RITONAVIR MYLAN 100mg tablets medication leaflet

Ritonavir Mylan 100 mg film-coated tablets

Each film-coated tablet contains 100 mg of ritonavir.

Each film-coated tablet contains 87.75 mg of sodium.

For the full list of excipients, see section 6.1.

Film-coated tablet

Yellow, capsule shaped, biconvex, beveled edge film-coated tablet, approximately 19.1 mm x10.2 mm, debossed with ‘M163’ on one side and blank on the other side.

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

Ritonavir Mylan should be administered by physicians who are experienced in the treatment of HIVinfection.

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 apharmacokinetic enhancer at the noted doses.

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 1,000 mg twice daily with ritonavir 100 mg twice daily in antiretroviral treatment (ART)experienced patients.

Initiate treatment with saquinavir 500 mg twice daily with ritonavir 100 mg twice daily for the first7 days, then saquinavir 1,000 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 notbe used in treatment-naïve patients.

Darunavir 600 mg twice daily with ritonavir 100 mg twice daily in ART experienced patients.

Darunavir 800 mg once daily with ritonavir 100 mg once daily may be used in some ART experiencedpatients. Refer to the darunavir Summary of Product Characteristics for further information on oncedaily 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 dose recommendations,refer to the product information of other Protease Inhibitors approved for co-administration withritonavir.

As ritonavir is primarily metabolised by the liver, ritonavir may be appropriate for use with caution asa pharmacokinetic enhancer in patients with renal insufficiency depending on the specific proteaseinhibitor with which it is co-administered. However, since the renal clearance of ritonavir isnegligible, 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.

Ritonavir should not be given as a pharmacokinetic enhancer to patients with decompensated liverdisease, (see section 4.3). In the absence of pharmacokinetic studies in patients with stable severehepatic impairment (Child Pugh Grade C) without decompensation, caution should be exercised whenritonavir is used as a pharmacokinetic enhancer as increased levels of the co-administered PI mayoccur. Specific recommendations for use of ritonavir as a pharmacokinetic enhancer in patients withhepatic impairment are dependent on the protease inhibitor with which it is co-administered. The SPCof the co-administered PI should be reviewed for specific dosing information in this patientpopulation.

Ritonavir dosed as an antiretroviral agent

The recommended dose of ritonavir is 600 mg (6 tablets) twice daily (total of 1,200 mg per day) bymouth.

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 increasedby 100 mg (1 tablet) twice daily increments up to 600 mg twice daily over a period of no longer than14 days. Patients should not remain on 300 mg twice daily for more than 3 days.

Paediatric population (2 years of age and above)

The recommended dose of ritonavir in children is 350 mg/m2 by mouth twice daily and should notexceed 600 mg twice daily. Ritonavir should be started at 250 mg/m2 and increased at 2 to 3 dayintervals 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 otherpharmaceutical forms.

Table 1. Dose conversion from powder for oral suspension to tablets for children

Powder for oral suspension Tablet dosedose175 mg (2.2 ml) twice daily 200 mg in the morning and 200 mg in the evening350 mg (4.4 ml) twice daily 400 mg in the morning and 300 mg in the evening437.5 mg (5.5 ml) twice daily 500 mg in the morning and 400 mg in the evening525 mg (6.6 ml) twice daily 500 mg in the morning and 500 mg in the evening

Ritonavir is not recommended in children below 2 years of age due to lack of data on safety andefficacy.

Pharmacokinetic data indicated that no dose adjustment is necessary for elderly patients (see section5.2).

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

Ritonavir is principally metabolised and eliminated by the liver. Pharmacokinetic data indicate that nodose adjustment is necessary in patients with mild to moderate hepatic impairment (see section 5.2).

Ritonavir must not be given to patients with severe hepatic impairment (see section 4.3).

The safety and efficacy of ritonavir in children aged below 2 years has not been established. Currentlyavailable data are described in sections 5.1 and 5.2 but no recommendation on a posology can bemade.

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

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

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 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 patientswith 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 medicinal products are contraindicated whenused with ritonavir and unless otherwise noted, the contraindication is based on the potential forritonavir to inhibit metabolism of the co-administered medicinal product, resulting in increasedexposure to the co-administered medicinal product and risk of clinically significant adverse events.

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 whenritonavir is used as a pharmacokinetic enhancer (e.g. rifabutin and voriconazole):

Table 2. Medicinal products that are contraindicated when used with Ritonavir

Medicinal product class Medicinal products within Rationaleclass

Concomitant medicinal product levels increased or decreasedα1-Adrenoreceptor Antagonist Alfuzosin Increased plasmaconcentrations of alfuzosinwhich may lead to severehypotension (see section 4.5).

Analgesics Pethidine, propoxyphene Increased plasmaconcentrations of norpethidineand propoxyphene. Thereby,increasing the risk of seriousrespiratory depression orhaematologic abnormalities, orother serious adverse effectsfrom these agents.

Antianginal Ranolazine Increased plasmaconcentrations of ranolazinewhich may increase thepotential for serious and/orlife-threatening reactions (seesection 4.5).

Anticancer Neratinib Increased plasmaconcentrations of neratinibwhich may increase thepotential for serious and/orlife-threatening reactionsincluding hepatotoxicity (seesection 4.5).

Venetoclax Increased plasmaconcentrations of venetoclax.

Increased risk of tumor lysissyndrome at the dose initiationand during the dose-titrationphase (see section 4.5).

Antiarrhythmics Amiodarone, bepridil, Increased plasmadronedarone, encainide, concentrations of amiodarone,flecainide, propafenone, bepridil, dronedarone,quinidine encainide, flecainide,propafenone, quinidine.

Thereby, increasing the risk ofarrhythmias or other seriousadverse effects from theseagents.

Antibiotic Fusidic acid Increased plasmaconcentrations of fusidic acidand ritonavir.

Medicinal product class Medicinal products within Rationaleclass

Antifungal Voriconazole Concomitant use of ritonavir(400 mg twice daily and more)and voriconazole iscontraindicated due to areduction in voriconazoleplasma concentrations andpossible loss of effect (seesection 4.5).

Antihistamines Astemizole, terfenadine Increased plasmaconcentrations of astemizoleand terfenadine. Thereby,increasing the risk of seriousarrhythmias from these agents.

Anti-gout Colchicine Potential for serious and/orlife-threatening reactions inpatients with renal and/orhepatic impairment (seesections 4.4 and 4.5).

Antimycobacterial Rifabutin Concomitant use of ritonavir(500 mg twice daily) dosed asan antiretroviral agent andrifabutin due to an increase ofrifabutin serum concentrationsand risk of adverse reactionsincluding uveitis (see section4.4).

Recommendations regardinguse of ritonavir dosed as apharmacokinetic enhancer withrifabutin are noted in section4.5.

Antipsychotics/ Neuroleptics Lurasidone Increased plasmaconcentrations of lurasidonewhich may increase thepotential for serious and/orlife-threatening reactions (seesection 4.5).

Clozapine, pimozide Increased plasmaconcentrations of clozapineand pimozide. Thereby,increasing the risk of serioushaematologic abnormalities, orother serious adverse effectsfrom these agents.

Quetiapine Increased plasmaconcentrations of quetiapinewhich may lead to coma. Theconcomitant administrationwith quetiapine iscontraindicated (see section4.5).

Medicinal product class Medicinal products within Rationaleclass

Ergot derivatives Dihydroergotamine, Increased plasmaergonovine, ergotamine, concentrations of ergotmethylergonovine derivatives leading to acuteergot toxicity, includingvasospasm and ischaemia.

GI motility agent Cisapride Increased plasmaconcentrations of cisapride.

Thereby, increasing the risk ofserious arrhythmias from thisagent.

Lipid-modifying agents

HMG Co-A reductase Lovastatin, simvastatin Increased plasmainhibitors concentrations of lovastatinand simvastatin; thereby,increasing the risk of myopathyincluding rhabdomyolysis (seesection 4.5).

Microsomal triglyceride Lomitapide Increased plasmatransfer protein (MTTP) concentrations of lomitapideinhibitor (see section 4.5).

PDE5 inhibitor Avanafil Increased plasmaconcentrations of avanafil (seesections 4.4. and 4.5).

Sildenafil Contraindicated when used forthe treatment of pulmonaryarterial hypertension (PAH)only.

Increased plasmaconcentrations of sildenafil.

Thereby, increasing thepotential forsildenafil-associated adverseevents (which includehypotension and syncope). Seesection 4.4 and section 4.5 forco-administration of sildenafilin patients with erectiledysfunction.

Vardenafil Increased plasmaconcentrations of vardenafil(see sections 4.4. and 4.5).

Sedatives/hypnotics Clorazepate, diazepam, Increased plasmaestazolam, flurazepam, oral concentrations of clorazepate,midazolam and triazolam diazepam, estazolam,flurazepam, oral midazolamand triazolam. Thereby,increasing the risk of extremesedation and respiratorydepression from these agents.(For caution on parenterallyadministered midazolam, seesection 4.5.).

Medicinal product class Medicinal products within Rationaleclass

Ritonavir medicinal product level decreased

Herbal preparation St John’s wort Herbal preparations containing

St John’s wort (Hypericumperforatum) due to the risk ofdecreased plasmaconcentrations and reducedclinical effects of ritonavir (seesection 4.5).

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

HIV-1 infection.

When ritonavir is used as a pharmacokinetic enhancer with other PIs, full details on the warnings andprecautions 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 diarrhoeaduring treatment with ritonavir may compromise the absorption and efficacy (due to decreasedcompliance) of ritonavir or other concurrent medicinal products. Serious persistent vomiting and/ordiarrhoea associated with ritonavir use might also compromise renal function. It is advisable tomonitor renal function in patients with renal function impairment.

Haemophilia

There have been reports of increased bleeding, including spontaneous skin haematomas andhaemarthroses, in haemophiliac patients type A and B treated with protease inhibitors. In somepatients additional factor VIII was given. In more than a half of the reported cases, treatment withprotease inhibitors was continued or reintroduced if treatment had been discontinued. A causalrelationship 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.

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

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) orabnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive ofpancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated andritonavir 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 combinationantiretroviral therapy (CART), an inflammatory reaction to asymtomatic or residual opportunisticpathogens 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 andtreatment instituted when necessary.

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

Ritonavir should not be given to patients with decompensated liver disease (see section 4.2). Patientswith chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increasedrisk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapyfor 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 increasedfrequency of liver function abnormalities during combination antiretroviral therapy and should bemonitored according to standard practice. If there is evidence of worsening liver disease in suchpatients, interruption or discontinuation of treatment must be considered.

Renal disease

Since the renal clearance of ritonavir is negligible, the decrease in the total body clearance is notexpected 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).

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported in patients with advanced HIV-disease and/or long-term exposure to combinationantiretroviral therapy (CART). Patients should be advised to seek medical advice if they experiencejoint 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 somehealthy adult subjects. Rare reports of 2nd or 3rd degree atrioventricular block in patients withunderlying structural heart disease and pre-existing conduction system abnormalities or in patientsreceiving medicinal products known to prolong the PR interval (such as verapamil or atazanavir) havebeen reported in patients receiving ritonavir. Ritonavir should be used with caution in such patients(see section 5.1).

Ritonavir dosed as an antiretroviral agent

The following warnings and precautions should be considered when ritonavir is used as anantiretroviral agent. When ritonavir is used as a pharmacokinetic enhancer at the 100 mg and 200 mglevel it cannot be assumed that the following warnings and precautions will also apply. When ritonaviris used as a pharmacokinetic enhancer, full details on the warnings and precautions relevant to thatparticular PI must be considered, therefore the Summary of Product Characteristics, section 4.4, forthe particular PI 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 erectiledysfunction in patients receiving ritonavir. Co-administration of ritonavir with these medicinalproducts is expected to substantially increase their concentrations and may result in associated adversereactions such as hypotension and prolonged erection (see section 4.5). Concomitant use of avanafil orvardenafil with ritonavir is contraindicated (see section 4.3). Concomitant use of sildenafil withritonavir 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 formetabolism, thus concomitant use of ritonavir with simvastatin or lovastatin is not recommended dueto an increased risk of myopathy including rhabdomyolysis. Caution must also be exercised andreduced doses should be considered if ritonavir is used concurrently with atorvastatin, which ismetabolised 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. Themechanism of this interaction is not clear, but may be the result of transporter inhibition. When usedwith ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent, the lowest doses ofatorvastatin or rosuvastatin should be administered. The metabolism of pravastatin and fluvastatin isnot 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 interactions have been reported in patients treated with colchicine and stronginhibitors of CYP3A like ritonavir (see sections 4.3 and 4.5).

Particular caution should be used when prescribing ritonavir in patients taking digoxin sinceco-administration of ritonavir with digoxin is expected to increase digoxin levels. The increaseddigoxin levels may lessen over time (see section 4.5).

In patients who are already taking digoxin when ritonavir is introduced, the digoxin dose should bereduced to one-half of the patients’ normal dose and patients need to be followed more closely thanusual 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 introducedmore gradually than usual. Digoxin levels should be monitored more intensively than usual during thisperiod, with dose adjustments made, as necessary, based on clinical, electrocardiographic and digoxinlevel findings.

Ethinylestradiol

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

Glucocorticoids

Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolised by CYP3A4is not recommended unless the potential benefit of treatment outweighs the risk of systemiccorticosteroid 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 isa 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 doseinteraction 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 increasedbleeding (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 couldpotentially increase the risk of bedaquiline-related adverse reactions. Therefore, combination ofbedaquiline with ritonavir should be avoided. However, if the benefit outweighs the risk,co-administration of bedaquiline with ritonavir must be done with caution. More frequentelectrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.5 andrefer to the bedaquiline Summary of Product Characteristics).

Delamanid

Co-administration of delamanid with a strong inhibitor of CYP3A (ritonavir) may increase exposure todelamanid metabolite, which has been associated with QTc prolongation. Therefore, ifco-administration of delamanid with ritonavir is considered necessary, very frequent ECG monitoringthroughout the full delamanid treatment period is recommended (see section 4.5 and refer to thedelamanid Summary of Product Characteristics).

Ritonavir dosed as a pharmacokinetic enhancer

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

For a description of the mechanisms and potential mechanisms contributing to the interaction profileof the PIs, see section 4.5. Please also review the Summary of Product Characteristics for theparticular boosted PI.

Saquinavir

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

Saquinavir/ritonavir should not be given together with rifampicin, due to the risk of severehepatotoxicity (presenting as increased hepatic transaminases) if the three medicinal products aregiven together (see section 4.5).

Tipranavir

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

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

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

Co-administration of atazanavir with ritonavir at doses greater than 100 mg once daily has not beenclinically 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 withritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200 mg once daily could beconsidered. In this instance, close clinical monitoring is warranted. Refer to the Summary of Product

Characteristics for atazanavir for further details.

This medicinal product contains 87.75 mg sodium per tablet, equivalent to 4.4% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

The maximum daily dose of this product is equivalent to 53% of the WHO recommended maximumdaily intake for sodium.

Ritonavir is considered high in sodium. This should be particularly taken into account for those on alow sodium diet.

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent

Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidationwith the following ranked order: CYP3A4 > CYP2D6. Co-administration of ritonavir and medicinalproducts primarily metabolised by CYP3A may result in increased plasma concentrations of the othermedicinal product, which could increase or prolong its therapeutic and adverse effects. For selectedmedicinal products (e.g. alprazolam) the inhibitory effects of ritonavir on CYP3A4 may decrease overtime. Ritonavir also has a high affinity for P-glycoprotein and may inhibit this transporter. Theinhibitory effect of ritonavir (with or without other protease inhibitors) on P-gp activity may decreaseover time (e.g. digoxin and fexofenadine-see table “Ritonavir effects on non-antiretroviral medicinalproducts” below). Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8,

CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal productsmetabolised by these pathways, and may result in decreased systemic exposure to such medicinalproducts, which could decease or shorten their therapeutic effect.

Important information regarding medicinal product interactions when ritonavir is used as apharmacokinetic enhancer is also contained in the Summary of Product Characteristics of theco-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 metabolisingenzymes by St John’s wort. Herbal preparations containing St John’s wort must not be used incombination with ritonavir. If a patient is already taking St John’s wort, St John’s wort should bestopped 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 aftercessation 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.delavirdine, efavirenz, phenytoin and rifampicin). These interactions are noted in the medicinalproduct interaction tables below.

Medicinal products that are affected by the use of ritonavir

Interactions between ritonavir and protease inhibitors, antiretroviral agents other than proteaseinhibitors and other non-antiretroviral medicinal products are listed in the tables below. This list is notintended to be inclusive or comprehensive. Individual SmPCs should be consulted.

Table 3. Medicinal product interactions - Ritonavir with protease inhibitors

Co-administered Dose of Dose of Medicinal AUC Cminmedicinal product co-administered ritonavir productmedicinal product (mg) assessed(mg)

Amprenavir 600 q12 h 100 q12 h Amprenavir2 ↑ 64% ↑ 5 fold

Ritonavir increases the serum levels of amprenavir as a result of CYP3A4 inhibition.

Clinical studies confirmed the safety and efficacy of 600 mg amprenavir twice dailywith ritonavir 100 mg twice daily. Ritonavir oral solution should not beco-administered with amprenavir oral solution to children due to the risk of toxicityfrom excipients in the two formulations. For further information, physicians shouldrefer to the Summary of Product Characteristics for amprenavir.

Atazanavir 300 q24 h 100 q24 h Atazanavir ↑ 86% ↑ 11 fold

Atazanavir1 ↑ 2 fold ↑ 3-7 fold

Ritonavir increases the serum levels of atazanavir as a result of CYP3A4 inhibition.

Clinical studies confirmed the safety and efficacy of 300 mg atazanavir once daily withritonavir 100 mg once daily in treatment experienced patients. For further information,physicians should refer to the Summary of Product Characteristics for atazanavir.

Darunavir 600, single 100 q12 h 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 doseshigher than 100 mg twice daily have not been studied with darunavir. For furtherinformation, refer to the Summary of Product Characteristics for darunavir.

Fosamprenavir 700 q12 h 100 q12 h 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 itstherapeutic effect. Clinical studies confirmed the safety and efficacy of fosamprenavir700 mg twice daily with ritonavir 100 mg twice daily. Ritonavir doses higher than100 mg twice daily have not been studied with fosamprenavir. For further information,physicians should refer to the Summary of Product Characteristics for fosamprenavir.

Indinavir 800 q12 h 100 q12 h Indinavir3 ↑ 178% ND

Ritonavir ↑ 72% ND400 q12 h 400 q12 h Indinavir3 ↔ ↑ 4 fold

Ritonavir ↔ ↔

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 notbeen established.

Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved withdoses 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 therisk of nephrolithiasis may be increased.

Nelfinavir 1,250 q12 h 100 q12 h Nelfinavir ↑ 20 to 39% ND750, single 500 q12 h Nelfinavir ↑ 152% ND

Ritonavir ↔ ↔

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 notbeen established.

Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved withdoses higher than 100 mg twice daily.

Co-administered Dose of Dose of Medicinal AUC Cminmedicinal product co-administered ritonavir productmedicinal product (mg) assessed(mg)

Saquinavir 1,000 q12 h 100 q12 h Saquinavir4 ↑ 15-fold ↑ 5-fold

Ritonavir ↔ ↔400 q12 h 400 q12 h Saquinavir4 ↑ 17-fold ND

Ritonavir ↔ ↔

Ritonavir increases the serum levels of saquinavir as a result of CYP3A4 inhibition.

Saquinavir should only be given in combination with ritonavir. Ritonavir 100 mg twicedaily with saquinavir 1,000 mg twice daily provides saquinavir systemic exposure over24 hours similar to or greater than those achieved with saquinavir 1,200 mg three timesdaily without ritonavir.

In a clinical study investigating the interaction of rifampicin 600 mg once daily andsaquinavir 1,000 mg with ritonavir 100 mg twice daily in healthy volunteers, severehepatocellular toxicity with transaminase elevations up to > 20-fold the upper limit ofnormal after 1 to 5 days of co-administration was noted. Due to the risk of severehepatotoxicity, saquinavir/ritonavir should not be given together with rifampicin.

For further information, physicians should refer to the Summary of Product

Characteristics for saquinavir.

Tipranavir 500 q12 h 200 q12 h Tipranavir ↑ 11 fold ↑ 29 fold

Ritonavir ↓ 40% ND

Ritonavir increases the serum levels of tipranavir as a result of CYP3A inhibition.

Tipranavir must be given with low dose ritonavir to ensure its therapeutic effect. Dosesof ritonavir less than 200 mg twice daily should not be used with tipranavir as theymight alter the efficacy of the combination. For further information, physicians shouldrefer to the Summary of Product Characteristics for tipranavir.

ND: Not determined.1 Based on cross-study comparison to 400 mg atazanavir once daily alone.2 Based on cross-study comparison to 1,200 mg amprenavir twice daily alone.3 Based on cross-study comparison to 800 mg indinavir three times daily alone.4 Based on cross-study comparison to 600 mg saquinavir three times daily alone.

Table 4. Medicinal product interactions - Ritonavir with antiretroviral agents other thanprotease inhibitors

Co-administered Dose of Dose of Medicinal AUC Cminmedicinal co-administered ritonavir (mg) productproduct medicinal assessedproduct (mg)

Didanosine 200 q12 h 600 q12 h 2 h Didanosine ↓ 13% ↔later

As ritonavir is recommended to be taken with food and didanosine should be taken on anempty stomach, dosing should be separated by 2.5 h. Dose alterations should not benecessary.

Delavirdine 400 q8 h 600 q12 h Delavirdine1 ↔ ↔

Ritonavir ↑ 50% ↑ 75%

Based on comparison to historical data, the pharmacokinetics of delavirdine did notappear to be affected by ritonavir. When used in combination with delavirdine, dosereduction of ritonavir may be considered.

Efavirenz 600 q24 h 500 q12 h Efavirenz ↑ 21%

Ritonavir ↑ 17%

A higher frequency of adverse reactions (e.g., dizziness, nausea, paraesthesia) andlaboratory abnormalities (elevated liver enzymes) have been observed when efavirenz isco-administered with ritonavir dosed as an antiretroviral agent.

Maraviroc 100 q12 h 100 q12 h 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 furtherinformation, refer to the Summary of Product Characteristics for maraviroc.

Co-administered Dose of Dose of Medicinal AUC Cminmedicinal co-administered ritonavir (mg) productproduct medicinal assessedproduct (mg)

Nevirapine 200 q12 h 600 q12 h Nevirapine ↔ ↔

Ritonavir ↔ ↔

Co-administration of ritonavir with nevirapine does not lead to clinically relevantchanges in the pharmacokinetics of either nevirapine or ritonavir.

Raltegravir 400 single 100 q12 h Raltegravir ↓ 16% ↓ 1%

Co-administration of ritonavir and raltegravir results in a minor reduction in raltegravirlevels.

Zidovudine 200 q8 h 300 q6 h Zidovudine ↓ 25% ND

Ritonavir may induce the glucuronidation of zidovudine, resulting in slightly decreasedlevels of zidovudine. Dose alterations should not be necessary.

ND: Not determined1 Based on parallel group comparison.

Table 5. Ritonavir effects on non-antiretroviral co-administered medicinal products

Co-administered medicinal Dose of co- Dose of Effect on co- Effect on co-products administered ritonavir administered administeredmedicinal products (mg) medicinal medicinal(mg) products AUC products

Cmax

Alpha1-Adrenoreceptor antagonist

Alfuzosin Ritonavir co-administration is likely to result in increased plasmaconcentrations of alfuzosin and is therefore contraindicated (seesection 4.3).

Amphetamine derivatives

Amphetamine Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6and as a result is expected to increase concentrations of amphetamineand its derivatives. Careful monitoring of therapeutic and adverseeffects is recommended when these medicinal products areconcomitantly administered with antiretroviral doses of ritonavir (seesection 4.4).

Analgesics

Buprenorphine 16 q24 h 100 q12 h ↑ 57% ↑ 77%

Norbuprenorphine ↑ 33% ↑ 108%

Glucuronide metabolites ↔ ↔

The increases of plasma levels of buprenorphine and its activemetabolite did not lead to clinically significant pharmacodynamicchanges in a population of opioid tolerant patients. Adjustment to thedose of buprenorphine or ritonavir may therefore not be necessarywhen the two are dosed together. When ritonavir is used in combinationwith another protease inhibitor and buprenorphine, the SPC of theco-administered protease inhibitor should be reviewed for specificdosing information.

Pethidine, propoxyphene Ritonavir co-administration is likely to result in increased plasmaconcentrations of norpethidine and propoxyphene and is thereforecontraindicated (see section 4.3).

Fentanyl Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviralagent inhibits CYP3A4 and as a result is expected to increase theplasma concentrations of fentanyl. Careful monitoring of therapeuticand adverse effects (including respiratory depression) is recommendedwhen fentanyl is concomitantly administered with ritonavir.

Co-administered medicinal Dose of co- Dose of Effect on co- Effect on co-products administered ritonavir administered administeredmedicinal products (mg) medicinal medicinal(mg) products AUC products

Cmax

Methadone1 5, single dose 500 q12 h, ↓ 36% ↓ 38%

Increased methadone dose may be necessary when concomitantlyadministered with ritonavir dosed as an antiretroviral agent or as apharmacokinetic enhancer due to induction of glucuronidation. Doseadjustment should be considered based on the patient’s clinicalresponse to methadone therapy.

Morphine Morphine levels may be decreased due to induction of glucuronidationby co-administered ritonavir dosed as an antiretroviral agent or as apharmacokinetic enhancer.

Antianginal

Ranolazine Due to CYP3A inhibition by ritonavir, concentrations of ranolazine areexpected to increase. The concomitant administration with ranolazine iscontraindicated (see section 4.3).

Antiarrhythmics

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

Digoxin 0.5 single IV dose 300 q12 h, ↑ 86% ND3 days0.4 single oral dose 200 q12 h, ↑ 22% ↔13 days

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

Antiasthmatic

Theophylline1 3 mg/kg q8 h 500 q12 h ↓ 43% ↓ 32%

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

Anticancer agents and kinase inhibitors

Afatinib 20 mg, single dose 200 q12 h/1 h ↑ 48% ↑ 39%before40 mg, single dose 200 q12 h/co- ↑ 19% ↑ 4%administered40 mg, single dose 200 q12 h/6 h ↑ 11% ↑ 5%after

Serum concentrations may be increased due to Breast Cancer

Resistance Protein (BCRP) and acute P-gp inhibition by ritonavir. Theextent of increase in AUC and Cmax depends on the timing of ritonaviradministration. Caution should be exercised in administering afatinibwith ritonavir (refer to the afatinib SmPC). Monitor for ADRs related toafatinib.

Abemaciclib Serum concentrations may be increased due to CYP3A4 inhibition byritonavir.

Co-administration of abemaciclib and ritonavir should be avoided. Ifthis co-administration is judged unavoidable, refer to the abemaciclib

SmPC for dose adjustment recommendations. Monitor for ADRsrelated to abemaciclib.

Co-administered medicinal Dose of co- Dose of Effect on co- Effect on co-products administered ritonavir administered administeredmedicinal products (mg) medicinal medicinal(mg) products AUC products

Cmax

Apalutamide Apalutamide is a moderate to strong CYP3A4 inducer and this maylead to a decreased exposure of ritonavir and potential loss of virologicresponse. In addition, serum concentrations may be increased whenco-administered with ritonavir resulting in the potential for seriousadverse events including seizure.

Concomitant use of ritonavir with apalutamide is not recommended.

Ceritinib Serum concentrations may be increased due to CYP3A and P-gpinhibition by ritonavir. Caution should be exercised in administeringceritinib with ritonavir. Refer to the ceritinib SmPC for dose adjustmentrecommendations. Monitor for ADRs related to ceritinib.

Dasatinib, nilotinib, vincristine, Serum concentrations may be increased when co-administered withvinblastine ritonavir resulting in the potential for increased incidence of adversereactions.

Encorafenib Serum concentrations may be increased when co-administered withritonavir which may increase the risk of toxicity, including the risk ofserious adverse events such as QT interval prolongation.

Co-administration of encorafenib and ritonavir should be avoided. Ifthe benefit is considered to outweigh the risk and ritonavir must beused, patients should be carefully monitored for safety.

Fostamatinib Co-administration of fostamatinib with ritonavir may increasefostamatinib metabolite R406 exposure resulting in dose-relatedadverse events such as hepatotoxicity, neutropenia, hypertension, ordiarrhoea. Refer to the fostamatinib SmPC for dose reductionrecommendations if such events occur.

Ibrutinib Serum concentrations of ibrutinib may be increased due to CYP3Ainhibition by ritonavir, resulting in increased risk for toxicity includingrisk of tumor lysis syndrome. Co-administration of ibrutinib andritonavir should be avoided. If the benefit is considered to outweigh therisk and ritonavir must be used, reduce the ibrutinib dose to 140 mg andmonitor patient closely for toxicity.

Neratinib Serum concentrations may be increased due to CYP3A4 inhibition byritonavir.

Concomitant use of neratinib with ritonavir is contraindicated due toserious and/or life threatening potential reactions includinghepatotoxicity (see section 4.3).

Venetoclax Serum concentrations may be increased due to CYP3A inhibition byritonavir, resulting in increased risk of tumour lysis syndrome at thedose initiation and during the ramp-up phase (see section 4.3 and referto the venetoclax SmPC).

For patients who have completed the ramp-up phase and are on a steadydaily 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).

Co-administered medicinal Dose of co- Dose of Effect on co- Effect on co-products administered ritonavir administered administeredmedicinal products (mg) medicinal medicinal(mg) products AUC products

Cmax

Anticoagulants

Dabigatran etexilate Serum concentrations may be increased due to P-gp inhibition by

Edoxaban ritonavir. Clinical monitoring and/or dose reduction of the direct oralanticoagulants (DOAC) should be considered when a DOACtransported by P-gp but not metabolised by CYP3A4, includingdabigatran etexilate and edoxaban, is co-administered with ritonavir.

Rivaroxaban 10, single dose 600 q12 h ↑ 153% ↑ 55%

Inhibition of CYP3A and P-gp lead to increased plasma levels andpharmacodynamic effects of rivaroxaban which may lead to anincreased bleeding risk. Therefore, the use of ritonavir is notrecommended in patients receiving rivaroxaban.

Vorapaxar Serum concentrations may be increased due to CYP3A inhibition byritonavir. The co-administration of vorapaxar with ritonavir is notrecommended (see section 4.4 and refer to the vorapaxar SmPC).

Warfarin 5, single dose 400 q12 h

S-Warfarin ↑ 9% ↓ 9%

R-Warfarin ↑ 33% ↔

Induction of CYP1A2 and CYP2C9 lead to decreased levels of

R-warfarin while little pharmacokinetic effect is noted on S-warfarinwhen co-administered with ritonavir. Decreased R-warfarin levels maylead to reduced anticoagulation, therefore it is recommended thatanticoagulation parameters are monitored when warfarin isco-administered with ritonavir dosed as an antiretroviral agent or as apharmacokinetic enhancer.

Anticonvulsants

Carbamazepine Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviralagent inhibits CYP3A4 and as a result is expected to increase theplasma concentrations of carbamazepine. Careful monitoring oftherapeutic and adverse effects is recommended when carbamazepine isconcomitantly administered with ritonavir.

Divalproex, lamotrigine, Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviralphenytoin agent induces oxidation by CYP2C9 and glucuronidation and as a resultis expected to decrease the plasma concentrations of anticonvulsants.

Careful monitoring of serum levels or therapeutic effects isrecommended when these medicinal products are concomitantlyadministered with ritonavir. Phenytoin may decrease serum levels ofritonavir.

Antidepressants

Amitriptyline, fluoxetine, Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6imipramine, nortriptyline, and as a result is expected to increase concentrations of imipramine,paroxetine, sertraline amitriptyline, nortriptyline, fluoxetine, paroxetine or sertraline. Carefulmonitoring of therapeutic and adverse effects is recommended whenthese medicinal products are concomitantly administered withantiretroviral doses of ritonavir (see section 4.4).

Desipramine 100, single oral dose 500 q12 h ↑ 145% ↑ 22%

The AUC and Cmax of the 2-hydroxy metabolite were decreased 15 and67%, respectively. Dose reduction of desipramine is recommendedwhen co-administered with ritonavir dosed as an antiretroviral agent.

Co-administered medicinal Dose of co- Dose of Effect on co- Effect on co-products administered ritonavir administered administeredmedicinal products (mg) medicinal medicinal(mg) products AUC products

Cmax

Trazodone 50, single dose 200 q12 h ↑ 2.4-fold ↑ 34%

An increase in the incidence in trazodone-related adverse reactions wasnoted when co-administered with ritonavir dosed as an antiretroviralagent or as a pharmacokinetic enhancer. If trazodone is co-administeredwith ritonavir, the combination should be used with caution, initiatingtrazodone at the lowest dose and monitoring for clinical response andtolerability.

Anti-gout treatments

Colchicine Concentrations of colchicine are expected to increase whenco-administered with ritonavir.

Life-threatening and fatal drug interactions have been reported inpatients treated with colchicine and ritonavir (CYP3A4 and P-gpinhibition) in patients with renal and/or hepatic impairment (seesections 4.3 and 4.4). Refer to the colchicine prescribing information.

Antihistamines

Astemizole, terfenadine Ritonavir co-administration is likely to result in increased plasmaconcentrations of astemizole and terfenadine and is thereforecontraindicated (see section 4.3).

Fexofenadine Ritonavir may modify P-glycoprotein mediated fexofenadine effluxwhen dosed as an antiretroviral agent or as a pharmacokinetic enhancerresulting in increased concentrations of fexofenadine. Increasedfexofenadine levels may lessen over time as induction develops.

Loratadine Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviralagent inhibits CYP3A and as a result is expected to increase the plasmaconcentrations of loratadine. Careful monitoring of therapeutic andadverse effects is recommended when loratadine is concomitantlyadministered with ritonavir.

Anti-infectives

Fusidic acid Ritonavir co-administration is likely to result in increased plasmaconcentrations of both fusidic acid and ritonavir and is thereforecontraindicated (see section 4.3).

Rifabutin1 150 daily 500 q12 h ↑ 4-fold ↑ 2.5-fold25-O-desacetyl rifabutin ↑ 38-fold ↑ 16-foldmetabolite

Due to the large increase in rifabutin AUC, the concomitant use ofrifabutin with ritonavir dosed as an antiretroviral agent iscontraindicated (see section 4.3). The reduction of the rifabutin doseto 150 mg 3 times per week may be indicated for select PIs whenco-administered with ritonavir as a pharmacokinetic enhancer. The

Summary of Product Characteristics of the co-administered proteaseinhibitor should be consulted for specific recommendations.

Consideration should be given to official guidance on the appropriatetreatment of tuberculosis in HIV-infected patients.

Rifampicin Although rifampicin may induce metabolism of ritonavir, limited dataindicate that when high doses of ritonavir (600 mg twice daily) isco-administered with rifampicin, the additional inducing effect ofrifampicin (next to that of ritonavir itself) is small and may have noclinical relevant effect on ritonavir levels in high-dose ritonavirtherapy.

The effect of ritonavir on rifampicin is not known.

Co-administered medicinal Dose of co- Dose of Effect on co- Effect on co-products administered ritonavir administered administeredmedicinal products (mg) medicinal medicinal(mg) products AUC products

Cmax

Voriconazole 200 q12 h 400 q12 h ↓ 82% ↓ 66%200 q12 h 100 q12 h ↓ 39% ↓ 24%

Concomitant use of ritonavir dosed as an antiretroviral agent andvoriconazole is contraindicated due to reduction in voriconazoleconcentrations (see section 4.3). Co-administration of voriconazole andritonavir dosed as a pharmacokinetic enhancer should be avoided,unless an assessment of the benefit/risk to the patient justifies the use ofvoriconazole.

Atovaquone Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviralagent induces glucuronidation and as a result is expected to decreasethe plasma concentrations of atovaquone. Careful monitoring of serumlevels or therapeutic effects is recommended when atovaquone isconcomitantly administered with ritonavir.

Bedaquiline No interaction study is available with ritonavir only. In an interactionstudy of single-dose bedaquiline and multiple dose lopinavir/ritonavir,the AUC of bedaquiline was increased by 22%. This increase is likelydue to ritonavir and a more pronounced effect may be observed duringprolonged co-administration. Due to the risk of bedaquiline relatedadverse events, co-administration should be avoided. If the benefitoutweighs the risk, co-administration of bedaquiline with ritonavir mustbe done with caution. More frequent electrocardiogram monitoring andmonitoring of transaminases is recommended (see section 4.4 and referto the bedaquiline Summary of Product Characteristics).

Clarithromycin 500 q12 h 200 q8 h ↑ 77% ↑ 31%14-OH clarithromycin metabolite ↓ 100% ↓ 99%

Due to the large therapeutic window of clarithromycin no dosereduction should be necessary in patients with normal renal function.

Clarithromycin doses greater than 1 g per day should not beco-administered with ritonavir dosed as an antiretroviral agent or as apharmacokinetic enhancer. For patients with renal impairment, aclarithromycin dose reduction should be considered: for patients withcreatinine clearance of 30 to 60 ml/min the dose should be reduced by50%, for patients with creatinine clearance less than 30 ml/min the doseshould be reduced by 75%.

Delamanid No interaction study is available with ritonavir only. In a healthyvolunteer drug interaction study of delamanid 100 mg twice daily andlopinavir/ritonavir 400/100 mg twice daily for 14 days, the exposure ofthe delamanid metabolite DM-6705 was 30% increased. Due to the riskof QTc prolongation associated with DM-6705, if co-administration ofdelamanid with ritonavir is considered necessary, very frequent ECGmonitoring throughout the full delamanid treatment period isrecommended (see section 4.4 and refer to the delamanid Summary of

Product Characteristics)

Erythromycin, itraconazole Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviralagent inhibits CYP3A4 and as a result is expected to increase theplasma concentrations of erythromycin and itraconazole. Carefulmonitoring of therapeutic and adverse effects is recommended whenerythromycin or itraconazole is used concomitantly administered withritonavir.

Co-administered medicinal Dose of co- Dose of Effect on co- Effect on co-products administered ritonavir administered administeredmedicinal products (mg) medicinal medicinal(mg) products AUC products

Cmax

Ketoconazole 200 daily 500 q12 h ↑ 3.4-fold ↑ 55%

Ritonavir inhibits CYP3A-mediated metabolism of ketoconazole. Dueto an increased incidence of gastrointestinal and hepatic adversereactions, a dose reduction of ketoconazole should be considered whenco-administered with ritonavir dosed as an antiretroviral agent or as apharmacokinetic enhancer.

Sulfamethoxazole/Trimethoprim2 800/160, single dose 500 q12 h ↓ 20%/↑ 20% ↔

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

Antipsychotics/Neuroleptics

Clozapine, pimozide Ritonavir co-administration is likely to result in increased plasmaconcentrations of clozapine or pimozide and is thereforecontraindicated (see section 4.3).

Haloperidol, risperidone, Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6thioridazine and as a result is expected to increase concentrations of haloperidol,risperidone and thioridazine. Careful monitoring of therapeutic andadverse effects is recommended when these medicinal products areconcomitantly administered with antiretroviral doses of ritonavir.

Lurasidone Due to CYP3A inhibition by ritonavir, concentrations of lurasidone areexpected to increase. The concomitant administration with lurasidone iscontraindicated (see section 4.3).

Quetiapine Due to CYP3A inhibition by ritonavir, concentrations of quetiapine areexpected to increase. Concomitant administration of ritonavir andquetiapine is contraindicated as it may increase quetiapine-relatedtoxicity (see section 4.3).

β2-agonist (long acting)

Salmeterol Ritonavir inhibits CYP3A4 and as a result a pronounced increase in theplasma concentrations of salmeterol is expected. Therefore concomitantuse is not recommended.

Calcium channel antagonists

Amlodipine, diltiazem, Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviralnifedipine agent inhibits CYP3A4 and as a result is expected to increase theplasma concentrations of calcium channel antagonists. Carefulmonitoring of therapeutic and adverse effects is recommended whenthese medicinal products are concomitantly administered with ritonavir.

Endothelin antagonists

Bosentan Co-administration of bosentan and ritonavir may increase steady statebosentan maximum concentrations (Cmax) and area under the curve(AUC).

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

Ergot derivatives

Dihydroergotamine, ergonovine, Ritonavir co-administration is likely to result in increased plasmaergotamine, methylergonovine concentrations of ergot derivatives and is therefore contraindicated(see section 4.3).

Co-administered medicinal Dose of co- Dose of Effect on co- Effect on co-products administered ritonavir administered administeredmedicinal products (mg) medicinal medicinal(mg) products AUC products

Cmax

GI motility agent

Cisapride Ritonavir co-administration is likely to result in increased plasmaconcentrations of cisapride and is therefore contraindicated (seesection 4.3).

HCV Direct Acting Antiviral

Glecaprevir/pibrentasvir Serum concentrations may be increased due to P-glycoprotein, BCRPand OATP1B inhibition by ritonavir.

Concomitant administration of glecaprevir/pibrentasvir and ritonavir isnot recommended due to an increased risk of ALT elevations associatedwith increased glecaprevir exposure.

HCV protease inhibitor

Simeprevir 200 qd 100 q12 h ↑ 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 ritonavirwith simeprevir.

HMG co-A reductase inhibitors

Atorvastatin, fluvastatin, HMG-CoA reductase inhibitors which are highly dependent on CYP3Alovastatin, pravastatin, metabolism, such as lovastatin and simvastatin, are expected to haverosuvastatin, simvastatin markedly increased plasma concentrations when co-administered withritonavir dosed as an antiretroviral agent or as a pharmacokineticenhancer. Since increased concentrations of lovastatin and simvastatinmay predispose patients to myopathies, including rhabdomyolysis, thecombination of these medicinal products with ritonavir iscontraindicated (see section 4.3). Atorvastatin is less dependent on

CYP3A for metabolism. While rosuvastatin elimination is notdependent on CYP3A, an elevation of rosuvastatin exposure has beenreported with ritonavir co-administration. The mechanism of thisinteraction is not clear, but may be the result of transporter inhibition.

When used with ritonavir dosed as a pharmacokinetic enhancer or as anantiretroviral agent, the lowest possible doses of atorvastatin orrosuvastatin should be administered. The metabolism of pravastatin andfluvastatin is not dependent on CYP3A, and interactions are notexpected with ritonavir. If treatment with an HMG-CoA reductaseinhibitor is indicated, pravastatin or fluvastatin is recommended.

Hormonal contraceptive

Ethinylestradiol 50 μg, single dose 500 q12 h ↓ 40% ↓ 32%

Due to reductions in ethinylestradiol concentrations, barrier or othernon-hormonal methods of contraception should be considered withconcomitant ritonavir use when dosed as an antiretroviral agent or as apharmacokinetic enhancer. Ritonavir is likely to change the uterinebleeding profile and reduce the effectiveness of estradiol-containingcontraceptives (see section 4.4).

Immunosuppressants

Cyclosporine, tacrolimus, Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviraleverolimus agent inhibits CYP3A4 and as a result is expected to increase theplasma concentrations of cyclosporine, tacrolimus or everolimus.

Careful monitoring of therapeutic and adverse effects is recommendedwhen these medicinal products are concomitantly administered withritonavir.

Co-administered medicinal Dose of co- Dose of Effect on co- Effect on co-products administered ritonavir administered administeredmedicinal products (mg) medicinal medicinal(mg) products AUC products

Cmax

Lipid-modifying agents

Lomitapide CYP3A4 inhibitors increase the exposure of lomitapide, with stronginhibitors increasing exposure approximately 27-fold. Due to CYP3Ainhibition by ritonavir, concentrations of lomitapide are expected toincrease. Concomitant use of ritonavir with lomitapide iscontraindicated (see prescribing information for lomitapide) (seesection 4.3).

Phosphodiesterase (PDE5) inhibitors

Avanafil 50, single dose 600 q12 h ↑ 13-fold ↑ 2.4-fold

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

Sildenafil 100, single dose 500 q12 h ↑ 11-fold ↑ 4-fold

Concomitant use of sildenafil for the treatment of erectile dysfunctionwith ritonavir dosed as an antiretroviral agent or as a pharmacokineticenhancer should be with caution and in no instance should sildenafildoses exceed 25 mg in 48 hours (see also section 4.4). Concomitant useof sildenafil with ritonavir is contraindicated in pulmonary arterialhypertension patients (see section 4.3).

Tadalafil 20, single dose 200 q12 h ↑ 124% ↔

The concomitant use of tadalafil for the treatment of erectiledysfunction with ritonavir dosed as an antiretroviral agent or as apharmacokinetic enhancer should be with caution at reduced doses ofno more than 10 mg tadalafil every 72 hours with increased monitoringfor adverse reactions (see section 4.4).

When tadalafil is used concurrently with ritonavir in patients withpulmonary arterial hypertension, refer to the tadalafil Summary of

Product Characteristics.

Vardenafil 5, single dose 600 q12 h ↑ 49-fold ↑ 13-fold

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

Co-administered medicinal Dose of co- Dose of Effect on co- Effect on co-products administered ritonavir administered administeredmedicinal products (mg) medicinal medicinal(mg) products AUC products

Cmax

Sedatives/hypnotics

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

Midazolam is extensively metabolised by CYP3A4. Co-administrationwith ritonavir may cause a large increase in the concentration of thisbenzodiazepine. No medicinal product interaction study has beenperformed for the co-administration of ritonavir with benzodiazepines.

Based on data for other CYP3A4 inhibitors, plasma concentrations ofmidazolam are expected to be significantly higher when midazolam isgiven orally. Therefore, ritonavir should not be co-administered withorally administered midazolam (see section 4.3), whereas cautionshould be used with co-administration of ritonavir and parenteralmidazolam. Data from concomitant use of parenteral midazolam withother protease inhibitors suggest a possible 3 - 4 fold increase inmidazolam plasma levels. If ritonavir is co-administered withparenteral midazolam, it should be done in an intensive care unit (ICU)or similar setting which ensures close clinical monitoring andappropriate medical management in case of respiratory depressionand/or prolonged sedation. Dose adjustment for midazolam should beconsidered, especially if more than a single dose of midazolam isadministered.

Triazolam 0.125, single dose 200, 4 doses ↑ > 20 fold ↑ 87%

Ritonavir co-administration is likely to result in increased plasmaconcentrations of triazolam and is therefore contraindicated (seesection 4.3).

Pethidine 50, oral single dose 500 q12 h ↓ 62% ↓ 59%

Norpethidine metabolite ↑ 47% ↑ 87%

The use of pethidine and ritonavir is contraindicated due to theincreased concentrations of the metabolite, norpethidine, which hasboth analgesic and CNS stimulant activity. Elevated norpethidineconcentrations may increase the risk of CNS effects (e.g., seizures), seesection 4.3.

Alprazolam 1, single dose 200 q12 h, ↑ 2.5 fold ↔2 days500 q12 h, ↓ 12% ↓ 16%10 days

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

Buspirone Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviralagent inhibits CYP3A and as a result is expected to increase the plasmaconcentrations of buspirone. Careful monitoring of therapeutic andadverse effects is recommended when buspirone concomitantlyadministered with ritonavir.

Sleeping agent

Zolpidem 5 200, 4 doses ↑ 28% ↑ 22%

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

Co-administered medicinal Dose of co- Dose of Effect on co- Effect on co-products administered ritonavir administered administeredmedicinal products (mg) medicinal medicinal(mg) products AUC products

Cmax

Smoke cessation

Buproprion 150 100 q12 h ↓ 22% ↓ 21%150 600 q12 h ↓ 66% ↓ 62%

Bupropion is primarily metabolised by CYP2B6. Concurrentadministration of bupropion with repeated doses of ritonavir isexpected to decrease bupropion levels. These effects are thought torepresent induction of bupropion metabolism. However, becauseritonavir has also been shown to inhibit CYP2B6 in vitro, therecommended dose of bupropion should not be exceeded. In contrast tolong-term administration of ritonavir, there was no significantinteraction with bupropion after short-term administration of low dosesof ritonavir (200 mg twice daily for 2 days), suggesting reductions inbupropion concentrations may have onset several days after initiationof ritonavir co-administration.

Steroids

Inhaled, injectable or intranasal Systemic corticosteroid effects including Cushing's syndrome andfluticasone propionate, adrenal suppression (plasma cortisol levels were noted to be decreasedbudesonide, triamcinolone 86% in the above study) have been reported in patients receivingritonavir and inhaled or intranasal fluticasone propionate; similareffects could also occur with other corticosteroids metabolised by

CYP3A e.g., budesonide and triamcinolone. Consequently,concomitant administration of ritonavir dosed as an antiretroviral agentor as a pharmacokinetic enhancer and these glucocorticoids is notrecommended unless the potential benefit of treatment outweighs therisk of systemic corticosteroid effects (see section 4.4). A dosereduction of the glucocorticoid should be considered with closemonitoring 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 reductionmay be required over a longer period.

Dexamethasone Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviralagent inhibits CYP3A and as a result is expected to increase the plasmaconcentrations of dexamethasone. Careful monitoring of therapeuticand adverse effects is recommended when dexamethasone isconcomitantly administered with ritonavir.

Prednisolone 20 200 q12 h ↑ 28% ↑ 9%

Careful monitoring of therapeutic and adverse effects is recommendedwhen prednisolone is concomitantly administered with ritonavir. The

AUC of the metabolite prednisolone increased by 37 and 28% after 4and 14 days ritonavir, respectively.

Thyroid hormone replacement therapy

Levothyroxine Post-marketing cases have been reported indicating a potentialinteraction between ritonavir containing products and levothyroxine.

Thyroid-stimulating hormone (TSH) should be monitored in patientstreated with levothyroxine at least the first month after starting and/orending ritonavir treatment.

ND: Not determined1 Based on a parallel group comparison2 Sulfamethoxazole was co-administered with trimethoprim

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

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

Ritonavir dosed as a pharmacokinetic enhancer

Important information regarding medicinal product interactions when ritonavir is used apharmacokinetic enhancer is also contained in the Summary of Product Characteristics of theco-administered protease inhibitor.

Proton pump inhibitors and H2-receptor antagonists

Proton pump inhibitors and H2-receptor antagonists (e.g. omeprazole or ranitidine) may reduceconcentrations for co-administered protease inhibitors. For specific information regarding the impactof co-administration of acid reducing agents, refer to the Summary of Product Characteristics of theco-administered protease inhibitor. Based on interaction studies with the ritonavir boosted proteaseinhibitors (lopinavir/ritonavir, atazanavir), concurrent administration of omeprazole or ranitidine doesnot significantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change ofexposure (about 6 - 18%).

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

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

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 onmilk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2)developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in a breastfedinfant, women living with HIV should not breast-feed their infants if they are receiving ritonavir.

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

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

Ritonavir dosed as a pharmacokinetic enhancer

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

Ritonavir dosed as an antiretroviral agent

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

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

The following adverse reactions of moderate to severe intensity with possible or probable relationshipto ritonavir have been reported. Within each frequency grouping, adverse reactions are presented inorder 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 theavailable data).

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

Table 6. Adverse reactions in clinical studies and post-marketing in adult patients

System Order Class Frequency Adverse reaction

Blood and lymphatic system Common Decreased white blood cells, decreaseddisorders haemoglobin, decreased neutrophils, increasedeosinophils, thrombocytopenia

Uncommon Increased neutrophils

Immune system disorders Common Hypersensitivity including urticaria, and faceoedema

Rare Anaphylaxis

Metabolism and nutrition Common Hypercholesterolaemia, hypertriglyceridaemia,disorders gout, oedema and peripheral oedema,dehydration (usually associated withgastrointestinal 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 inattention, syncope, seizure

System Order Class Frequency Adverse reaction

Eye disorders Common Blurred vision

Cardiac disorders Uncommon Myocardial infarction

Vascular disorders Common Hypertension, hypotension includingorthostatic hypotension, peripheral coldness

Respiratory, thoracic and Very common Pharyngitis, oropharyngeal pain, coughmediastinal disorders

Gastrointestinal disorders Very common Abdominal pain (upper and lower), nausea,diarrhoea (including severe with electrolyteimbalance), vomiting, dyspepsia

Common Anorexia, flatulence, mouth ulcer,gastrointestinal haemorrhage, gastroesophagealreflux disease, pancreatitis

Hepatobiliary disorders Common Hepatitis (including increased AST, ALT,

GGT), blood bilirubin increased (includingjaundice)

Skin and subcutaneous tissue Very common Pruritus, rash (including erythematous anddisorders maculopapular)

Common Acne

Rare Stevens Johnson syndrome, toxic epidermalnecrolysis (TEN)

Musculoskeletal and Very common Arthralgia and back painconnective tissue disorders

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 Common Menorrhagiabreast disorders

General disorders and Very common Fatigue including asthenia, flushing, feelingadministration site conditions hot

Common Fever, weight loss

Investigations Common Increased amylase, decreased free and totalthyroxin

Uncommon Increased glucose, increased magnesium,increased alkaline phosphatase

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

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) havealso been reported; however, the reported time to onset is more variable and can occur many monthsafter initiation of treatment (see section 4.4).

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

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged riskfactors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).

The frequency of this is unknown (see section 4.4).

Paediatric populations

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Human experience of acute overdose with ritonavir is limited. One patient in clinical studies tookritonavir 1,500 mg/day for two days and reported paraesthesia, which resolved after the dose wasdecreased. A case of renal failure with eosinophilia has been reported.

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

There is no specific antidote for overdose with ritonavir. Treatment of overdose with ritonavir shouldconsist of general supportive measures including monitoring of vital signs and observation of theclinical status of the patient. Due to the solubility characteristics and possibility of transintestinalelimination, it is proposed that management of overdose could entail gastric lavage and administrationof activated charcoal. Since ritonavir is extensively metabolised by the liver and is highly proteinbound, dialysis is unlikely to be beneficial in significant removal of the medicinal product.

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

Ritonavir dosed as a pharmacokinetic enhancer

Pharmacokinetic enhancement by ritonavir is based on ritonavir’s activity as a potent inhibitor of

CYP3A- mediated metabolism. The degree of enhancement is related to the metabolic pathway of theco-administered protease inhibitor and the impact of the co-administered protease inhibitor on themetabolism of ritonavir. Maximal inhibition of metabolism of the co-administered protease inhibitor isgenerally achieved with ritonavir doses of 100 mg daily to 200 mg twice daily, and is dependent onthe co-administered protease inhibitor. For additional information on the effect of ritonavir onco-administered protease inhibitor metabolism, see section 4.5 and refer to the Summary of Product

Characteristics of the particular co-administered PIs.

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 polyproteinprecursor which leads to the production of HIV particles with immature morphology that are unable toinitiate new rounds of infection. Ritonavir has selective affinity for the HIV protease and has littleinhibitory activity against human aspartyl proteases.

Ritonavir was the first protease inhibitor (approved in 1996) for which efficacy was proven in a studywith clinical endpoints. However, due to ritonavir’s metabolic inhibitory properties its use as apharmacokinetic enhancer of other protease inhibitors is the prevalent use of ritonavir in clinicalpractice (see section 4.2).

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. Themaximum mean (95% upper confidence bound) difference in QTcF from placebo was 5.5 (7.6) for400 mg twice daily ritonavir. The Day 3 ritonavir exposure was approximately 1.5 fold higher thanthat 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 relevantthreshold of 500 msec.

Modest prolongation of the PR interval was also noted in subjects receiving ritonavir in the same studyon Day 3. The mean changes from baseline in PR interval ranged from 11.0 to 24.0 msec in the12 hour interval post dose. Maximum PR interval was 252 msec and no second or third degree heartblock was observed (see section 4.4).

Ritonavir-resistant isolates of HIV-1 have been selected in vitro and isolated from patients treated withtherapeutic 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 positions20, 33, 36, 46, 54, 71, and 90) can also contribute to ritonavir resistance. In general, as mutationsassociated with ritonavir resistance accumulate, susceptibility to select other PIs may decrease due tocross-resistance. The Summary of Product Characteristics of other protease inhibitors or officialcontinuous updates should be consulted for specific information regarding protease mutationsassociated with reduced response to these agents.

Clinical pharmacodynamic data

The effects of ritonavir (alone or combined with other antiretroviral agents) on biological markers ofdisease 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 patientsextensively pre-treated with nucleoside analogues and baseline CD4 cell counts ≤ 100 cells/μl showeda reduction in mortality and AIDS defining events. The mean average change from baseline over16 weeks for HIV RNA levels was -0.79 log10 (maximum mean decrease: 1.29 log10) in the ritonavirgroup versus -0.01 log10 in the control group. The most frequently used nucleosides in this study werezidovudine, 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 reducedviral load in plasma and increased CD4 count. The mean average change from baseline over 48 weeksfor 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.

The continuation of ritonavir therapy should be evaluated by viral load because of the possibility ofthe emergence of resistance as described under section 4.1.

Paediatric use

In an open label study completed in 1998 in HIV infected, clinically stable children there was asignificant 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 age4 weeks to 2 years received ritonavir 350 or 450 mg/m2 every 12 hours co-administered withzidovudine 160 mg/m2 every 8 hours and lamivudine 4 mg/kg every 12 hours. In intent to treatanalyses, 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 wereprotease inhibitor naive and naive to lamivudine and/or stavudine received ritonavir 350 or 450 mg/m2every 12 hours co-administered with lamivudine and stavudine. In intent to treat analyses, 50% and57% 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.

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

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

Table 7. Ritonavir dosing regimen100 mg once 100 mg twice 200 mg once 200 mg twice 600 mg twicedaily daily1 daily daily daily

Cmax (μg/ml) 0.84 ± 0.39 0.89 3.4 ± 1.3 4.5 ± 1.3 11.2 ± 3.6

Ctrough (μg/ml) 0.08 ± 0.04 0.22 0.16 ± 0.10 0.6 ± 0.2 3.7 ± 2.6

AUC12 or 24 6.6 ± 2.4 6.2 20.0 ± 5.6 21.92 ± 6.48 77.5 ± 31.5(μg*h/ml)t1/2 (h) ~5 ~5 ~4 ~8 ~3 to 5

Cl/F (L/h) 17.2 ± 6.6 16.1 10.8 ± 3.1 10.0 ± 3.2 8.8 ± 3.21 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 ritonavir tablet. Administration of a single 100 mgdose of ritonavir 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 AUCand Cmax.

The apparent volume of distribution (VB/F) of ritonavir is approximately 20 - 40 l after a single600 mg dose. The protein binding of ritonavir in human plasma is approximately 98 - 99% and isconstant over the concentration range of 1.0 - 100 μg/ml. Ritonavir binds to both human alpha 1-acidglycoprotein (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 ofapproximately 1 measured in rat lymph nodes suggests that ritonavir distributes into lymphatic tissues.

Ritonavir penetrates minimally into the brain.

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

Low doses of ritonavir have shown profound effects on the pharmacokinetics of other proteaseinhibitors (and other products metabolised by CYP3A4) and other protease inhibitors may influencethe pharmacokinetics of ritonavir (see section 4.5).

Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir wasprimarily 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 foundto be a major route of elimination of ritonavir. This was consistent with the observations in animalstudies.

No clinically significant differences in AUC or Cmax were noted between males and females. Ritonavirpharmacokinetic parameters were not statistically significantly associated with body weight or leanbody mass. Ritonavir plasma exposures in patients 50 - 70 years of age when dosed 100 mg incombination with lopinavir or at higher doses in the absence of other protease inhibitors is similar tothat 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 tomoderate hepatic impairment (Child Pugh Class A and B, 400 mg twice daily) exposure to ritonavirafter 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 areexpected in patients with renal impairment.

Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children above2 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 werecomparable 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 inpaediatric patients above 2 years of age than in adult subjects.

Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children less than2 years of age receiving doses ranging from 350 to 450 mg/m2 twice daily. Ritonavir concentrations inthis 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/m2in 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, thyroidgland and kidney. Hepatic changes involved hepatocellular, biliary and phagocytic elements and wereaccompanied 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 havenot been seen in dogs. Ultrastructural evidence suggests that these retinal changes may be secondary tophospholipidosis. However, clinical studies revealed no evidence of medicinal product-induced ocularchanges in humans. All thyroid changes were reversible upon discontinuation of ritonavir.

Clinical investigation in humans has revealed no clinically significant alteration in thyroid functiontests. Renal changes including tubular degeneration, chronic inflammation and proteinurea were notedin rats and are felt to be attributable to species-specific spontaneous disease. Furthermore, no clinicallysignificant renal abnormalities were noted in clinical studies.

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

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

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

Tablet

Copovidone

Sorbitan laurate

Silica, colloidal anhydrous

Sodium chloride

Sodium stearyl fumarate

Hypromellose

Titanium dioxide (E171)

Macrogols

Hydroxypropylcellulose

Talc

Iron oxide yellow (E172)

Silica, colloidal anhydrous

Polysorbate 80

Not applicable.

2 years.

For HDPE bottle: After first opening, use within 45 days.

Do not store above 30 °C.

Store in the original packaging in order to protect from moisture.

HDPE bottle with polypropylene screw cap with aluminium induction sealing liner wad and adesiccant.

Pack sizes: 30, 90, 100 and multipack containing 90 (3 bottles of 30) film-coated tablets.

OPA/Alu/PVC-Alu blister pack containing 30 and 90 tablets.

OPA/Alu/PVC-Alu perforated unit dose blister pack containing 30 x 1, 90 x 1 tablets.

Not all pack sizes may be marketed.

No special requirements.

Mylan Pharmaceuticals Limited

Damastown Industrial Park,

Mulhuddart, Dublin 15,

DUBLIN

Ireland

EU/1/17/1242/001

EU/1/17/1242/002

EU/1/17/1242/003

EU/1/17/1242/004

EU/1/17/1242/005

EU/1/17/1242/006

EU/1/17/1242/007

EU/1/17/1242/008

Date of first authorisation: 10 November 2017

Date of latest renewal:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu