degree atrioventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving medicinal products known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving ritonavir. Busvir should be used with caution in such patients.

Interactions with other medicinal products

Ritonavir dosed as an antiretroviral agent

PDE5 inhibitors

Particular caution should be used when prescribing sildenafil or tadalafil for the treatment of erectile dysfunction in patients receiving ritonavir. Co-administration of ritonavir with these medicinal products is expected to substantially increase their concentrations and may result in associated adverse reactions such as hypotension and prolonged erection. Concomitant use of avanafil or vardenafil with ritonavir is contraindicated. Concomitant use of sildenafil with ritonavir is contraindicated in pulmonary arterial hypertension patients.

HMG-CoA reductase inhibitors

The HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A for metabolism, thus concomitant use of ritonavir with simvastatin or lovastatin is not recommended due to an increased risk of myopathy including rhabdomyolysis. Caution must also be exercised and reduced doses should be considered if ritonavir is used concurrently with atorvastatin, which is metabolised to a lesser extent by CYP3A. While rosuvastatin elimination is not dependent on CYP3A, an elevation of rosuvastatin exposure has been reported with ritonavir co-administration. The mechanism of this interaction is not clear, but may be the result of transporter inhibition. When used with ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent, the lowest doses of atorvastatin or rosuvastatin should be administered. The metabolism of pravastatin and fluvastatin is not dependent of CYP3A, and interactions are not expected with ritonavir. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.

Colchicine

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A like ritonavir.

Digoxin

Particular caution should be used when prescribing ritonavir in patients taking digoxin since co-administration of ritonavir with digoxin is expected to increase digoxin levels. The increased digoxin levels may lessen over time.

In patients who are already taking digoxin when ritonavir is introduced, the digoxin dose should be reduced to one-half of the patients' normal dose and patients need to be followed more closely than usual for several weeks after initiating co-administration of ritonavir and digoxin.

In patients who are already taking ritonavir when digoxin is introduced, digoxin should be introduced more gradually than usual. Digoxin levels should be monitored more intensively than usual during this period, with dose adjustments made, as necessary, based on clinical, electrocardiographic and digoxin level findings.

Ethinyl estradiol

Barrier or other non-hormonal methods of contraception should be considered when administering ritonavir at therapeutic or low doses as ritonavir is likely to reduce the effect and change the uterine bleeding profile when co-administered with estradiol-containing contraceptives.

Glucocorticoids

Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.

Trazodone

Particular caution should be used when prescribing ritonavir in patients using trazodone. Trazodone is a CYP3A4 substrate and co-administration of ritonavir is expected to increase trazodone levels. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed in single dose interaction studies in healthy volunteers

Rivaroxaban

It is not recommended to use ritonavir in patients receiving rivaroxaban, due to the risk of increased bleeding.

Riociguat

The concomitant use of ritonavir is not recommended due to potential increase in riociguat exposure.

Vorapaxar

The concomitant use of ritonavir is not recommended due to potential increase in vorapaxar exposure.

Bedaquiline

Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could potentially increase the risk of bedaquiline-related adverse reactions.).

Delamanid

Ritonavir dosed as a pharmacokinetic enhancer

The interaction profiles of HIV-protease inhibitors, co-administered with low dose ritonavir, are dependant on the specific co-administered protease inhibitor.

Saquinavir

Doses of ritonavir higher than 100 mg twice daily should not be used. Higher doses of ritonavir have been shown to be associated with an increased incidence of adverse reactions. Co-administration of saquinavir and ritonavir has led to severe adverse reactions, mainly diabetic ketoacidosis and liver disorders, especially in patients with pre-existing liver disease.

Saquinavir/ritonavir should not be given together with rifampicin, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three medicines are given together.

Tipranavir

Co-administration of tipranavir with 200 mg of ritonavir has been associated with reports of clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity.

Doses of ritonavir lower than 200 mg twice daily should not be used as they might alter the efficacy profile of the combination.

Fosamprenavir

Co-administration of fosamprenavir with ritonavir in doses greater than 100 mg twice daily has not been clinically evaluated. The use of higher ritonavir doses might alter the safety profile of the combination and therefore is not recommended.

Atazanavir

Co-administration of atazanavir with ritonavir at doses greater than 100 mg once daily has not been clinically evaluated. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and therefore is not recommended. Only when atazanavir with ritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200mg once daily could be considered. In this instance, close clinical monitoring is warranted. Refer to the Summary of Product Characteristics for atazanavir for further details.

Busvir is not a cure for HIV-1 infection or AIDS. Patients receiving Busvir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 infection.

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

When Busvir is used as a pharmacokinetic enhancer with other Protease inhibitors, full details on the warnings and precautions relevant to that particular protease inhibitor should be considered, therefore the Summary of Product Characteristics for the particular protease inhibitor must be consulted.

Busvir tablets contains sodium

This medicine contains 0.362 mg sodium per tablet. To be taken into consideration by patients on a controlled sodium diet.

Busvir dosed as an antiretroviral agent or as a pharmacokinetic enhancer

Patients with chronic diarrhoea or malabsorption

Extra monitoring is recommended when diarrhoea occurs. The relatively high frequency of diarrhoea during treatment with Busvir may compromise the absorption and efficacy (due to decreased compliance) of Busvir or other concurrent medicinal products. Serious persistent vomiting and/or diarrhoea associated with Busvir use might also compromise renal function. It is advisable to monitor renal function in patients with renal function impairment.

Haemophilia

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than a half of the reported cases, treatment with protease inhibitors 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.

Weight and metabolic parameters:

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose, reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Pancreatitis

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and Busvir tablets therapy should be discontinued if a diagnosis of pancreatitis is made.

Immune Reconstitution InflammatorySyndrome

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 mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

Liver disease

Busvir should not be given to patients with decompensated liver disease. 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 reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer 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.

Renal disease

Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice.

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 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.

PR interval prolongation

Busvir has been shown to cause modest asymptomatic prolongation of the PR interval in some healthy adult subjects. Rare reports of 2nd or 3rd degree atrioventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving medicinal products known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving Busvir. Busvir tablets should be used with caution in such patients.

Interactions with other medicinal products

Busvir dosed as an antiretroviral agent

The following Warnings and Precautions should be considered when Busvir is used as an antiretroviral agent.

PDE5 inhibitors

Particular caution should be used when prescribing sildenafil or tadalafil for the treatment of erectile dysfunction in patients receiving Busvir. Co-administration of Busvir with these medicinal products is expected to substantially increase their concentrations and may result in associated adverse reactions such as hypotension and prolonged erection.

Concomitant use of avanafil or vardenafil with Busvir is contraindicated. Concomitant use of sildenafil with Busvir is contraindicated in pulmonary arterial hypertension patients.

HMG-CoA reductase inhibitors

The HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A for metabolism, thus concomitant use of Busvir with simvastatin or lovastatin is not recommended due to an increased risk of myopathy including rhabdomyolysis. Caution must also be exercised and reduced doses should be considered if Busvir is used concurrently with atorvastatin, which is metabolised to a lesser extent by CYP3A. While rosuvastatin elimination is not dependent on CYP3A, an elevation of rosuvastatin exposure has been reported with Busvir co-administration. The mechanism of this interaction is not clear, but may be the result of transporter inhibition. When used with Busvir dosed as a pharmacokinetic enhancer or as an antiretroviral agent, the lowest doses of atorvastatin or rosuvastatin should be administered. The metabolism of pravastatin and fluvastatin is not dependent of CYP3A, and interactions are not expected with Busvir. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.

Colchicine

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A like Busvir.

Digoxin

Particular caution should be used when prescribing Busvir in patients taking digoxin since co-administration of Busvir with digoxin is expected to increase digoxin levels. The increased digoxin levels may lessen over time.

In patients who are already taking digoxin when Busvir is introduced, the digoxin dose should be reduced to one-half of the patients' normal dose and patients need to be followed more closely than usual for several weeks after initiating co- administration of Busvir and digoxin.

In patients who are already taking Busvir when digoxin is introduced, digoxin should be introduced more gradually than usual. Digoxin levels should be monitored more intensively than usual during this period, with dose adjustments made, as necessary, based on clinical, electrocardiographic and digoxin level findings.

Ethinyl estradiol

Barrier or other non-hormonal methods of contraception should be considered when administering Busvir at therapeutic or low doses as Busvir is likely to reduce the effect and change the uterine bleeding profile when co- administered with estradiol-containing contraceptives.

Glucocorticoids

Concomitant use of Busvir and fluticasone or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.

Trazodone

Particular caution should be used when prescribing Busvir in patients using trazodone. Trazodone is a CYP3A4 substrate and co-administration of Busvir is expected to increase trazodone levels. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed in single dose interaction studies in healthy volunteers

Rivaroxaban

It is not recommended to use Busvir in patients receiving rivaroxaban, due to the risk of increased bleeding.

Riociguat

The concomitant use of Busvir is not recommended due to potential increase in riociguat exposure.

Vorapaxar

The concomitant use of Busvir is not recommended due to potential increase in vorapaxar exposure.

Bedaquiline

Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could potentially increase the risk of bedaquiline-related adverse reactions.).

Delamanid

Co-administration of delamanid with a strong inhibitor of CYP3A (Busvir) may increase exposure to delamanid metabolite, which has been associated with QTc prolongation.).

Busvir dosed as a pharmacokinetic enhancer

The interaction profiles of HIV-protease inhibitors, co-administered with low dose Busvir, are dependent on the specific co-administered protease inhibitor.

Saquinavir

Doses of Busvir higher than 100 mg twice daily should not be used. Higher doses of Busvir have been shown to be associated with an increased incidence of adverse reactions. Co-administration of saquinavir and Busvir has led to severe adverse reactions, mainly diabetic ketoacidosis and liver disorders, especially in patients with pre-existing liver disease.

Saquinavir/Busvir should not be given together with rifampicin, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three medicines are given together.

Tipranavir

Co-administration of tipranavir with 200 mg of Busvir has been associated with reports of clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co- infection, as these patients have an increased risk of hepatotoxicity.

Doses of Busvir lower than 200 mg twice daily should not be used as they might alter the efficacy profile of the combination.

Fosamprenavir

Co-administration of fosamprenavir with Busvir in doses greater than 100 mg twice daily has not been clinically evaluated. The use of higher Busvir doses might alter the safety profile of the combination and therefore is not recommended.

Atazanavir

Co-administration of atazanavir with Busvir at doses greater than 100 mg once daily has not been clinically evaluated. The use of higher Busvir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and therefore is not recommended. Only when atazanavir with Busvir is co- administered with efavirenz, a dose increase of Busvir to 200 mg once daily could be considered. In this instance, close clinical monitoring is warranted. Refer to the Summary of Product Characteristics for atazanavir for further details.

Summary of the safety profile

Ritonavir dosed as a pharmacokinetic enhancer

Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on the specific co-administered PI. For information on adverse reactions refer to the SPC of the specific co-administered PI.

Ritonavir dosed as an antiretroviral agent

Adverse reactions from clinical trials and post-marketing experience in adult patients

The most frequently reported adverse drug reactions among patients receiving ritonavir alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia) and fatigue/asthenia.

Tabulated list of adverse reactions

The following adverse reactions of moderate to severe intensity with possible or probable relationship to ritonavir have been reported. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); rare (> 1/10,000 to < 1/1,000); not known (cannot be estimated from the available data).

Events noted as having frequency not known were identified via post-marketing surveillance.

Description of selected adverse reactions

Hepatic transaminase elevations exceeding five times the upper limit or normal, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir alone or in combination with other antiretrovirals.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.

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. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis.

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.

Paediatric populations

The safety profile of Busvir in children 2 years of age and older is similar to that seen in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme:

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Summary of the safety profile

Busvir dosed as a pharmacokinetic enhancer

Adverse reactions associated with the use of Busvir as a pharmacokinetic enhancer are dependent on the specific co-administered protease inhibitor. For information on adverse reactions refer to the Summary of Product Characteristics of the specific co-administered protease inhibitor.

Busvir dosed as an antiretroviral agent

Adverse reactions from clinical trials and post-marketing experience in adult patients

The most frequently reported adverse drug reactions among patients receiving Busvir alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhoea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paraesthesia and oral paraesthesia) and fatigue/asthenia.

Tabulated list of adverse reactions

The following adverse reactions of moderate to severe intensity with possible or probable relationship to Busvir have been reported. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); rare (> 1/10,000 to < 1/1,000); not known (cannot be estimated from the available data).

Events noted as having frequency not known were identified via post-marketing surveillance

Description of selected adverse reactions

Hepatic transaminase elevations exceeding five times the upper limit or normal, clinical hepatitis, and jaundice have occurred in patients receiving Busvir alone or in combination with other antiretrovirals.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.

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. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

Pancreatitis has been observed in patients receiving Busvir therapy, including those who developed hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis.

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.

Paediatric populations

The safety profile of Busvir in children 2 years of age and older is similar to that seen in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms

Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/day for two days and reported paraesthesia, which resolved after the dose was decreased. A case of renal failure with eosinophilia has been reported.

The signs of toxicity observed in animals (mice and rats) included decreased activity, ataxia, dyspnoea and tremors.

Management

There is no specific antidote for overdose with ritonavir. Treatment of overdose with ritonavir should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Due to the solubility characteristics and possibility of transintestinal elimination, it is proposed that management of overdose could entail gastric lavage and administration of activated charcoal. Since ritonavir is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the medicine.

Symptoms

Human experience of acute overdose with Busvir is limited. One patient in clinical trials took Busvir 1500 mg/day for two days and reported paraesthesia, which resolved after the dose was decreased. A case of renal failure with eosinophilia has been reported.

The signs of toxicity observed in animals (mice and rats) included decreased activity, ataxia, dyspnoea and tremors.

Management

There is no specific antidote for overdose with Busvir. Treatment of overdose with Busvir should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Due to the solubility characteristics and possibility of transintestinal elimination, it is proposed that management of overdose could entail gastric lavage and administration of activated charcoal. Since Busvir is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the medicine.

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors ATC code: J05AE03

Ritonavir dosed as a pharmacokinetic enhancer

Ritonavir dosed as an antiretroviral agent

Ritonavir is an orally active peptidomimetic inhibitor of the HIV-1 and HIV-2 aspartyl proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to the production of HIV particles with immature morphology that are unable to initiate new rounds of infection. Ritonavir has selective affinity for the HIV protease and has little inhibitory activity against human aspartyl proteases.

Ritonavir was the first protease inhibitor (approved in 1996) for which efficacy was proven in a study with clinical endpoints. However, due to ritonavir's metabolic inhibitory properties its use as a pharmacokinetic enhancer of other protease inhibitors is the prevalent use of ritonavir in clinical practice.

Effects on the Electrocardiogram

QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) difference in QTcF from placebo was 5.5 (7.6) for 400 mg twice daily ritonavir. The Day 3 ritonavir exposure was approximately 1.5 fold higher than that observed with the 600 mg twice daily dose at steady state. No subject experienced an increase in QTcF of > 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec.

Modest prolongation of the PR interval was also noted in subjects receiving ritonavir in the same study on Day 3. The mean changes from baseline in PR interval ranged from 11.0 to 24.0 msec in the 12 hour interval post dose. Maximum PR interval was 252 msec and no second or third degree heart block was observed.

Resistance

Ritonavir-resistant isolates of HIV-1 have been selected in vitro and isolated from patients treated with therapeutic doses of ritonavir.

Reduction in the antiretroviral activity of ritonavir is primarily associated with the protease mutations V82A/F/T/S and I84V. Accumulation of other mutations in the protease gene (including at positions 20, 33, 36, 46, 54, 71, and 90) can also contribute to ritonavir resistance. In general, as mutations associated with ritonavir resistance accumulate, susceptibility to select other PIs may decrease due to cross-resistance. The Summary of Product Characteristics of other protease inhibitors or official continuous updates should be consulted for specific information regarding protease mutations associated with reduced response to these agents.

Clinical pharmacodynamic data

The effects of ritonavir (alone or combined with other antiretroviral agents) on biological markers of disease activity such as CD4 cell count and viral RNA were evaluated in several studies involving HIV-1 infected patients. The following studies are the most important.

Adult Use

A controlled study completed in 1996 with ritonavir as add-on therapy in HIV-1 infected patients extensively pre-treated with nucleoside analogues and baseline CD4 cell counts ≤ 100 cells/μl showed a reduction in mortality and AIDS defining events. The mean average change from baseline over 16 weeks for HIV RNA levels was -0.79 log₁₀ (maximum mean decrease: 1.29 log₁₀) in the ritonavir group versus -0.01 log₁₀ in the control group. The most frequently used nucleosides in this study were zidovudine, stavudine, didanosine and zalcitabine.

In a study completed in 1996 recruiting less advanced HIV-1 infected patients (CD4 200-500 cells/μl) without previous antiretroviral therapy, ritonavir in combination with zidovudine or alone reduced viral load in plasma and increased CD4 count. The mean average change from baseline over 48 weeks for HIV RNA levels was -0.88 log₁₀ in the ritonavir group versus -0.66 log₁₀ in the ritonavir + zidovudine group versus -0.42 log₁₀ in the zidovudine group.

Paediatric Use

In an open label trial completed in 1998 in HIV infected, clinically stable children there was a significant difference (p = 0.03) in the detectable RNA levels in favour of a triple regimen (ritonavir, zidovudine and lamivudine) following 48 weeks treatment.

In a study completed in 2003, 50 HIV-1 infected, protease inhibitor and lamivudine naïve children age 4 weeks to 2 years received ritonavir 350 or 450 mg/m² every 12 hours co-administered with zidovudine 160 mg/m² every 8 hours and lamivudine 4 mg/kg every 12 hours. In intent to treat analyses, 72% and 36% of patients achieved reduction in plasma HIV-1 RNA of ≤ 400 copies/ml at Week 16 and 104, respectively. Response was similar in both dosing regimens and across patient age.

In a study completed in 2000, 76 HIV-1 infected children aged 6 months to 12 years who were protease inhibitor naive and naive to lamivudine and/or stavudine received ritonavir 350 or 450 mg/m² every 12 hours co-administered with lamivudine and stavudine. In intent to treat analyses, 50% and 57% of patients in the 350 and 450 mg/m² dose groups, respectively, achieved reduction in plasma HIV-1 RNA to ≤ 400 copies/ml at Week 48.

Pharmacotherapeutic group: antivirals for systemic use, Protease inhibitors ATC code: J05AE03

Busvir dosed as a pharmacokinetic enhancer

Pharmacokinetic enhancement by Busvir is based on Busvir's activity as a potent inhibitor of CYP3A- mediated metabolism.-administered Protease inhibitors.

Busvir dosed as an antiretroviral agent

Busvir is an orally active peptidomimetic inhibitor of the HIV-1 and HIV-2 aspartyl proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to the production of HIV particles with immature morphology that are unable to initiate new rounds of infection. Busvir has selective affinity for the HIV protease and has little inhibitory activity against human aspartyl proteases.

Busvir was the first PI (approved in 1996) for which efficacy was proven in a study with clinical endpoints. However, due to Busvir's metabolic inhibitory properties its use as a pharmacokinetic enhancer of other Protease inhibitors is the prevalent use of Busvir in clinical practice.

Effects on the Electrocardiogram

QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) difference in QTcF from placebo was 5.5 (7.6) for 400 mg twice daily Busvir. The Day 3 Busvir exposure was approximately 1.5 fold higher than that observed with the 600 mg twice daily dose at steady state. No subject experienced an increase in QTcF of > 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec.

Modest prolongation of the PR interval was also noted in subjects receiving Busvir in the same study on Day 3. The mean changes from baseline in PR interval ranged from 11.0 to 24.0 msec in the 12 hour interval post dose. Maximum PR interval was 252 msec and no second or third degree heart block was observed.

Resistance

Busvir-resistant isolates of HIV-1 have been selected in vitro and isolated from patients treated with therapeutic doses of Busvir.

Reduction in the antiretroviral activity of Busvir is primarily associated with the protease mutations V82A/F/T/S and I84V. Accumulation of other mutations in the protease gene (including at positions 20, 33, 36, 46, 54, 71, and 90) can also contribute to Busvir resistance. In general, as mutations associated with Busvir resistance accumulate, susceptibility to select other Protease inhibitors may decrease due to cross- resistance. The Summary of Product Characteristics of other Protease inhibitors or official continuous updates should be consulted for specific information regarding protease mutations associated with reduced response to these agents.

Clinical pharmacodynamic data

The effects of Busvir (alone or combined with other antiretroviral agents) on biological markers of disease activity such as CD4 cell count and viral RNA were evaluated in several studies involving HIV-1 infected patients. The following studies are the most important.

Adult Use

A controlled study completed in 1996 with Busvir as add-on therapy in HIV-1 infected patients extensively pre-treated with nucleoside analogues and baseline CD4 cell counts ≤ 100 cells/µ l showed a reduction in mortality and AIDS defining events. The mean average change from baseline over 16 weeks for HIV RNA levels was -0.79 log₁₀ (maximum mean decrease: 1.29 log₁₀) in the Busvir group versus - 0.01 log10 in the control group. The most frequently used nucleosides in this study were zidovudine, stavudine, didanosine and zalcitabine.

In a study completed in 1996 recruiting less advanced HIV-1 infected patients (CD4 200-500 cells/µ l) without previous antiretroviral therapy, Busvir in combination with zidovudine or alone reduced viral load in plasma and increased CD4 count. The mean average change from baseline over 48 weeks for HIV RNA levels was - 0.88 log₁₀ in the Busvir group versus -0.66 log10 in the Busvir + zidovudine group versus -0.42 log₁₀ in the zidovudine group.

Paediatric Use

In an open label trial completed in 1998 in HIV infected, clinically stable children there was a significant difference (p = 0.03) in the detectable RNA levels in favour of a triple regimen (Busvir, zidovudine and lamivudine) following 48 weeks treatment.

In a study completed in 2003, 50 HIV-1 infected, protease inhibitor and lamivudine naïve children age 4 weeks to 2 years received Busvir 350 or 450 mg/m² every 12 hours co- administered with zidovudine 160 mg/m² every 8 hours and lamivudine 4 mg/kg every 12 hours. In intent to treat analyses, 72% and 36% of patients achieved reduction in plasma HIV-1 RNA of ≤ 400 copies/ml at Week 16 and 104, respectively. Response was similar in both dosing regimens and across patient age.

In a study completed in 2000, 76 HIV-1 infected children aged 6 months to 12 years who were protease inhibitor naive and naive to lamivudine and/or stavudine received Busvir 350 or 450 mg/m² every 12 hours co-administered with lamivudine and stavudine. In intent to treat analyses, 50% and 57% of patients in the 350 and 450 mg/ m² dose groups, respectively, achieved reduction in plasma HIV-1 RNA to ≤ 400 copies/ml at Week 48.

Absorption

There is no parenteral formulation of ritonavir, therefore the extent of absorption and absolute bioavailability have not been determined. The pharmacokinetics of ritonavir during multiple dose regimens were studied in non-fasting HIV-infected adult volunteers. Upon multiple dosing, ritonavir accumulation is slightly less than predicted from a single dose due to a time and dose-related increase in apparent clearance (Cl/F). Trough concentrations of ritonavir decrease over time, possibly due to enzyme induction, but appeared to stabilise by the end of 2 weeks. The time to maximum concentration (T_max) remained constant at approximately 4 hours with increasing dose. Renal clearance averaged less than 0.1 l/h and was relatively constant throughout the dosage range.

The pharmacokinetic parameters observed with various dosing schemes of ritonavir alone are shown in the table below. Plasma concentrations of ritonavir after administration of a single 100 mg dose tablet are similar to the 100 mg soft gelatin capsule under fed conditions.

¹ Values expressed as geometric means. Note: ritonavir was dosed after a meal for all listed regimens.

Effects of food on oral absorption

Food slightly decreases the bioavailability of the Busvir tablet. Administration of a single 100 mg dose of Busvir tablet with a moderate fat meal (857 kcal, 31% calories from fat) or a high fat meal (907 kcal, 52% calories from fat) was associated with a mean decrease of 20-23% in ritonavir AUC and C_max.

Distribution

The apparent volume of distribution (V_B/F) of ritonavir is approximately 20 - 40 l after a single 600 mg dose. The protein binding of ritonavir in human plasma is approximately 98 - 99% and is constant over the concentration range of 1.0 - 100 μg/ml. Ritonavir binds to both human alpha 1-acid glycoprotein (AAG) and human serum albumin (HSA) with comparable affinities.

Tissue distribution studies with ¹⁴C-labelled ritonavir in rats showed the liver, adrenals, pancreas, kidneys and thyroid to have the highest concentrations of ritonavir. Tissue to plasma ratios of approximately 1 measured in rat lymph nodes suggests that ritonavir distributes into lymphatic tissues. Ritonavir penetrates minimally into the brain.

Metabolism

Ritonavir was noted to be extensively metabolised by the hepatic cytochrome P450 system, primarily by the CYP3A isozyme family and to a lesser extent by the CYP2D6 isoform. Animal studies as well as in vitro experiments with human hepatic microsomes indicated that ritonavir primarily underwent oxidative metabolism. Four ritonavir metabolites have been identified in man. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent compound. However, the AUC of the M-2 metabolite was approximately 3% of the AUC of parent compound.

Low doses of ritonavir have shown profound effects on the pharmacokinetics of other protease inhibitors (and other products metabolised by CYP3A4) and other protease inhibitors may influence the pharmacokinetics of ritonavir.

Elimination

Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, part of which is expected to be unabsorbed ritonavir. In these studies renal elimination was not found to be a major route of elimination of ritonavir. This was consistent with the observations in animal studies.

Special populations

No clinically significant differences in AUC or C_max were noted between males and females. Ritonavir pharmacokinetic parameters were not statistically significantly associated with body weight or lean body mass. Ritonavir plasma exposures in patients 50 - 70 years of age when dosed 100 mg in combination with lopinavir or at higher doses in the absence of other protease inhibitors is similar to that observed in younger adults.

Patients with impaired liver function

After multiple dosing of ritonavir to healthy volunteers (500 mg twice daily) and subjects with mild to moderate hepatic impairment (Child Pugh Class A and B, 400 mg twice daily) exposure to ritonavir after dose normalisation was not significantly different between the two groups.

Patients with impaired renal function

Ritonavir pharmacokinetic parameters have not been studied in patients with renal impairment. However, since the renal clearance of ritonavir is negligible, no changes in the total body clearance are expected in patients with renal impairment.

Paediatric patients

Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children above 2 years of age receiving doses ranging from 250 mg/m² twice daily to 400 mg/m² twice daily. Ritonavir concentrations obtained after 350 to 400 mg/m² twice daily in paediatric patients were comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m²) twice daily. Across dose groups, ritonavir oral clearance (CL/F/m²) was approximately 1.5 to 1.7 times faster in paediatric patients above 2 years of age than in adult subjects.

Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children less than 2 years of age receiving doses ranging from 350 to 450 mg/m² twice daily. Ritonavir concentrations in this study were highly variable and somewhat lower than those obtained in adults receiving 600 mg (approximately 330 mg/m²) twice daily. Across dose groups, ritonavir oral clearance (CL/F/m²) declined with age with median values of 9.0 L/h/m² in children less than 3 months of age, 7.8 L/h/m² in children between 3 and 6 months of age and 4.4 L/h/m² in children between 6 and 24 months of age.

Absorption

There is no parenteral formulation of Busvir, therefore the extent of absorption and absolute bioavailability have not been determined. The pharmacokinetics of Busvir during multiple dose regimens were studied in non-fasting HIV-infected adult volunteers. Upon multiple dosing, Busvir accumulation is slightly less than predicted from a single dose due to a time and dose-related increase in apparent clearance (Cl/F). Trough concentrations of Busvir decrease over time, possibly due to enzyme induction, but appeared to stabilise by the end of 2 weeks. The time to maximum concentration (T_max) remained constant at approximately 4 hours with increasing dose. Renal clearance averaged less than 0.1 l/h and was relatively constant throughout the dosage range.

The pharmacokinetic parameters observed with various dosing schemes of Busvir alone are shown in the table below. Plasma concentrations of Busvir after administration of a single 100 mg dose tablet are similar to the 100 mg soft gelatine capsule under fed conditions.

¹Values expressed as geometric means. Note: Busvir was dosed after a meal for all listed regimens.

Effects of food on oral absorption

Food slightly decreases the bioavailability of the Busvir film-coated tablets. Administration of a single 100 mg dose of Busvir film-coated tablets with a moderate fat meal (857 kcal, 31% calories from fat) or a high fat meal (907 kcal, 52% calories from fat) was associated with a mean decrease of 20-23% in Busvir AUC and C_max.

Distribution

The apparent volume of distribution (VB/F) of Busvir is approximately 20 - 40 l after a single 600 mg dose. The protein binding of Busvir in human plasma is approximately 98 - 99% and is constant over the concentration range of 1.0 - 100 µ g /ml. Busvir binds to both human alpha 1-acid glycoprotein (AAG) and human serum albumin (HSA) with comparable affinities.

Tissue distribution studies with ¹⁴C-labelled Busvir in rats showed the liver, adrenals, pancreas, kidneys and thyroid to have the highest concentrations of Busvir. Tissue to plasma ratios of approximately 1 measured in rat lymph nodes suggests that Busvir distributes into lymphatic tissues. Busvir penetrates minimally into the brain.

Metabolism

Busvir was noted to be extensively metabolised by the hepatic cytochrome P450 system, primarily by the CYP3A isozyme family and to a lesser extent by the CYP2D6 isoform. Animal studies as well as in vitro experiments with human hepatic microsomes indicated that Busvir primarily underwent oxidative metabolism. Four Busvir metabolites have been identified in man. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent compound. However, the AUC of the M-2 metabolite was approximately 3% of the AUC of parent compound.

Low doses of Busvir have shown profound effects on the pharmacokinetics of other Protease inhibitors and other products metabolised by CYP3A4) and other Protease inhibitors may influence the pharmacokinetics of Busvir.

Elimination

Human studies with radiolabelled Busvir demonstrated that the elimination of Busvir was primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, part of which is expected to be unabsorbed Busvir. In these studies renal elimination was not found to be a major route of elimination of Busvir. This was consistent with the observations in animal studies.

Special Populations

No clinically significant differences in AUC or C_max were noted between males and females. Busvir pharmacokinetic parameters were not statistically significantly associated with body weight or lean body mass. Busvir plasma exposures in patients 50 - 70 years of age when dosed 100 mg in combination with lopinavir or at higher doses in the absence of other Protease inhibitors is similar to that observed in younger adults.

Patients with impaired liver function

After multiple dosing of Busvir to healthy volunteers (500 mg twice daily) and subjects with mild to moderate hepatic impairment (Child Pugh Class A and B, 400 mg twice daily) exposure to Busvir after dose normalisation was not significantly different between the two groups.

Patients with impaired renal function

Busvir pharmacokinetic parameters have not been studied in patients with renal impairment. However, since the renal clearance of Busvir is negligible, no changes in the total body clearance are expected in patients with renal impairment.

Paediatric patients

Busvir steady-state pharmacokinetic parameters were evaluated in HIV infected children above 2 years of age receiving doses ranging from 250 mg/m² twice daily to 400 mg/m² twice daily. Busvir concentrations obtained after 350 to 400 mg/m² twice daily in paediatric patients were comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m²) twice daily. Across dose groups, Busvir oral clearance (CL/F/m²) was approximately 1.5 to 1.7 times faster in paediatric patients above 2 years of age than in adult subjects.

Busvir steady-state pharmacokinetic parameters were evaluated in HIV infected children less than 2 years of age receiving doses ranging from 350 to 450 mg/m² twice daily. Busvir concentrations in this study were highly variable and somewhat lower than those obtained in adults receiving 600 mg (approximately 330 mg/m²) twice daily. Across dose groups, Busvir oral clearance (CL/F/m²) declined with age with median values of 9.0 L/h/m² in children less than 3 months of age, 7.8 L/h/m² in children between 3 and 6 months of age and 4.4 L/h/m² in children between 6 and 24 months of age.

Repeated dose toxicity studies in animals identified major target organs as the liver, retina, thyroid gland and kidney. Hepatic changes involved hepatocellular, biliary and phagocytic elements and were accompanied by increases in hepatic enzymes. Hyperplasia of the retinal pigment epithelium (RPE) and retinal degeneration have been seen in all of the rodent studies conducted with ritonavir, but have not been seen in dogs. Ultrastructural evidence suggests that these retinal changes may be secondary to phospholipidosis. However, clinical trials revealed no evidence of medicinal product-induced ocular changes in humans. All thyroid changes were reversible upon discontinuation of ritonavir. Clinical investigation in humans has revealed no clinically significant alteration in thyroid function tests. Renal changes including tubular degeneration, chronic inflammation and proteinurea were noted in rats and are felt to be attributable to species-specific spontaneous disease. Furthermore, no clinically significant renal abnormalities were noted in clinical trials.

Developmental toxicity observed in rats (embryolethality, decreased foetal body weight and ossification delays and visceral changes, including delayed testicular descent) occurred mainly at a maternally toxic dosage. Developmental toxicity in rabbits (embryolethality, decreased litter size and decreased foetal weights) occurred at a maternally toxic dosage.

Ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Long term carcinogenicity studies of ritonavir in mice and rats revealed tumourigenic potential specific for these species, but are regarded as of no relevance for humans.

Repeated dose toxicity studies in animals identified major target organs as the liver, retina, thyroid gland and kidney. Hepatic changes involved hepatocellular, biliary and phagocytic elements and were accompanied by increases in hepatic enzymes. Hyperplasia of the retinal pigment epithelium (RPE) and retinal degeneration have been seen in all of the rodent studies conducted with Busvir, but have not been seen in dogs. Ultrastructural evidence suggests that these retinal changes may be secondary to phospholipidosis. However, clinical trials revealed no evidence of medicinal product-induced ocular changes in humans. All thyroid changes were reversible upon discontinuation of Busvir. Clinical investigation in humans has revealed no clinically significant alteration in thyroid function tests. Renal changes including tubular degeneration, chronic inflammation and proteinurea were noted in rats and are felt to be attributable to species-specific spontaneous disease. Furthermore, no clinically significant renal abnormalities were noted in clinical trials.

Developmental toxicity observed in rats (embryolethality, decreased foetal body weight and ossification delays and visceral changes, including delayed testicular descent) occurred mainly at a maternally toxic dosage. Developmental toxicity in rabbits (embryolethality, decreased litter size and decreased foetal weights) occurred at a maternally toxic dosage.

Busvir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and Escherichia coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Long term carcinogenicity studies of Busvir in mice and rats revealed tumourigenic potential specific for these species, but are regarded as of no relevance for humans.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements