NORVIR 100mg tablets medication leaflet

Norvir 100 mg powder for oral suspension

Each sachet of powder for oral suspension contains 100 mg of ritonavir.

For the full list of excipients, see section 6.1.

Powder for oral suspension.

Beige/pale yellow to yellow powder.

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

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 1000 mg twice daily with ritonavir 100 mg twice daily in ART experienced patients.

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

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

Darunavir 600 mg twice daily with ritonavir 100 mg twice daily in antiretroviral treatment(ART) experienced patients. Darunavir 800 mg once daily with ritonavir 100 mg once dailymay be used in some ART experienced patients. Refer to the darunavir Summary of Product

Characteristics for further information on once daily dosing in ART experienced patients.

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

Children and adolescents

Ritonavir is recommended for children 2 years of age and older. For further dosage recommendations,refer to the product information of other protease inhibitors approved for co-administration 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 Norvir powder for oral suspension is 600 mg (six sachets) twice daily bymouth and should be given with food.

Gradually increasing the dose of ritonavir when initiating therapy may help to improve tolerance.

Treatment should be initiated at 300 mg (three sachets) twice daily for a period of three days andincreased by 100 mg (one sachet) twice daily increments up to 600 mg twice daily over a period of nolonger than 14 days. Patients should not remain on 300 mg twice daily for more than 3 days.

Refer to Method of Administration section below and section 6.6 for details on preparing doses.

Children and adolescents (2 years of age and above)

The recommended dosage of Norvir powder for suspension in children is 350 mg/m² by mouth twicedaily and should not exceed 600 mg twice daily. Norvir should be started at 250 mg/m² and increasedat 2 to 3 day intervals by 50 mg/m² twice daily.

Paediatric dosage guidelines for Norvir powder for oral suspension (prepared as100 mg/10 ml)*†

Body Surface Twice Daily Dose Twice Daily Dose Twice Daily Dose

Area (m2) 250 mg/m2 300 mg/m2 350 mg/m20.25 6.4 ml (62.5 mg) 7.6 ml (76 mg) 8.8 ml (88 mg)0.50 12.6 ml (126 mg) 15.0 ml (150 mg) 17.6 ml (176 mg)0.75 18.8 ml (188 mg) 22.6 ml (226 mg) 26.4 ml (262.5 mg)1.00 25.0 ml (250 mg) 30.0 ml (300 mg) 35.0 ml (350 mg)1.25 31.4 ml (312.5 mg) 37.6 ml (376 mg) 43.8 ml (438mg)1.50 37.6 ml (376 mg) 45.0 ml (450 mg) 52.6 ml (526 mg)

*When mixed with 9.4 ml of liquid the concentration of the suspension is 10 mg/ml.

†In some instances, the volumes and/or doses have been adjusted to ensure the recommended final dose anddosing volume.

Body surface area can be calculated with the following equation: BSA (m2) = √(Height (cm) X Weight (kg) /3600)

To calculate the volume to be administered (in ml) for intermediate body surface areas not included inthe above table, the body surface area should be multiplied by a factor of: 25 for a dose of 250 mg/m²;30 for 300 mg/m²; and 35 for 350 mg/m².

Refer to Method of Administration section below and section 6.6 for details on preparing doses.

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 dosagerecommendations 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 Norvir 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.

Norvir powder for oral suspension is administered orally, poured on soft food (apple sauce or vanillapudding) or mixed with liquid (water, chocolate milk, or infant formula). For details on preparationand administration of the Norvir powder for oral suspension, see section 6.6. Any mixing outside therecommendations is the responsibility of the health care professional or the user.

Norvir powder for oral suspension should be taken with food. The bitter aftertaste of Norvir powderfor oral suspension may be lessened if peanut butter, hazelnut chocolate spread, or black currant syrupare taken immediately after dose administration.

The prescribed dose of Norvir powder for oral suspension can be administered via a feeding tube afterbeing mixed with water as detailed in section 6.6. Follow the instructions for the feeding tube toadminister the medicine.

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 medicines are contraindicated when used withritonavir and unless otherwise noted, the contraindication is based on the potential for ritonavir toinhibit metabolism of the co-administered medicinal product, resulting in increased exposure to theco-administered medicinal product and risk of clinically significant adverse effects.

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

Medicinal Product Medicinal Products Rationale

Class within Class

Concomitant medicinal product levels increased or decreased1-Adrenoreceptor Alfuzosin Increased plasma concentrations of alfuzosin

Antagonist which may lead to severe hypotension (seesection 4.5).

Analgesics Pethidine, Increased plasma concentrations ofpropoxyphene norpethidine and propoxyphene. Thereby,increasing the risk of serious respiratorydepression or haematologic abnormalities, orother serious adverse effects from these agents.

Antianginal Ranolazine Increased plasma concentrations of ranolazinewhich may increase the potential for seriousand/or life-threatening reactions (see section4.5).

Anticancer Neratinib Increased plasma concentrations of neratinibwhich may increase the potential for seriousand/or life-threatening reactions includinghepatotoxicity (see section 4.5).

Venetoclax Increased plasma concentrations of venetoclax.

Increased risk of tumor lysis syndrome at thedose initiation and during the dose-titrationphase (see section 4.5).

Antiarrhythmics Amiodarone, bepridil, Increased plasma concentrations of amiodarone,dronedarone, bepridil, dronedarone, encainide, flecanide,encainide, flecanide, propafenone, quinidine. Thereby, increasingpropafenone, quinidine the risk of arrhythmias or other serious adversereactions from these agents.

Antibiotic Fusidic Acid Increased plasma concentrations of fusidic acidand ritonavir.

Antifungal Voriconazole Concomitant use of ritonavir (400 mg twicedaily and more) and voriconazole iscontraindicated due to a reduction invoriconazole plasma concentrations andpossible loss of effect (see section 4.5).

Anti-gout Colchicine Potential for serious and/or life-threateningreactions in patients with renal and/or hepaticimpairment (see sections 4.4 and 4.5).

Antihistamines Astemizole, Increased plasma concentrations of astemizoleterfenadine and terfenadine. Thereby, increasing the risk ofserious arrhythmias from these agents.

Antimycobacterial Rifabutin Concomitant use of ritonavir (500 mg twicedaily) dosed as an antiretroviral agent andrifabutin due to an increase of rifabutin serumconcentrations and risk of adverse eventsincluding uveitis (see section 4.4).

Recommendations regarding use of ritonavirdosed as a pharmacokinetic enhancer withrifabutin are noted in section 4.5.

Antipsychotics/ Lurasidone Increased plasma concentrations of lurasidone

Neuroleptics which may increase the potential for seriousand/or life-threatening reactions (see section4.5).

Clozapine, pimozide Increased plasma concentrations of clozapineand pimozide. Thereby, increasing the risk ofserious haematologic abnormalities, or otherserious adverse effects from these agents.

Quetiapine Increased plasma concentrations of quetiapinewhich may lead to coma. The concomitantadministration with quetiapine iscontraindicated (see section 4.5).

Ergot Derivatives Dihydroergotamine, Increased plasma concentrations of ergotergonovine, derivatives leading to acute ergot toxicity,ergotamine, including vasospasm and ischaemia.methylergonovine

GI motility agent Cisapride Increased plasma concentrations of cisapride.

Thereby, increasing the risk of seriousarrhythmias from this agent.

Lipid-modifying agents

HMG Co-A Reductase Lovastatin, simvastatin Increased plasma concentrations of lovastatin

Inhibitors and simvastatin; thereby, increasing the risk ofmyopathy including rhabdomyolysis (seesection 4.5).

Microsomal Lomitapide Increased plasma concentrations of lomitapidetriglyceride transfer (see section 4.5).protein (MTTP)inhibitor

PDE5 inhibitors Avanafil Increased plasma concentrations of avanafil(see section 4.4. and 4.5).

Sildenafil Contraindicated when used for the treatment ofpulmonary arterial hypertension (PAH) only.

Increased plasma concentrations of sildenafil.

Thereby, increasing the potential for sildenafil-associated adverse events (which includehypotension and syncope). See section 4.4 andsection 4.5 for co-administration of sildenafil inpatients with erectile dysfunction.

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

Sedatives/hypnotics Clorazepate, diazepam, Increased plasma concentrations of clorazepate,estazolam, flurazepam, diazepam, estazolam, flurazepam, oraloral midazolam and midazolam and triazolam. Thereby, increasingtriazolam the risk of extreme sedation and respiratorydepression from these agents. (For caution onparenterally administered midazolam, seesection 4.5).

Ritonavir medicinal product level decreased

Herbal Preparation St. John’s wort Herbal preparations containing St John’s wort(Hypericum perforatum) due to the risk ofdecreased plasma concentrations and reducedclinical effects of ritonavir (see section 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 and

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

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).

Medication error

Special attention should be given to the accurate calculation of the dose of Norvir, transcription of themedication order, dispensing information and dosing instructions to minimise the risk for medicationerrors and underdose. This is especially important for infants and young children.

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. Norvir should be used with caution in such patients (seesection 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. Whenritonavir is used as a pharmacokinetic enhancer, full details on the warnings and precautions relevantto that particular PI must be considered, therefore the Summary of Product Characteristics, section 4.4,for the 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 avanafilor vardenafil 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 drug interactions have been reported in patients treated with colchicine andstrong inhibitors 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 patient 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 duringthis period, with dose adjustments made, as necessary, based on clinical, electrocardiographic anddigoxin level findings.

Ethinyl estradiol

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 medicines are giventogether (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 inpatients with 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 200mg once daily could beconsidered. In this instance, close clinical monitoring is warranted. Refer to the Summary of Product

Characteristics for atazanavir for further details.

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 productmetabolising enzymes by St John’s wort. Herbal preparations containing St John’s wort must not beused in combination with ritonavir. If a patient is already taking St John’s wort, St John’s wort shouldbe stopped and if possible check viral levels. Ritonavir levels may increase on stopping St John’swort. The dose of ritonavir may need adjusting. The inducing effect may persist for at least 2 weeksafter cessation of treatment with St John’s wort (see section 4.3).

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

Medicinal product 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.

Medicinal Product Interactions - Ritonavir with Protease Inhibitors

Co- Dose of Co-administered Dose of NORVIR Medicinal AUC Cminadministered Medicinal Product (mg) (mg) Product

Medicinal Assessed

Product

Amprenavir 600 q12h 100 q12h Amprenavir1 ↑ 64% ↑ 5 fold

Ritonavir increases the serum levels of amprenavir as a result of CYP3A4 inhibition. Clinicaltrials confirmed the safety and efficacy of 600 mg amprenavir twice daily with ritonavir 100 mgtwice daily. For further information, physicians should refer to the Summary of Product

Characteristics for amprenavir.

Atazanavir 300 q24h 100 q24h Atazanavir ↑ 86% ↑ 11 fold

Atazanavir2 ↑ 2 fold ↑ 3-7 fold

Ritonavir increases the serum levels of atazanavir as a result of CYP3A4 inhibition. Clinicaltrials confirmed the safety and efficacy of 300 mg atazanavir once daily with ritonavir 100 mgonce daily in treatment experienced patients. For further information, physicians should refer tothe Summary of Product Characteristics for atazanavir.

Darunavir 600, single 100 q12h Darunavir ↑ 14 fold

Ritonavir increases the serum levels of darunavir as a result of CYP3A inhibition. Darunavirmust be given with ritonavir to ensure its therapeutic effect. Ritonavir doses higher than100 mg twice daily have not been studied with darunavir. For further information, refer to the

Summary of Product Characteristics for darunavir.

Fosamprenavir 700 q12h 100 q12h Amprenavir ↑ 2.4 fold ↑ 11 fold

Ritonavir increases the serum levels of amprenavir (from fosamprenavir) as a result of CYP3A4inhibition. Fosamprenavir must be given with ritonavir to ensure its therapeutic effect. Clinicaltrials confirmed the safety and efficacy of fosamprenavir 700 mg twice daily with ritonavir100 mg twice daily. Ritonavir doses higher than 100 mg twice daily have not been studied withfosamprenavir. For further information, physicians should refer to the Summary of Product

Characteristics for fosamprenavir.

Indinavir 800 q12h 100 q12h Indinavir3 ↑ 178% ND

Ritonavir ↑ 72% ND400 q12h 400 q12h Indinavir3 ↔ ↑ 4 fold

Ritonavir ↔ ↔

Ritonavir increases the serum levels of indinavir as a result of CYP3A4 inhibition. Appropriatedoses for this combination, with respect to efficacy and safety, have not been established.

Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doseshigher than 100 mg twice daily. In cases of co-administration of ritonavir (100 mg twice daily)and indinavir (800 mg twice daily) caution is warranted as the risk of nephrolithiasis may beincreased.

Nelfinavir 1250 q12h 100 q12h Nelfinavir ↑ 20to39% ND750, single 500 q12h Nelfinavir ↑ 152% ND

Ritonavir ↔ ↔

Ritonavir increases the serum levels of nelfinavir as a result of CYP3A4 inhibition. Appropriatedoses for this combination, with respect to efficacy and safety, have not been established.

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

Saquinavir 1000 q12h 100 q12h Saquinavir4 ↑ 15-fold ↑ 5-fold

Ritonavir ↔ ↔400 q12h 400 q12h Saquinavir4 ↑ 17-fold ND

Ritonavir ↔ ↔

Ritonavir increases the serum levels of saquinavir as a result of CYP3A4 inhibition. Saquinavirshould only be given in combination with ritonavir. Ritonavir 100 mg twice daily withsaquinavir 1000 mg twice daily provides saquinavir systemic exposure over 24 hours similar toor greater than those achieved with saquinavir 1200 mg three times daily without ritonavir.

In a clinical study investigating the interaction of rifampicin 600 mg once daily and saquinavir1000 mg with ritonavir 100 mg twice daily in healthy volunteers, severe hepatocellular toxicitywith transaminase elevations up to > 20-fold the upper limit of normal after 1 to 5 days ofco-administration was noted. Due to the risk of severe hepatoxicity, saquinavir/ritonavir shouldnot be given together with rifampicin.

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

Tipranavir 500 q12h 200 q12h Tipranavir ↑ 11 fold ↑ 29 fold

Ritonavir ↓ 40% ND

Ritonavir increases the serum levels of tipranavir as a result of CYP3A inhibition. Tipranavirmust be given with low dose ritonavir to ensure its therapeutic effect. Doses of ritonavir lessthan 200 mg twice daily should not be used with tipranavir as they might alter the efficacy of thecombination. For further information, physicians should refer to the Summary of Product

Characteristics for tipranavir.

ND: Not determined.

1. Based on cross-study comparison to 1200 mg amprenavir twice daily alone.

2. Based on cross-study comparison to 400 mg atazanavir once 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.

Medicinal product interactions - Ritonavir with antiretroviral agents other than proteaseinhibitors

Co- Dose of Co- Dose of Medicinal Product AUC Cminadministered administered NORVIR (mg) Assessed

Medicinal Medicinal

Product Product(mg)

Didanosine 200 q12h 600 q12h 2 h Didanosine ↓ 13% ↔later

As ritonavir is recommended to be taken with food and didanosine should be taken on an emptystomach, dosing should be separated by 2.5 h. Dose alterations should not be necessary.

Delavirdine 400 q8h 600 q12h Delavirdine1 ↔ ↔

Ritonavir ↑ 50% ↑ 75%

Based on comparison to historical data, the pharmacokinetics of delavirdine did not appear to beaffected by ritonavir. When used in combination with delavirdine, dose reduction of ritonavirmay be considered.

Efavirenz 600 q24h 500 q12h Efavirenz ↑ 21%

Ritonavir ↑ 17%

A higher frequency of adverse reactions (e.g., dizziness, nausea, paraesthesia) and laboratoryabnormalities (elevated liver enzymes) have been observed when efavirenz is co-administeredwith ritonavir dosed as an antiretroviral agent.

Maraviroc 100 q12h 100 q12h Maraviroc ↑161% ↑28%

Ritonavir increases the serum levels of maraviroc as a result of CYP3A inhibition. Maravirocmay be given with ritonavir to increase the maraviroc exposure. For further information, refer tothe Summary of Product Characteristics for maraviroc.

Nevirapine 200 q12h 600 q12h Nevirapine ↔ ↔

Ritonavir ↔ ↔

Co-administration of ritonavir with nevirapine does not lead to clinically relevant changes in thepharmacokinetics of either nevirapine or ritonavir.

Raltegravir 400 single 100 q12h Raltegravir ↓ 16% ↓ 1%

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

Zidovudine 200 q8h 300 q6h Zidovudine ↓ 25% ND

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

ND: Not determined1. Based on parallel group comparison.

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Alpha1-Adrenoreceptor

Antagonist

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

Amphetamine Derivatives

Amphetamine Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 and as a resultis expected to increase concentrations of amphetamine and its derivatives. Carefulmonitoring of therapeutic and adverse effects is recommended when these medicinesare concomitantly administered with antiretroviral doses of ritonavir (see section4.4).

Analgesics

Buprenorphine 16 q24h 100 q12h ↑ 57% ↑ 77%

Norbuprenorphine ↑ 33% ↑ 108%

Glucuronide metabolites  

The increases of plasma levels of buprenorphine and its active metabolite did notlead to clinically significant pharmacodynamic changes in a population of opioidtolerant patients. Adjustment to the dose of buprenorphine or ritonavir maytherefore not be necessary when the two are dosed together. When ritonavir is usedin combination with another protease inhibitor and buprenorphine, the SPC of theco-administered protease inhibitor should be reviewed for specific dosinginformation.

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

Fentanyl Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits

CYP3A4 and as a result is expected to increase the plasma concentrations offentanyl. Careful monitoring of therapeutic and adverse effects (includingrespiratory depression) is recommended when fentanyl is concomitantlyadministered with ritonavir.

Methadone1 5, single dose 500 q12h, ↓ 36% ↓ 38%

Increased methadone dose may be necessary when concomitantly administered withritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer due toinduction of glucuronidation. Dose adjustment should be considered based on thepatient’s clinical response to methadone therapy.

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

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Antianginal

Ranolazine Due to CYP3A inhibition by ritonavir, concentrations of ranolazine are expected toincrease. The concomitant administration with ranolazine is contraindicated (seesection 4.3).

Antiarrthymics

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

Digoxin 0.5 single IV dose 300 q12h, 3 days ↑ 86% ND0.4 single oral dose 200 q12h, 13 days ↑ 22% 

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

Antiasthmatic

Theophylline1 3 mg/kg q8h 500 q12h ↓ 43% ↓ 32%

An increased dose of theophylline may be required when co-administered withritonavir, due to induction of CYP1A2.

Anticancer agents and kinaseinhibitors

Afatinib 20 mg, single dose 200 q12h/1h ↑ 48% ↑ 39%40 mg, single dose before40 mg, single dose 200 q12h/ co- ↑ 19% ↑ 4%administered200 q12h/6h after ↑ 11% ↑ 5%

Serum concentrations may be increased due to Breast Cancer Resistance Protein(BCRP) and acute P-gp inhibition by ritonavir. The extent of increase in AUC and

Cmax depends on the timing of ritonavir administration. Caution should be exercisedin administering afatinib with Norvir (refer to the afatinib SmPC). Monitor for

ADRs related to afatinib.

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

Co-administration of abemaciclib and Norvir should be avoided. If thisco-administration is judged unavoidable, refer to the abemaciclib SmPC for dosageadjustment recommendations. Monitor for ADRs related to abemaciclib.

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

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

Concomitant use of ritonavir with apalutamide is not recommended.

Ceritinib Serum concentrations may be increased due to CYP3A and P-gp inhibition byritonavir. Caution should be exercised in administering ceritinib with Norvir. Referto the ceritinib SmPC for dosage adjustment recommendations. Monitor for ADRsrelated to ceritinib.

Dasatinib, nilotinib, vincristine, Serum concentrations may be increased when co-administered with ritonavirvinblastine resulting in the potential for increased incidence of adverse events.

Encorafenib Serum concentrations may be increased when co-administered with ritonavir whichmay increase the risk of toxicity, including the risk of serious adverse events such as

QT interval prolongation. Co-administration of encorafenib and ritonavir should beavoided. If the benefit is considered to outweigh the risk and ritonavir must be used,patients should be carefully monitored for safety.

Fostamatinib Co-administration of fostamatinib with ritonavir may increase fostamatinibmetabolite R406 exposure resulting in dose-related adverse events such ashepatotoxicity, neutropenia, hypertension, or diarrhoea. Refer to the fostamatinib

SmPC for dose reduction recommendations if such events occur.

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

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

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

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

For patients who have completed the ramp-up phase and are on a steady daily doseof venetoclax, reduce the venetoclax dose by at least 75% when used with strong

CYP3A inhibitors (refer to the venetoclax SmPC for dosing instructions).

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Anticoagulants

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

Edoxaban monitoring and/or dose reduction of the direct oral anticoagulants (DOAC) shouldbe considered when a DOAC transported by P-gp but not metabolised by CYP3A4,including dabigatran etexilate and edoxaban, is co-administered with ritonavir.

Rivaroxaban 10, single dose 600 q12h ↑ 153% ↑ 55%

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

Vorapaxar Serum concentrations may be increased due to CYP3A inhibition by ritonavir. Theco-administration of vorapaxar with Norvir is not recommended (see section 4.4 andrefer to the vorapaxar SmPC).

Warfarin 5, single dose 400 q12h

S-Warfarin ↑ 9% ↓ 9%

R-Warfarin ↓ 33% ↔

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

Anticonvulsants

Carbamazepine Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits

CYP3A4 and as a result is expected to increase the plasma concentrations ofcarbamazepine. Careful monitoring of therapeutic and adverse effects isrecommended when carbamazepine is concomitantly administered with ritonavir.

Divalproex, lamotrigine, phenytoin Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inducesoxidation by CYP2C9 and glucuronidation and as a result is expected to decreasethe plasma concentrations of anticonvulsants. Careful monitoring of serum levels ortherapeutic effects is recommended when these medicines are concomitantlyadministered with ritonavir. Phenytoin may decrease serum levels of ritonavir.

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Antidepressants

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

Desipramine 100, single oral dose 500 q12h ↑ 145% ↑ 22%

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

Trazodone 50, single dose 200 q12h ↑ 2.4-fold ↑ 34%

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

Anti-gout treatments

Colchicine Concentrations of colchicine are expected to increase when coadministered withritonavir.

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

Antihistamines

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

Fexofenadine Ritonavir may modify P-glycoprotein mediated fexofenadine efflux when dosed asan antriretroviral agent or as a pharmacokinetic enhancer resulting in increasedconcentrations of fexofenadine. Increased fexofenadine levels may lessen over timeas induction develops.

Loratadine Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits

CYP3A and as a result is expected to increase the plasma concentrations ofloratadine. Careful monitoring of therapeutic and adverse effects is recommendedwhen loratidine is concomitantly administered with ritonavir.

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Anti-infectives

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

Rifabutin1 150 daily 500 q12h, ↑ 4-fold ↑ 2.5-fold25-O-desacetyl rifabutin metabolite ↑ 38-fold ↑ 16-fold

Due to the large increase in rifabutin AUC, the concomitant use of rifabutin withritonavir dosed as an antiretroviral agent is contraindicated (see section 4.3). Thereduction of the rifabutin dose to 150 mg 3 times per week may be indicated forselect PIs when co-administered with ritonavir as a pharmacokinetic enhancer. The

Summary of Product Characteristics of the co-administered protease inhibitor shouldbe consulted for specific recommendations. Consideration should be given toofficial guidance on the appropriate treatment of tuberculosis in HIV-infectedpatients.

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

Voriconazole 200 q12h 400 q12h ↓ 82% ↓ 66%200 q12h 100 q12h ↓ 39% ↓ 24%

Concomitant use of ritonavir dosed as an antiretroviral agent and voriconazole iscontraindicated due to reduction in voriconazole concentrations (see section 4.3).

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

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

Bedaquiline No interaction study is available with ritonavir only. In an interaction study ofsingle-dose bedaquiline and multiple dose lopinavir/ritonavir, the AUC ofbedaquiline was increased by 22%. This increase is likely due to ritonavir and amore pronounced effect may be observed during prolonged co-administration. Dueto the risk of bedaquiline related adverse events, co-administration should beavoided. If the benefit outweighs the risk, co-administration of bedaquiline withritonavir must be done with caution. More frequent electrocardiogram monitoringand monitoring of transaminases is recommended (see section 4.4 and refer to thebedaquiline Summary of Product Characteristics).

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Clarithromycin 500 q12h 200 q8h ↑ 77% ↑ 31%14-OH clarithromycin metabolite ↓ 100% ↓ 99%

Due to the large therapeutic window of clarithromycin no dose reduction should benecessary in patients with normal renal function. Clarithromycin doses greater than1 g per day should not be co-administered with ritonavir dosed as an antiretroviralagent or as a pharmacokinetic enhancer. For patients with renal impairment, aclarithromycin dose reduction should be considered: for patients with creatinineclearance of 30 to 60 ml/min the dose should be reduced by 50%, for patients withcreatinine clearance less than 30 ml/min the dose should be reduced by 75%.

Delamanid No interaction study is available with ritonavir only. In a healthy volunteer druginteraction study of delamanid 100 mg twice daily and lopinavir/ritonavir400/100 mg twice daily for 14 days, the exposure of the delamanid metabolite DM-6705 was 30% increased. Due to the risk of QTc prolongation associated with

DM-6705, if co-administration of delamanid with ritonavir is considered necessary,very frequent ECG monitoring throughout the full delamanid treatment period 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 antiretroviral agent inhibits

CYP3A4 and as a result is expected to increase the plasma concentrations oferythromycin and itraconazole. Careful monitoring of therapeutic and adverseeffects is recommended when erythromycin or itraconazole is used concomitantlyadministered with ritonavir.

Ketoconazole 200 daily 500 q12h ↑ 3.4-fold ↑ 55%

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

Sulfamethoxazole/Trimethoprim2 800/160, single dose 500 q12h ↓ 20%/↑ 20% ↔

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

Antipsychotics/Neuroleptics

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

Haloperidol, risperidone, thioridazine Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 and as a resultis expected to increase concentrations of haloperidol, risperidone and thioridazine.

Careful monitoring of therapeutic and adverse effects is recommended when thesemedicines are concomitantly administered with antiretroviral doses of ritonavir.

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Lurasidone Due to CYP3A inhibition by ritonavir, concentrations of lurasidone are expected toincrease. The concomitant administration with lurasidone is contraindicated (seesection 4.3).

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

β2-agonist (long acting)

Salmeterol Ritonavir inhibits CYP3A4 and as a result a pronounced increase in the plasmaconcentrations of salmeterol is expected. Therefore concomitant use is notrecommended.

Calcium channel antagonists

Amlodipine, diltiazem, nifedipine Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits

CYP3A4 and as a result is expected to increase the plasma concentrations ofcalcium channel antagonists. Careful monitoring of therapeutic and adverse effectsis recommended when these medicines are concomitantly administered withritonavir.

Endothelin antagonists

Co-administration of bosentan and ritonavir may increase steady state

Bosentanbosentan maximum concentrations (Cmax) and area under the curve (AUC)

Serum concentrations may be increased due to CYP3A and P-gp inhibition by

Riociguatritonavir. The co-administration of riociguat with Norvir is not recommended (seesection 4.4 and refer to riociguat SmPC).

Ergot Derivatives

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

GI motility agent

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

HCV Direct Acting Antiviral

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Glecaprevir/pibrentasvir Serum concentrations may be increased due to P-glycoprotein, BCRP and OATP1Binhibition by ritonavir.

Concomitant administration of glecaprevir/pibrentasvir and Norvir is notrecommended due to an increased risk of ALT elevations associated with increasedglecaprevir exposure.

HCV Protease Inhibitor

Simeprevir 200 qd 100 q12h ↑ 7.2-fold ↑ 4.7-fold

Ritonavir increases plasma concentrations of simeprevir as a result of CYP3A4inhibition. It is not recommended to co-administer ritonavir with simeprevir.

HMG Co-A Reductase

Atorvastatin, Fluvastatin, Lovastatin, HMG-CoA reductase inhibitors which are highly dependent on CYP3A metabolism,

Pravastatin, Rosuvastatin, Simvastatin such as lovastatin and simvastatin, are expected to have markedly increased plasmaconcentrations when co-administered with ritonavir dosed as an antiretroviral agentor as a pharmacokinetic enhancer. Since increased concentrations of lovastatin andsimvastatin may predispose patients to myopathies, including rhabdomyolysis, thecombination of these medicinal products with ritonavir is contraindicated (seesection 4.3). Atorvastatin is less dependent on CYP3A for metabolism. Whilerosuvastatin elimination is not dependent on CYP3A, an elevation of rosuvastatinexposure has been reported with ritonavir co-administration. The mechanism of thisinteraction is not clear, but may be the result of transporter inhibition. When usedwith ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent, thelowest possible doses of atorvastatin or rosuvastatin should be administered. Themetabolism of pravastatin and fluvastatin is not dependent on CYP3A, andinteractions are not expected with ritonavir. If treatment with an HMG-CoAreductase inhibitor is indicated, pravastatin or fluvastatin is recommended.

Hormonal contraceptive

Ethinyl estradiol 50 µg, single dose 500 q12h ↓ 40% ↓ 32%

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

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Immunosupressants

Cyclosporine, tacrolimus, everolimus Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits

CYP3A4 and as a result is expected to increase the plasma concentrations ofcyclosporine, tacrolimus or everolimus. Careful monitoring of therapeutic andadverse effects is recommended when these medicines are concomitantlyadministered with ritonavir.

Lipid-modifying agents

Lomitapide CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitorsincreasing exposure approximately 27-fold. Due to CYP3A inhibition by ritonavir,concentrations of lomitapide are expected to increase. Concomitant use of Norvirwith lomitapide is contraindicated (see prescribing information for lomitapide) (seesection 4.3).

Phosphodiesterase (PDE5)inhibitors

Avanafil 50, single dose 600 q12h ↑ 13-fold ↑ 2.4-fold

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

Sildenafil 100, single dose 500 q12h ↑ 11-fold ↑ 4-fold

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

Tadalafil 20, single dose 200 q12h ↑ 124% ↔

The concomitant use of tadalafil for the treatment of erectile dysfunction withritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer should bewith caution at reduced doses of no more than 10 mg tadalafil every 72 hours withincreased monitoring for 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 q12h ↑ 49-fold ↑ 13-fold

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

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Sedatives/hynoptics

Clorazepate, diazepam, estazolam, Ritonavir co-administration is likely to result in increased plasma concentrations offlurazepam, oral and parenteral clorazepate, diazepam, estazolam and flurazepam and is therefore contraindicatedmidazolam (see section 4.3).

Midazolam is extensively metabolised by CYP3A4. Co-administration with Norvirmay cause a large increase in the concentration of this benzodiazepine. Nomedicinal product interaction study has been performed for the co-administration of

Norvir with benzodiazepines. Based on data for other CYP3A4 inhibitors, plasmaconcentrations of midazolam are expected to be significantly higher whenmidazolam is given orally. Therefore, Norvir should not be co-administered withorally administered midazolam (see section 4.3), whereas caution should be usedwith co-administration of Norvir and parenteral midazolam. Data from concomitantuse of parenteral midazolam with other protease inhibitors suggest a possible 3 - 4fold increase in midazolam plasma levels. If Norvir is co-administered withparenteral midazolam, it should be done in an intensive care unit (ICU) or similarsetting which ensures close clinical monitoring and appropriate medicalmanagement in case of respiratory depression and/or prolonged sedation. Dosageadjustment for midazolam should be considered, especially if more than a singledose of midazolam is administered.

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

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

Pethidine 50, oral single dose 500 q12h ↓ 62% ↓ 59%

Norpethidine metabolite ↑ 47% ↑ 87%

The use of pethidine and ritonavir is contraindicated due to the increasedconcentrations of the metabolite, norpethidine, which has both analgesic and CNSstimulant activity. Elevated norpethidine concentrations may increase the risk of

CNS effects (e.g., seizures), see section 4.3.

Alprazolam 1, single dose 200 q12h, 2 days ↑ 2.5 fold ↔500 q12h, 10 ↓ 12% ↓ 16%days

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

Buspirone Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits

CYP3A and as a result is expected to increase the plasma concentrations ofbuspirone. Careful monitoring of therapeutic and adverse effects is recommendedwhen buspirone concomitantly administered with ritonavir.

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Sleeping agent

Zolpidem 5 200, 4 doses ↑ 28% ↑ 22%

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

Smoke cessation

Bupropion 150 100 q12h ↓ 22% ↓ 21%150 600 q12h ↓ 66% ↓ 62%

Bupropion is primarily metabolised by CYP2B6. Concurrent administration ofbupropion with repeated doses of ritonavir is expected to decrease bupropion levels.

These effects are thought to represent induction of bupropion metabolism.

However, because ritonavir has also been shown to inhibit CYP2B6 in vitro, therecommended dose of bupropion should not be exceeded. In contrast to long-termadministration of ritonavir, there was no significant interaction with bupropion aftershort-term administration of low doses of ritonavir (200 mg twice daily for 2 days),suggesting reductions in bupropion concentrations may have onset several days afterinitiation of ritonavir co-administration.

Steroids

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

Dexamethasone Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits

CYP3A and as a result is expected to increase the plasma concentrations ofdexamethasone. Careful monitoring of therapeutic and adverse effects isrecommended when dexamethasone is concomitantly administered with ritonavir.

Prednisolone 20 200 q12h ↑ 28% ↑ 9%

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

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Thyroid hormone replacementtherapy

Levothyroxine Post-marketing cases have been reported indicating a potential interaction betweenritonavir containing products and levothyroxine. Thyroid-stimulating hormone(TSH) should be monitored in patients treated with levothyroxine at least the firstmonth after starting and/or ending 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 the co-administered protease inhibitor.

Proton pump inhibitors and H2-receptor antagonists

Proton pump inhibitors and H2-receptor antagonists (e.g. omeprazole or ranitidine) may 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). Norvir can be used during pregnancy if clinicallyneeded.

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 Norvir.

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 trials 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, undesirable effects are presented inorder of decreasing seriousness: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon(≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); not known (cannot be estimated from theavailable data).

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

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

System Order Class Frequency Adverse reaction

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

Uncommon Increased neutrophils

Immune system disorders Common Hypersensitivity, including urticaria andface oedema.

Rare Anaphylaxis

Metabolism and nutrition Common Hypercholesterolaemia,disorders hypertriglyceridaemia, gout, oedema andperipheral oedema, dehydration (usuallyassociated with gastrointestinal symptoms)

Uncommon Diabetes mellitus

Rare Hyperglycaemia

Nervous system disorders Very common Dysgeusia, oral and peripheral paraesthesia,headache, dizziness, peripheral neuropathy

Common Insomnia, anxiety, confusion, disturbance inattention, syncope, seizure

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,gastroesophageal reflux disease, pancreatitis

Hepatobiliary disorders Common Hepatitis (including increased AST, ALT,

GGT), blood bilirubin increased (includingjaundice)

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

System Order Class Frequency Adverse reaction

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

Common Acne

Rare Stevens Johnson syndrome, toxic epidermalnecrolysis (TEN)

Musculosketal and connective Very common Arthralgia and back paintissue 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 breast Common Menorrhagiadisorders

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

Common Fever, weight loss

Investigations Common Increased amylase, decreased free and totalthyroxine

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 developedhypertriglyceridaemia. In some cases fatalities have been observed. Patients with advanced HIVdisease may be at risk of elevated triglycerides and pancreatitis (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged 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 Norvir 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 trials tookritonavir 1500 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 medicine.

Pharmaco-therapeutic group: antiviral 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 inhibitoris generally 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 the 12hour 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/l showeda reduction in mortality and AIDS defining events. The mean average change from baseline over 16weeks 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/l)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 trial 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 has 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. Renalclearance averaged less than 0.1 l/h and was relatively constant throughout the dosage range.

The pharmacokinetic parameters observed with various dosing schemes of ritonavir alone are shownin the table below.

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)t½ (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

Administration of a single 100 mg dose of ritonavir powder for oral suspension with a moderate fatmeal (617 kcal, 29% calories from fat) was associated with a mean decrease of 23 and 39% inritonavir AUCinf and Cmax respectively, relative to fasting conditions. Administration with a high fatmeal (917 kcal, 60% calories from fat) was associated with a mean decrease of 32 and 49% inritonavir AUCinf and Cmax respectively, relative to fasting conditions.

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 g/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.

Ritonavir pharmacokinetic parameters were not statistically significantly associated with body weightor lean body 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 above 2years of age receiving doses ranging from 250 mg/m² twice daily to 400 mg/m² twice daily. Ritonavirconcentrations obtained after 350 to 400 mg/m² twice daily in paediatric patients were comparable tothose obtained in adults receiving 600 mg (approximately 330 mg/m²) twice daily. Across dosegroups, ritonavir oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster in paediatricpatients 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 secondaryto phospholipidosis. However, clinical trials revealed no evidence of medicinal product-inducedocular changes 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, noclinically significant renal abnormalities were noted in clinical trials.

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

Ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo 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.

Copovidone

Sorbitan laurate

Silica, colloidal anhydrous

Not applicable.

36 months.

Following mixing with food or liquid as described in section 4.2: consume within 2 hours.

Store below 30°C.

Polyethylene/aluminium/polyethylene terephthalate foil sachet. 30 sachets per carton. Packaged witha mixing cup and two 10 ml calibrated oral dosing syringes.

For details on preparation and administration of Norvir powder for oral suspension, refer the patient orcare giver to the Package Leaflet, section 3.

Administering with food

- The entire contents of each sachet is to be poured over a small amount of soft food (e.g. applesauce or vanilla pudding). All of the mixed soft food must be administered within 2 hours.

Administering with liquid

The entire contents of each sachet should be suspended in 9.4 ml of liquid (water, chocolate milk, orinfant formula) giving a final concentration of 10 mg per ml. The patient/caregiver is to be instructedto follow the directions below:

- The oral dosing syringe and mixing cup should be washed in warm water and dish soap, thenrinsed and allowed to air dry prior to first use.

- Draw up 9.4 ml of liquid using the provided oral dosing syringe, remove the bubbles, andtransfer the liquid to the mixing cup. All measuring should be done in ml using the syringe.

- Pour the entire contents of 1 sachet (100 mg) into the mixing cup.

- Close the lid and shake hard for at least 90 seconds until all the lumps have dissolved.

- Let the liquid stand for 10 minutes in order for most of the bubbles to disappear.

- Use the provided oral dosing syringe to measure and administer the prescribed ml volume (seesection 4.2). Be sure to remove the bubbles prior to dose administration.

- Once the powder is mixed, the prepared suspension should be used within 2 hours.

- Discard any mixture remaining in the mixing cup.

- The oral dosing syringe and mixing cup should be cleaned immediately with warm water anddish soap after use.

- If the syringe breaks or becomes hard to use, the syringe should be thrown away and the newone used.

AbbVie Deutschland GmbH & Co. KG

Knollstrasse67061 Ludwigshafen

Germany

EU/1/96/016/009

Date of first authorisation: 26 August 1996

Date of latest renewal: 26 August 2006

Detailed information on this product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu