4.1. Therapeutic indications

Ritonavir is indicated as a pharmacokinetic enhancer of co-administered protease inhibitors as part of antiretroviral combination therapy in human immunodeficiency virus-1 (HIV-1) infected patients (adults and children of 2 years of age and older).

4.2. Posology and method of administration

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

Ritonavir film-coated tablets are administered orally and should be ingested with food (see section 5.2).

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

Posology

Ritonavir is no longer recommended in clinical practice at the antiretroviral dose of 1 200 mg (600 mg twice daily).

Ritonavir's use as a pharmacokinetic enhancer of other protease inhibitors is the prevalent use in clinical practice. Ritonavir's Product Information has been updated to reflect its common use as a pharmacokinetic enhancer of concomitantly administered antiviral agents. Previous information that was generated when used as an antiretroviral agent is retained as this is still considered clinically relevant.

Ritonavir dosed as a pharmacokinetic enhancer

When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors 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 ritonavir as a pharmacokinetic enhancer at the noted doses.

Adults

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.

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 SmPC 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 SmPC of other Protease Inhibitors approved for co-administration with ritonavir.

Special populations

Elderly

Pharmacokinetic data indicated that no dose adjustment is necessary for elderly patients (see section 5.2). For specific dosing information for the co-administered protease inhibitor in elderly patients, refer to the SmPC of the co-administered protease inhibitor.

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 SmPC of the co-administered protease inhibitor.

Hepatic impairment

Ritonavir should not be given as a pharmacokinetic enhancer to patients with decompensated liver disease, (see section 4.3). 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 protease inhibitor 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 SmPC of the co-administered protease inhibitor should be reviewed for specific dosing information in this patient population.

Paediatric population

The safety and efficacy of Norvir in children aged below 2 years has not been established. Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

When ritonavir is used as a pharmacokinetic enhancer of other protease inhibitors, consult the SmPC of the co-administered protease inhibitor for contraindications.

Ritonavir should not be given 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 enzyme-modulating effect of ritonavir may be dose dependent (see section 5.1). 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.

Medicinal Product Class

Medicinal Products within Class

Rationale

Concomitant medicinal product levels increased or decreased

α1-Adrenoreceptor Antagonist

Alfuzosin

Increased plasma concentrations of alfuzosin which may lead to severe hypotension (see section 4.5).

Analgesics

Pethidine, propoxyphene

Increased plasma concentrations of norpethidine and propoxyphene. Thereby, increasing the risk of serious respiratory depression or haematologic abnormalities, or other serious adverse effects from these agents.

Antianginal

Ranolazine

Increased plasma concentrations of ranolazine which may increase the potential for serious and/or life-threatening reactions (see section 4.5).

Anticancer

Neratinib

Increased plasma concentrations of neratinib which may increase the potential for serious and/or life-threatening reactions including hepatotoxicity (see section 4.5).

Venetoclax

Increased plasma concentrations of venetoclax. Increased risk of tumor lysis syndrome at the dose initiation and during the dose-titration phase (see section 4.5).

Antiarrhythmics

Amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine

Increased plasma concentrations of amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine. Thereby, increasing the risk of arrhythmias or other serious adverse effects from these agents.

Antibiotic

Fusidic Acid

Increased plasma concentrations of fusidic acid and ritonavir.

Antihistamines

Astemizole, terfenadine

Increased plasma concentrations of astemizole and terfenadine. Thereby, increasing the risk of serious arrhythmias from these agents.

Anti-gout

Colchicine

Potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment (see sections 4.4 and 4.5).

Antipsychotics/ Neuroleptics

Lurasidone

Increased plasma concentrations of lurasidone which may increase the potential for serious and/or life-threatening reactions (see section 4.5).

Clozapine, pimozide

Increased plasma concentrations of clozapine and pimozide. Thereby, increasing the risk of serious haematologic abnormalities, or other serious adverse effects from these agents.

Quetiapine

Increased plasma concentrations of quetiapine which may lead to coma. The concomitant administration with quetiapine is contraindicated (see section 4.5).

Ergot Derivatives

Dihydroergotamine, ergonovine, ergotamine, methylergonovine

Increased plasma concentrations of ergot derivatives leading to acute ergot toxicity, including vasospasm and ischaemia.

GI motility agent

Cisapride

Increased plasma concentrations of cisapride. Thereby, increasing the risk of serious arrhythmias from this agent.

Lipid-modifying agents

HMG Co-A Reductase Inhibitors

Lovastatin, simvastatin

Increased plasma concentrations of lovastatin and simvastatin; thereby, increasing the risk of myopathy including rhabdomyolysis (see section 4.5).

Microsomal triglyceride transfer protein (MTTP) inhibitor

Lomitapide

Increased plasma concentrations of lomitapide (see section 4.5).

PDE5 inhibitor

Avanafil

Increased plasma concentrations of avanafil (see section 4.4. and 4.5).

Sildenafil

Contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) only. Increased plasma concentrations of sildenafil. Thereby, increasing the potential for sildenafil-associated adverse events (which include hypotension and syncope). See section 4.4 and section 4.5 for co-administration of sildenafil in patients with erectile dysfunction.

Vardenafil

Increased plasma concentrations of vardenafil (see section 4.4. and 4.5).

Sedatives/hypnotics

Clorazepate, diazepam, estazolam, flurazepam, oral midazolam and triazolam

Increased plasma concentrations of clorazepate, diazepam, estazolam, flurazepam, oral midazolam and triazolam. Thereby, increasing the risk of extreme sedation and respiratory depression from these agents. (For caution on parenterally administered midazolam, see section 4.5.).

Ritonavir medicinal product level decreased

Herbal Preparation

St. John's Wort

Herbal preparations containing St John's wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of ritonavir (see section 4.5).

4.4. Special warnings and precautions for use

General

Ritonavir 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 SmPCfor the particular protease inhibitor must be consulted.

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.

Ritonavir dosed 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 Norvir therapy should be discontinued if a diagnosis of pancreatitis is made (see section 4.8).

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 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 and autoimmune hepatitis) 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 (see section 4.2). 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

Since the renal clearance of ritonavir is negligible, a decrease in the total body clearance of ritonavir is not expected in patients with renal impairment (see also section 4.2).

Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate (DF) in clinical practice (see section 4.8).

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 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 ritonavir. Ritonavir should be used with caution in such patients (see section 5.1).

Interactions with other medicinal products

Ritonavir dosed as a pharmacokinetic enhancer with HIV-protease inhibitors

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

For a description of the mechanisms and potential mechanisms contributing to the interaction profile of the protease inhibitors, see section 4.5. Please also review the SmPC for the particular boosted protease inhibitor.

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 200 mg once daily could be considered. In this instance, close clinical monitoring is warranted. Refer to the SmPC for atazanavir for further details.

Other non-antiretroviral medicinal products co-administered with ritonavir

The following warnings and precautions should be considered if ritonavir is used as an antiretroviral agent. When ritonavir is used as a pharmacokinetic enhancer at the 100 mg and 200 mg level it cannot be assumed that the following warnings and precautions will also apply. When ritonavir is used as a pharmacokinetic enhancer, full details on the warnings and precautions relevant to that particular protease inhibitor must be considered, therefore the SmPC, section 4.4, for the particular protease inhibitor must be consulted to determine if the information below is applicable.

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 (see section 4.5). Concomitant use of avanafil or vardenafil with ritonavir is contraindicated (see section 4.3). Concomitant use of sildenafil with ritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3).

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 (see section 4.5).

Colchicine

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A like ritonavir (see sections 4.3 and 4.5).

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 (see section 4.5).

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 oestradiol

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 (see section 4.5).

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 (see section 4.5).

Rivaroxaban

It is not recommended to use ritonavir in patients receiving rivaroxaban, due to the risk of increased bleeding (see section 4.5).

Riociguat

The concomitant use of ritonavir is not recommended due to potential increase in riociguat exposure (see section 4.5).

Vorapaxar

The concomitant use of ritonavir is not recommended due to potential increase in vorapaxar exposure (see section 4.5).

Bedaquiline

Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could potentially increase the risk of bedaquiline-related adverse reactions. Therefore, combination of bedaquiline with ritonavir should be avoided. However, if the benefit outweighs the risk, co-administration of bedaquiline with ritonavir must be done with caution. More frequent electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.5 and refer to the bedaquiline SmPC).

Delamanid

Co-administration of delamanid with a strong inhibitor of CYP3A (ritonavir) may increase exposure to delamanid metabolite, which has been associated with QTc prolongation. Therefore, if co-administration of delamanid with ritonavir is considered necessary, very frequent ECG monitoring throughout the full delamanid treatment period is recommended (see section 4.5 and refer to the delamanid SmPC).

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Ritonavir dosed as a pharmacokinetic enhancer

Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6. Co-administration of ritonavir and medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, which could increase or prolong its therapeutic and adverse effects. For selected medicinal products (e.g. alprazolam) the inhibitory effects of ritonavir on CYP3A4 may decrease over time. Ritonavir also has a high affinity for P-glycoprotein and may inhibit this transporter. The inhibitory effect of ritonavir (with or without other protease inhibitors) on P-gp activity may decrease over time (e.g. digoxin and fexofenadine-see table “Ritonavir effects on non-antiretroviral medicinal products” below). Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products metabolised by these pathways, and may result in decreased systemic exposure to such medicinal products, which could decease or shorten their therapeutic effect.

Important information regarding medicinal product interactions when ritonavir is used as a pharmacokinetic enhancer is also contained in the SmPC of the co-administered protease inhibitor.

Medicinal products that affect ritonavir levels

Serum levels of ritonavir can be reduced by concomitant use of herbal preparations containing St John's wort (Hypericum perforatum). This is due to the induction of medicinal product metabolising enzymes by St John's wort. Herbal preparations containing St John's wort must not be used in combination with ritonavir. If a patient is already taking St John's wort, St John's wort should be stopped and if possible check viral levels. Ritonavir levels may increase on stopping St John's wort. The dose of ritonavir may need adjusting. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's wort (see section 4.3).

Serum levels of ritonavir may be affected by select co-administered medicinal products (e.g. phenytoin and rifampicin). These interactions are noted in the medicinal product interaction tables below.

Medicinal products that are affected by the use of ritonavir

Interactions between ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors and other non-antiretroviral medicinal products are listed in the tables below. This list is not intended to be inclusive or comprehensive. Individual SmPCs should be consulted.

Medicinal Product Interactions – Ritonavir with Protease Inhibitors

Co-administered Medicinal Product

Dose of Co-administered Medicinal Product (mg)

Dose of NORVIR (mg)

Medicinal Product Assessed

AUC

Cmin

Atazanavir

300 q24h

100 q24h

Atazanavir

Atazanavir1

↑ 86%

↑ 2 fold

↑ 11 fold

↑ 3-7 fold

Ritonavir increases the serum levels of atazanavir as a result of CYP3A4 inhibition. Clinical trials confirmed the safety and efficacy of 300 mg atazanavir once daily with ritonavir 100 mg once daily in treatment experienced patients. For further information, physicians should refer to the SmPC for atazanavir.

Darunavir

600, single

100 q12h

Darunavir

↑ 14 fold

Ritonavir increases the serum levels of darunavir as a result of CYP3A inhibition. Darunavir must be given with ritonavir to ensure its therapeutic effect. Ritonavir doses higher than 100 mg twice daily have not been studied with darunavir. For further information, refer to the SmPC for darunavir.

Fosamprenavir

700 q12h

100 q12h

Amprenavir

↑ 2.4 fold

↑ 11 fold

Ritonavir increases the serum levels of amprenavir (from fosamprenavir) as a result of CYP3A4 inhibition. Fosamprenavir must be given with ritonavir to ensure its therapeutic effect. Clinical trials confirmed the safety and efficacy of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily. Ritonavir doses higher than 100 mg twice daily have not been studied with fosamprenavir. For further information, physicians should refer to the SmPC for fosamprenavir.

Indinavir

800 q12h

100 q12h

Indinavir2

Ritonavir

↑ 178%

↑ 72%

ND

ND

Ritonavir increases the serum levels of indinavir as a result of CYP3A4 inhibition. Appropriate doses for this combination, with respect to efficacy and safety, have not been established. Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doses higher than 100 mg twice daily. In cases of co-administration of ritonavir (100 mg twice daily) and indinavir (800 mg twice daily) caution is warranted as the risk of nephrolithiasis may be increased.

Nelfinavir

1250 q12h

100 q12h

Nelfinavir

↑ 20to39%

ND

Ritonavir increases the serum levels of nelfinavir as a result of CYP3A4 inhibition. Appropriate doses for this combination, with respect to efficacy and safety, have not been established. Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doses higher than 100 mg twice daily.

ND: Not determined.

1. Based on cross-study comparison to 400 mg atazanavir once daily alone.

2. Based on cross-study comparison to 800 mg indinavir three times daily alone.

Medicinal product interactions – Ritonavir with antiretroviral agents other than protease inhibitors

Co-administered Medicinal Product

Dose of Co-administered Medicinal Product (mg)

Dose of NORVIR (mg)

Medicinal Product Assessed

AUC

Cmin

Maraviroc

100 q12h

100 q12h

Maraviroc

↑ 161%

↑ 28%

Ritonavir increases the serum levels of maraviroc as a result of CYP3A inhibition. Maraviroc may be given with ritonavir to increase the maraviroc exposure. For further information, refer to the SmPC for maraviroc.

Raltegravir

400 single

100 q12h

Raltegravir

↓ 16%

↓ 1%

Co-adminsitration of ritonavir and raltegravir results in a minor reduction in raltegravir levels

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products

Dose of Co-administered Medicinal Products (mg)

Dose of NORVIR (mg)

Effect on Co-administered Medicinal Products AUC

Effect on Co-administered Medicinal Products Cmax

Alpha1-Adrenoreceptor Antagonist

Alfuzosin

Ritonavir co-administration is likely to result in increased plasma concentrations of alfuzosin and is therefore contraindicated (see section 4.3).

Amphetamine Derivatives

Amphetamine

Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 and as a result is expected to increase concentrations of amphetamine and its derivatives. Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with antiretroviral doses of ritonavir (see section 4.4).

Analgesics

Buprenorphine

Norbuprenorphine

Glucuronide metabolites

16 q24h

100 q12h

↑ 57%

↑ 33%

↔

↑ 77%

↑ 108%

↔

The increases of plasma levels of buprenorphine and its active metabolite did not lead to clinically significant pharmacodynamic changes in a population of opioid tolerant patients. Adjustment to the dose of buprenorphine or ritonavir may therefore not be necessary when the two are dosed together. When ritonavir is used in combination with another protease inhibitor and buprenorphine, the SmPC of the co-administered protease inhibitor should be reviewed for specific dosing information.

Pethidine, propoxyphene

Ritonavir co-administration is likely to result in increased plasma concentrations of norpethidine and propoxyphene and is therefore contraindicated (see section 4.3).

Fentanyl

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of fentanyl. Careful monitoring of therapeutic and adverse effects (including respiratory depression) is recommended when fentanyl is concomitantly administered with ritonavir.

Methadone1

5, single dose

500 q12h,

↓ 36%

↓ 38%

Increased methadone dose may be necessary when concomitantly administered with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer due to induction of glucuronidation. Dose adjustment should be considered based on the patient's clinical response to methadone therapy.

Morphine

Morphine levels may be decreased due to induction of glucuronidation by co-administered ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer.

Antianginal

Ranolazine

Due to CYP3A inhibition by ritonavir, concentrations of ranolazine are expected to increase. The concomitant administration with ranolazine is contraindicated (see section 4.3).

Antiarrthymics

Amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine

Ritonavir co-administration is likely to result in increased plasma concentrations of amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, and quinidine and is therefore contraindicated (see section 4.3).

Digoxin

0.5 single IV dose

0.4 single oral dose

300 q12h, 3 days

200 q12h, 13 days

↑ 86%

↑ 22%

ND

↔

This interaction may be due to modification of P-glycoprotein mediated digoxin efflux by ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer. Increased digoxin levels observed in patients receiving ritonavir may lessen over time as induction develops (see section 4.4).

Antiasthmatic

Theophylline1

3 mg/kg q8h

500 q12h

↓ 43%

↓ 32%

An increased dose of theophyline may be required when co-administered with ritonavir, due to induction of CYP1A2.

Anticancer agents and kinase inhibitors

Afatinib

20 mg, single dose

40 mg, single dose

40 mg, single dose

200 q12h/1h before

200 q12h/ co-administered

200 q12h/6h after

↑ 48%

↑ 19%

↑ 11%

↑ 39%

↑ 4%

↑ 5%

Serum concentrations may be increased due to Breast Cancer Resistance Protein (BCRP) and acute P-gp inhibition by ritonavir. The extent of increase in AUC and Cmax depends on the timing of ritonavir administration. Caution should be exercised in administering afatinib with ritonavir (refer to the afatinib SmPC). Monitor for ADRs related to afatinib.

Abemaciclib

Serum concentrations may be increased due to CYP3A4 inhibition by ritonavir.

Co-administration of abemaciclib and ritonavir should be avoided. If this co-administration is judged unavoidable, refer to the abemaciclib SmPC for dosage adjustment recommendations. Monitor for ADRs related to abemaciclib.

Apalutamide

Apalutamide is a moderate to strong CYP3A4 inducer and this may lead to a decreased exposure of ritonavir and potential loss of virologic response. In addition, serum concentrations may be increased when co-administered with ritonavir resulting in the potential for serious adverse events including seizure.

Concomitant use of ritonavir with apalutamide is not recommended.

Ceritinib

Serum concentrations may be increased due to CYP3A and P-gp inhibition by ritonavir. Caution should be exercised in administering ceritinib with ritonavir. Refer to the ceritinib SmPC for dosage adjustment recommendations. Monitor for ADRs related to ceritinib.

Dasatinib, nilotinib, vincristine, vinblastine

Serum concentrations may be increased when co-administered with ritonavir resulting in the potential for increased incidence of adverse reactions.

Encorafenib

Serum concentrations may be increased when co-administered with ritonavir which may increase the risk of toxicity, including the risk of serious adverse events such as QT interval prolongation. Co-administration of encorafenib and ritonavir should be avoided. If the benefit is considered to outweigh the risk and ritonavir must be used, patients should be carefully monitored for safety.

Fostamatinib

Co-administration of fostamatinib with ritonavir may increase fostamatinib metabolite R406 exposure resulting in dose-related adverse events such as hepatotoxicity, neutropenia, hypertension, or diarrhoea. Refer to the fostamatinib SmPC for dose reduction recommendations if such events occur.

Ibrutinib

Serum concentrations of ibrutinib may be increased due to CYP3A inhibition by ritonavir, resulting in increased risk for toxicity including risk of tumor lysis syndrome. Co-administration of ibrutinib and ritonavir should be avoided. If the benefit is considered to outweigh the risk and ritonavir must be used, reduce the ibrutinib dose to 140 mg and monitor patient closely for toxicity.

Neratinib

Serum concentrations may be increased due to CYP3A4 inhibition by ritonavir.

Concomitant use of neratinib with ritonavir is contraindicated due to serious and/or life-threatening potential reactions including hepatotoxicity (see section 4.3).

Venetoclax

Serum concentrations may be increased due to CYP3A inhibition by ritonavir, resulting in increased risk of tumor lysis syndrome at the dose initiation and during the ramp-up phase (see section 4.3 and refer to the venetoclax SmPC).

For patients who have completed the ramp-up phase and are on a steady daily dose of venetoclax, reduce the venetoclax dose by at least 75% when used with strong CYP3A inhibitors (refer to the venetoclax SmPC for dosing instructions).

Anticoagulants

Dabigatran etexilate

Edoxaban

Serum concentrations may be increased due to P-gp inhibition by ritonavir. Clinical monitoring and/or dose reduction of the direct oral anticoagulants (DOAC) should be considered when a DOAC transported by P-gp but not metabolised by CYP3A4, including dabigatran etexilate and edoxaban, is co-administered with ritonavir.

Rivaroxaban

10, single dose

600 q12h

↑ 153%

↑ 55%

Inhibition of CYP3A and P-gp lead to increased plasma levels and pharmacodynamic effects of rivaroxaban which may lead to an increased bleeding risk. Therefore, the use of ritonavir is not recommended in patients receiving rivaroxaban.

Vorapaxar

Serum concentrations may be increased due to CYP3A inhibition by ritonavir. The co-administration of vorapaxar with ritonavir is not recommended (see section 4.4 and refer to the vorapaxar SmPC).

Warfarin

S-Warfarin

R-Warfarin

5, single dose

400 q12h

↑ 9%

↓ 33%

↓ 9%

↔

Induction of CYP1A2 and CYP2C9 lead to decreased levels of R-warfarin while little pharmacokinetic effect is noted on S- warfarin when co-administered with ritonavir. Decreased R-warfarin levels may lead to reduced anticoagulation, therefore it is recommended that anticoagulation parameters are monitored when warfarin is co-administered with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer.

Anticonvulsants

Carbamazepine

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of carbamazepine. Careful monitoring of therapeutic and adverse effects is recommended when carbamazepine is concomitantly administered with ritonavir.

Divalproex, lamotrigine, phenytoin

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent induces oxidation by CYP2C9 and glucuronidation and as a result is expected to decrease the plasma concentrations of anticonvulsants. Careful monitoring of serum levels or therapeutic effects is recommended when these medicines are concomitantly administered with ritonavir. Phenytoin may decrease serum levels of ritonavir.

Antidepressants

Amitriptyline, fluoxetine, imipramine, nortriptyline, paroxetine, sertraline

Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 and as a result is expected to increase concentrations of imipramine, amitriptyline, nortriptyline, fluoxetine, paroxetine or sertraline. Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with antiretroviral doses of ritonavir (see section 4.4).

Desipramine

100, single oral dose

500 q12h

↑ 145%

↑ 22%

The AUC and Cmax of the 2-hydroxy metabolite were decreased 15 and 67%, respectively. Dosage reduction of desipramine is recommended when co-administered with ritonavir dosed as an antiretroviral agent.

Trazodone

50, single dose

200 q12h

↑ 2.4-fold

↑ 34%

An increase in the incidence in trazodone-related adverse reactions was noted when co-administered with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer. If trazodone is co-administered with ritonavir, the combination should be used with caution, initiating trazodone at the lowest dosage and monitoring for clinical response and tolerability.

Anti-gout treatments

Colchicine

Concentrations of colchicine are expected to increase when coadministered with ritonavir.

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and ritonavir (CYP3A4 and P-gp inhibition) in patients with renal and/or hepatic impairment (see sections 4.3 and 4.4). Refer to the colchicine SmPC.

Antihistamines

Astemizole, terfenadine

Ritonavir co-administration is likely to result in increased plasma concentrations of astemizole and terfenadine and is therefore contraindicated (see section 4.3).

Fexofenadine

Ritonavir may modify P-glycoprotein mediated fexofenadine efflux when dosed as an antriretroviral agent or as a pharmacokinetic enhancer resulting in increased concentrations of fexofenadine. Increased fexofenadine levels may lessen over time as induction develops.

Loratadine

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A and as a result is expected to increase the plasma concentrations of loratadine. Careful monitoring of therapeutic and adverse effects is recommended when loratidine is concomitantly administered with ritonavir.

Anti-infectives

Fusidic Acid

Ritonavir co-administration is likely to result in increased plasma concentrations of both fusidic acid and ritonavir and is therefore contraindicated (see section 4.3).

Rifabutin1

25-O-desacetyl rifabutin metabolite

150 daily

500 q12h,

↑ 4-fold

↑ 38-fold

↑ 2.5-fold

↑ 16-fold

The reduction of the rifabutin dose to 150 mg 3 times per week may be indicated for select PIs when co-administered with ritonavir as a pharmacokinetic enhancer. The SmPCof the co-administered protease inhibitor should be consulted for specific recommendations. Consideration should be given to official guidance on the appropriate treatment of tuberculosis in HIV-infected patients.

Rifampicin

Although rifampicin may induce metabolism of ritonavir, limited data indicate that when high doses of ritonavir (600 mg twice daily) is co-administered with rifampicin, the additional inducing effect of rifampicin (next to that of ritonavir itself) is small and may have no clinical relevant effect on ritonavir levels in high-dose ritonavir therapy. The effect of ritonavir on rifampicin is not known.

Voriconazole

200 q12h

100 q12h

↓ 39%

↓ 24%

Co-administration of voriconazole and ritonavir dosed as a pharmacokinetic enhancer should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

Atovaquone

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent induces glucuronidation and as a result is expected to decrease the plasma concentrations of atovaquone. Careful monitoring of serum levels or therapeutic effects is recommended when atovaquone is concomitantly administered with ritonavir.

Bedaquiline

No interaction study is available with ritonavir only. In an interaction study of single-dose bedaquiline and multiple dose lopinavir/ritonavir, the AUC of bedaquiline was increased by 22%. This increase is likely due to ritonavir and a more pronounced effect may be observed during prolonged co-administration. Due to the risk of bedaquiline related adverse events, co-administration should be avoided. If the benefit outweighs the risk, co-administration of bedaquiline with ritonavir must be done with caution. More frequent electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.4 and refer to the bedaquiline SmPC).

Clarithromycin

14-OH clarithromycin metabolite

500 q12h

200 q8h

↑ 77%

↓ 100%

↑ 31%

↓ 99%

Due to the large therapeutic window of clarithromycin no dose reduction should be necessary in patients with normal renal function. Clarithromycin doses greater than 1 g per day should not be co-administered with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer. For patients with renal impairment, a clarithromycin dose reduction should be considered: for patients with creatinine clearance of 30 to 60 ml/min the dose should be reduced by 50%, for patients with creatinine clearance less than 30 ml/min the dose should be reduced by 75%.

Delamanid

No interaction study is available with ritonavir only. In a healthy volunteer drug interaction study of delamanid 100 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily for 14 days, the exposure of the delamanid metabolite DM-6705 was 30% increased. Due to the risk of QTc prolongation associated with DM-6705, if co-administration of delamanid with ritonavir is considered necessary, very frequent ECG monitoring throughout the full delamanid treatment period is recommended (see section 4.4 and refer to the delamanidSmPC).

Erythromycin, itraconazole

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of erythromycin and itraconazole. Careful monitoring of therapeutic and adverse effects is recommended when erythromycin or itraconazole is used concomitantly administered with ritonavir.

Ketoconazole

200 daily

500 q12h

↑ 3.4-fold

↑ 55%

Ritonavir inhibits CYP3A-mediated metabolism of ketoconazole. Due to an increased incidence of gastrointestinal and hepatic adverse reactions, a dose reduction of ketoconazole should be considered when co-administered with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer.

Sulfamethoxazole/Trimethoprim2

800/160, single dose

500 q12h

↓ 20% / ↑ 20%

↔

Dose alteration of sulfamethoxazole/trimethoprim during concomitant ritonavir therapy should not be necessary.

Antipsychotics/Neuroleptics

Clozapine, pimozide

Ritonavir co-administration is likely to result in increased plasma concentrations of clozapine or pimozide and is therefore contraindicated (see section 4.3).

Haloperidol, risperidone, thioridazine

Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 and as a result is expected to increase concentrations of haloperidol, risperidone and thioridazine. Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with antiretroviral doses of ritonavir.

Lurasidone

Due to CYP3A inhibition by ritonavir, concentrations of lurasidone are expected to increase. The concomitant administration with lurasidone is contraindicated (see section 4.3).

Quetiapine

Due to CYP3A inhibition by ritonavir, concentrations of quetiapine are expected to increase. Concomitant administration of ritonavir and quetiapine is contraindicated as it may increase quetiapine-related toxicity (see section 4.3).

β2-agonist (long acting)

Salmeterol

Ritonavir inhibits CYP3A4 and as a result a pronounced increase in the plasma concentrations of salmeterol is expected. Therefore concomitant use is not recommended.

Calcium channel antagonists

Amlodipine, diltiazem, nifedipine

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of calcium channel antagonists. Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with ritonavir.

Endothelin antagonists

Bosentan

Co-administration of bosentan and ritonavir may increase steady state bosentan maximum concentr ations (Cmax) and area under the curve (AUC).

Riociguat

Serum concentrations may be increased due to CYP3A and P-gp inhibition by ritonavir. The co-administration of riociguat with ritonavir is not recommended (see section 4.4 and refer to riociguat SmPC).

Ergot Derivatives

Dihydroergotamine, ergonovine, ergotamine, methylergonovine

Ritonavir co-administration is likely to result in increased plasma concentrations of ergot derivatives and is therefore contraindicated (see section 4.3).

GI motility agent

Cisapride

Ritonavir co-administration is likely to result in increased plasma concentrations of cisapride and is therefore contraindicated (see section 4.3).

HCV Direct Acting Antiviral

Glecaprevir/pibrentasvir

Serum concentrations may be increased due to P-glycoprotein, BCRP and OATP1B inhibition by ritonavir.

Concomitant administration of glecaprevir/pibrentasvir and ritonavir is not recommended due to an increased risk of ALT elevations associated with increased glecaprevir exposure.

HCV Protease Inhibitor

Simeprevir

200 qd

100 q12h

↑ 7.2-fold

↑ 4.7-fold

Ritonavir increases plasma concentrations of simeprevir as a result of CYP3A4 inhibition. It is not recommended to co-administer ritonavir with simeprevir.

HMG Co-A Reductase Inhibitors

Atorvastatin, Fluvastatin, Lovastatin, Pravstatin, Rosuvastatin, Simvastatin

HMG-CoA reductase inhibitors which are highly dependent on CYP3A metabolism, such as lovastatin and simvastatin, are expected to have markedly increased plasma concentrations when co-administered with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer. Since increased concentrations of lovastatin and simvastatin may predispose patients to myopathies, including rhabdomyolysis, the combination of these medicinal products with ritonavir is contraindicated (see section 4.3). Atorvastatin is less dependent on CYP3A for metabolism. 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 possible doses of atorvastatin or rosuvastatin should be administered. The metabolism of pravastatin and fluvastatin is not dependent on CYP3A, and interactions are not expected with ritonavir. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.

Hormonal contraceptive

Ethinyl oestradiol

50 µg, single dose

500 q12h

↓ 40%

↓ 32%

Due to reductions in ethinyl oestradiol concentrations, barrier or other non-hormonal methods of contraception should be considered with concomitant ritonavir use when dosed as an antiretroviral agent or as a pharmacokinetic enhancer. Ritonavir is likely to change the uterine bleeding profile and reduce the effectiveness of estradiol-containing contraceptives (see section 4.4).

Immunosupressants

Cyclosporine, tacrolimus, everolimus

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of cyclosporine, tacrolimus or everolimus. Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with ritonavir.

Lipid-modifying agents

Lomitapide

CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Due to CYP3A inhibition by ritonavir, concentrations of lomitapide are expected to increase. Concomitant use of ritonavir with lomitapide is contraindicated (see SmPC for lomitapide) (see section 4.3).

Phosphodiesterase (PDE5) inhibitors

Avanafil

50, single dose

600 q12h

↑ 13-fold

↑ 2.4-fold

Concomitant use of avanafil with ritonavir is contraindicated (see section 4.3).

Sildenafil

100, single dose

500 q12h

↑ 11-fold

↑ 4-fold

Concomitant use of sildenafil for the treatment of erectile dysfunction with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer should be with caution and in no instance should sildenafil doses exceed 25 mg in 48 hours (see also section 4.4). Concomitant use of sildenafil with ritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3).

Tadalafil

20, single dose

200 q12h

↑ 124%

↔

The concomitant use of tadalafil for the treatment of erectile dysfunction with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer should be with caution at reduced doses of no more than 10 mg tadalafil every 72 hours with increased monitoring for adverse reactions (see section 4.4).

When tadalafil is used concurrently with ritonavir in patients with pulmonary arterial hypertension, refer to the tadalafil SmPC.

Vardenafil

5, single dose

600 q12h

↑ 49-fold

↑ 13-fold

Concomitant use of vardenafil with ritonavir is contraindicated (see section 4.3).

Sedatives/hypnotics

Clorazepate, diazepam, estazolam, flurazepam, oral and parenteral midazolam

Ritonavir co-administration is likely to result in increased plasma concentrations of clorazepate, diazepam, estazolam and flurazepam and is therefore contraindicated (see section 4.3).

Midazolam is extensively metabolised by CYP3A4. Co-administration with ritonavir may cause a large increase in the concentration of this benzodiazepine. No medicinal product interaction study has been performed for the co-administration of ritonavir 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, ritonavir should not be co-administered with orally administered midazolam (see section 4.3), whereas caution should be used with co-administration of ritonavir 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 ritonaviris 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.

Triazolam

0.125, single dose

200, 4 doses

↑ > 20 fold

↑ 87%

Ritonavir co-administration is likely to result in increased plasma concentrations of triazolam and is therefore contraindicated (see section 4.3).

Pethidine

Norpethidine metabolite

50, oral single dose

500 q12h

↓ 62%

↑ 47%

↓ 59%

↑ 87%

The use of pethidine and ritonavir is contraindicated due to the increased concentrations of the metabolite, norpethidine, which has both analgesic and CNS stimulant activity. Elevated norpethidine concentrations may increase the risk of CNS effects (e.g., seizures), see section 4.3.

Alprazolam

1, single dose

200 q12h, 2 days

500 q12h, 10 days

↑ 2.5 fold

↓ 12%

↔

↓ 16%

Alprazolam metabolism was inhibited following the introduction of ritonavir. After ritonavir use for 10 days, no inhibitory effect of ritonavir was observed. Caution is warranted during the first several days when alprazolam is co-administered with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer, before induction of alprazolam metabolism develops.

Buspirone

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A and as a result is expected to increase the plasma concentrations of buspirone. Careful monitoring of therapeutic and adverse effects is recommended when buspirone concomitantly administered with ritonavir.

Sleeping agent

Zolpidem

5

200, 4 doses

↑ 28%

↑ 22%

Zolpidem and ritonavir may be co-administered with careful monitoring for excessive sedative effects.

Smoke cessation

Bupropion

150

150

100 q12h

600 q12h

↓ 22%

↓ 66%

↓ 21%

↓ 62%

Bupropion is primarily metabolised by CYP2B6. Concurrent administration of bupropion with repeated doses of ritonavir is expected to decrease bupropion levels. These effects are thought to represent induction of bupropion metabolism. However, because ritonavir has also been shown to inhibit CYP2B6 in vitro, the recommended dose of bupropion should not be exceeded. In contrast to long-term administration of ritonavir, there was no significant interaction with bupropion after short-term administration of low doses of ritonavir (200 mg twice daily for 2 days), suggesting reductions in bupropion concentrations may have onset several days after initiation of ritonavir co-administration.

Steroids

Inhaled, injectable or intranasal fluticasone propionate, budesonide, triamcinolone

Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression (plasma cortisol levels were noted to be decreased 86% in the above study) have been reported in patients receiving ritonavir and inhaled or intranasal fluticasone propionate; similar effects could also occur with other corticosteroids metabolised by CYP3A e.g., budesonide and triamcinolone. Consequently, concomitant administration of ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4). A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g., beclomethasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may be required over a longer period.

Dexamethasone

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A and as a result is expected to increase the plasma concentrations of dexamethasone. Careful monitoring of therapeutic and adverse effects is recommended when dexamethasone is concomitantly administered with ritonavir.

Prednisolone

20

200 q12h

↑ 28%

↑ 9%

Careful monitoring of therapeutic and adverse effects is recommended when prednisolone is concomitantly administered with ritonavir. The AUC of the metabolite prednisolone increased by 37 and 28% after 4 and 14 days ritonavir, respectively.

Thyroid hormone replacement therapy

Levothyroxine

Post-marketing cases have been reported indicating a potential interaction between ritonavir containing products and levothyroxine. Thyroid-stimulating hormone (TSH) should be monitored in patients treated with levothyroxine at least the first month after starting and/or ending ritonavir treatment.

ND: Not determined

1. Based on a parallel group comparison

2. Sulfamethoxazole was co-administered with trimethoprim.

Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine or nefazodone. The possibility of medicinal product interaction cannot be excluded.

In addition to the interactions listed above, as ritonavir is highly protein bound, the possibility of increased therapeutic and toxic effects due to protein binding displacement of concomitant medicinal products should be considered.

Ritonavir dosed as a pharmacokinetic enhancer

Important information regarding medicinal product interactions when ritonavir is used a pharmacokinetic enhancer is also contained in the SmPC of the co-administered protease inhibitor.

Proton pump inhibitors and H2-receptor antagonists

Proton pump inhibitors and H2-receptor antagonists (e.g. omeprazole or ranitidine) may reduce concentrations for co-administered protease inhibitors. For specific information regarding the impact of co-administration of acid reducing agents, refer to the Summary of Product Characteristics of the co-administered protease inhibitor. Based on interaction studies with the ritonavir boosted protease inhibitors (lopinavir/ritonavir, atazanavir), concurrent administration of omeprazole or ranitidine does not significantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change of exposure (about 6 - 18%).

4.6. Fertility, pregnancy and lactation

Pregnancy

A large amount (6100 live births) of pregnant women were exposed to ritonavir during pregnancy; of these, 2800 live births were exposed during the first trimester. These data largely refer to exposures where ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower doses as a pharmacokinetic enhancer for other PIs. These data indicate no increase in the rate of birth defects compared to rates observed in population-based birth defect surveillance systems. Animal data have shown reproductive toxicity (see section 5.3). Norvir can be used during pregnancy if clinically needed.

Ritonavir adversely interacts with oral contraceptives (OCs). Therefore, an alternative, effective and safe method of contraception should be used during treatment.

Breast-feeding

Limited published data reports that ritonavir is present in human milk.

There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-postive infants) and (3) serious adverse reactions in a breastfed infant, women living with HIV should not breastfeed their infants if they are receiving Norvir.

Fertility

No human data on the effect of ritonavir on fertility are available. Animal studies do not indicate harmful effects of ritonavir on fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Dizziness is a known undesirable effect that should be taken into account when driving or using machinery.

4.8. Undesirable effects

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 protease inhibitor. For information on adverse reactions refer to the SmPC of the specific co-administered protease inhibitor.

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 (≥ 1/1 000 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.

Adverse reactions in clinical studies and post-marketing in adult patients

System Order Class

Frequency

Adverse reaction

Blood and lymphatic system disorders

Common

Decreased white blood cells, decreased haemoglobin, decreased neutrophils, increased eosinophils, thrombocytopenia

Uncommon

Increased neutrophils

Immune system disorders

Common

Hypersensitivity including urticaria, and face oedema

Rare

Anaphylaxis

Metabolism and nutrition disorders

Common

Hypercholesterolaemia, hypertriglyceridaemia, gout, oedema and peripheral oedema, dehydration (usually associated with gastrointestinal symptoms)

Uncommon

Diabetes mellitus

Rare

Hyperglycaemia

Nervous system disorders

Very common

Dysgeusia, oral and peripheral paraesthesia, headache, dizziness, peripheral neuropathy

Common

Insomnia, anxiety, confusion, disturbance in attention, syncope, seizure

Eye disorders

Common

Blurred vision

Cardiac disorders

Uncommon

Myocardial infarction

Vascular disorders

Common

Hypertension, hypotension including orthostatic hypotension, peripheral coldness

Respiratory, thoracic and mediastinal disorders

Very common

Pharyngitis, oropharyngeal pain, cough

Gastrointestinal disorders

Very common

Abdominal pain (upper and lower), nausea, diarrhoea (including severe with electrolyte imbalance), vomiting, dyspepsia

Common

Anorexia, flatulence, mouth ulcer, gastrointestinal haemorrhage, gastroesophageal reflux disease, pancreatitis

Hepatobiliary disorders

Common

Hepatitis (including increased AST, ALT, GGT), blood bilirubin increased (including jaundice)

Skin and subcutaneous tissue disorders

Very common

Pruritus, rash (including erythematous and maculopapular)

Common

Acne

Rare

Stevens Johnson syndrome, toxic epidermal necrolysis (TEN)

Musculosketal and connective tissue disorders

Very common

Arthralgia and back pain

Common

Myositis, rhabdomyolysis, myalgia, myopathy/CPK increased

Renal and urinary disorders

Common

Increased urination, renal impairment (e.g. oliguria, elevated creatinine)

Uncommon

Acute renal failure

Not known

Nephrolithiasis

Reproductive system and breast disorders

Common

Menorrhagia

General disorders and administration site conditions

Very common

Fatigue including asthenia, flushing, feeling hot

Common

Fever, weight loss

Investigations

Common

Increased amylase, decreased free and total thyroxin

Uncommon

Increased glucose, increased magnesium, increased alkaline phosphatase

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 (see section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and can occur many months after initiation of treatment (see section 4.4).

Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridaemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis (see section 4.4).

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

Paediatric population

The safety profile of Norvir 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

4.9. Overdose

Symptoms

Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1 500 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.