DARUNAVIR KRKA 600mg tablets medication leaflet

Darunavir Krka 600 mg film-coated tablets

Each film-coated tablet contains 600 mg darunavir.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Orangish brown, oval, biconvex film-coated tablets, engraved with a mark S2 on one side. Tabletdimension: 19.5 x 10 mm.

Darunavir Krka, co-administered with low dose ritonavir is indicated in combination with otherantiretroviral medicinal products for the treatment of patients with human immunodeficiency virus(HIV-1) infection (see section 4.2).

Darunavir Krka 600 mg tablets may be used to provide suitable dose regimens (see section 4.2): For the treatment of HIV-1 infection in antiretroviral treatment (ART)-experienced adultpatients, including those that have been highly pre-treated. For the treatment of HIV-1 infection in paediatric patients from the age of 3 years and at least15 kg body weight.

In deciding to initiate treatment with darunavir co-administered with low dose ritonavir, carefulconsideration should be given to the treatment history of the individual patient and the patterns ofmutations associated with different agents. Genotypic or phenotypic testing (when available) andtreatment history should guide the use of darunavir (see sections 4.2, pct. 4.4 and 5.1).

Therapy should be initiated by a healthcare provider experienced in the management of HIV infection.

After therapy with darunavir has been initiated, patients should be advised not to alter the dose, doseform or discontinue therapy without discussing with their healthcare provider.

Darunavir must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and incombination with other antiretroviral medicinal products. The Summary of Product Characteristics ofritonavir must, therefore, be consulted prior to initiation of therapy with darunavir.

Darunavir Krka 600 mg film coated tablets must not be chewed or crushed. This strength is notsuitable for doses below 600 mg. It is not possible to administer all paediatric doses with this product.

Other tablet strengths and formulations of darunavir are available.

ART-experienced adult patients

The recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily takenwith food. Darunavir Krka 600 mg tablets can be used to construct the twice daily 600 mg regimen.

ART-naïve adult patients

For dose recommendations in ART-naïve patients see the Summary of Product Characteristics for

Darunavir Krka 400 mg and 800 mg tablets.

ART-naïve paediatric patients (3 to 17 years of age and weighing at least 15 kg)

The weight-based dose of darunavir and ritonavir in paediatric patients is provided in the table below.

Table 1. Recommended dose for treatment-naïve paediatric patients (3 to 17 years) withdarunavir and ritonavira

Body weight (kg) Dose (once daily with food)≥ 15 kg to < 30 kg 600 mg darunavir/100 mg ritonavir once daily≥ 30 kg to < 40 kg 675 mg darunavir/100 mg ritonavir once daily≥ 40 kg 800 mg darunavir/100 mg ritonavir once dailya ritonavir oral solution: 80 mg/ml

ART-experienced paediatric patients (3 to 17 years of age and weighing at least 15 kg)

Darunavir twice daily taken with ritonavir taken with food is usually recommended.

A once daily dose regimen of darunavir taken with ritonavir taken with food may be used in patientswith prior exposure to antiretroviral medicinal products but without darunavir resistance associatedmutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100 000 copies/ml and CD4+ cellcount ≥ 100 cells x 106/L.

* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

The recommended dose of darunavir with low dose ritonavir for paediatric patients is based on bodyweight and should not exceed the recommended adult dose (600/100 mg twice daily or 800/100 mgonce daily).

Table 2. Recommended dose for treatment-experienced paediatric patients (3 to 17 years) withdarunavir and ritonavira

Body weight (kg) Dose (once daily with food) Dose(twice daily with food)≥ 15 kg-< 30 kg 600 mg darunavir/100 mg ritonavir 375 mg darunavir /50 mg ritonavironce daily twice daily≥ 30 kg-< 40 kg 675 mg darunavir /100 mg ritonavir 450 mg darunavir /60 mg ritonavironce daily twice daily≥ 40 kg 800 mg darunavir /100 mg ritonavir 600 mg darunavir /100 mg ritonavironce daily twice dailya with ritonavir oral solution: 80 mg/ml

For ART-experienced paediatric patients HIV genotypic testing is recommended. However, when HIVgenotypic testing is not feasible, the darunavir/ritonavir once daily dosing regimen is recommended in

HIV protease inhibitor-naïve paediatric patients and the twice daily dosing regimen is recommendedin HIV protease inhibitor-experienced patients.

In case a dose of darunavir and/or ritonavir is missed within 6 hours of the time it is usually taken,patients should be instructed to take the prescribed dose of darunavir and ritonavir with food as soonas possible. If this is noticed later than 6 hours after the time it is usually taken, the missed dose shouldnot be taken and the patient should resume the usual dosing schedule.

This guidance is based on the 15 hour half-life of darunavir in the presence of ritonavir and therecommended dosing interval of approximately 12 hours.

If a patient vomits within 4 hours of taking the medicinal product, another dose of darunavir withritonavir should be taken with food as soon as possible. If a patient vomits more than 4 hours aftertaking the medicinal product, the patient does not need to take another dose of darunavir with ritonaviruntil the next regularly scheduled time.

Limited information is available in this population, and therefore, darunavir should be used withcaution in this age group (see sections 4.4 and 5.2).

Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients withmild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, however, darunavirshould be used with caution in these patients. No pharmacokinetic data are available in patients withsevere hepatic impairment. Severe hepatic impairment could result in an increase of darunavirexposure and a worsening of its safety profile. Therefore, darunavir must not be used in patients withsevere hepatic impairment (Child-Pugh Class C) (see sections pct. 4.3, pct. 4.4 and 5.2).

No dose adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).

Darunavir/ritonavir should not be used in children with a body weight of less than 15 kg as the dosefor this population has not been established in a sufficient number of patients (see section 5.1).

Darunavir/ritonavir should not be used in children below 3 years of age because of safety concerns(see sections 4.4 and 5.3).

The weight-based dose regimen for darunavir and ritonavir is provided in the tables above.

No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum.

Darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potentialrisk (see sections 4.4, pct. 4.6 and 5.2).

Patients should be instructed to take darunavir with low dose ritonavir within 30 minutes aftercompletion of a meal. The type of food does not affect the exposure to darunavir (see sections 4.4, 4.5and 5.2).

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

Patients with severe (Child-Pugh Class C) hepatic impairment.

Combination of rifampicin with darunavir with concomitant low dose ritonavir (see section 4.5).

Co-administration with the combination product lopinavir/ritonavir (see section 4.5).

Co-administration with herbal preparations containing St John's wort (Hypericum perforatum) (seesection 4.5).

Co-administration of darunavir with low dose ritonavir, with active substances that are highlydependent on CYP3A for clearance and for which elevated plasma concentrations are associated withserious and/or life-threatening events. These active substances include e.g.:

 alfuzosin amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine astemizole, terfenadine colchicine when used in patients with renal and/or hepatic impairment (see section 4.5) ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine) elbasvir/grazoprevir cisapride dapoxetine domperidone naloxegol lurasidone, pimozide, quetiapine, sertindole (see section 4.5) triazolam, midazolam administered orally (for caution on parenterally administered midazolam,see section 4.5) sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil simvastatin, lovastatin and lomitapide (see section 4.5) ticagrelor (see section 4.5).

Regular assessment of virological response is advised. In the setting of lack or loss of virologicalresponse, resistance testing should be performed.

Darunavir must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and incombination with other antiretroviral medicinal products (see section 5.2). The Summary of Product

Characteristics of ritonavir as appropriate, must therefore be consulted prior to initiation of therapywith darunavir.

Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affectdarunavir concentrations. It is not recommended to alter the dose of ritonavir.

Darunavir binds predominantly to α1-acid glycoprotein. This protein binding is concentration-dependent indicative for saturation of binding. Therefore, protein displacement of medicinal productshighly bound to α1-acid glycoprotein cannot be ruled out (see section 4.5).

ART-experienced patients - once daily dosing

Darunavir used in combination with cobicistat or low dose ritonavir once daily in ART-experiencedpatients should not be used in patients with one or more darunavir resistance associated mutations(DRV-RAMs) or HIV-1 RNA ≥ 100 000 copies/ml or CD4+ cell count < 100 cells x 106/L (seesection 4.2). Combinations with optimised background regimen (OBRs) other than ≥ 2 NRTIs havenot been studied in this population. Limited data are available in patients with HIV-1 clades other than

B (see section 5.1).

Darunavir is not recommended for use in paediatric patients below 3 years of age or less than 15 kgbody weight (see sections 4.2 and 5.3).

Darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potentialrisk. Caution should be used in pregnant women with concomitant medicinal products which mayfurther decrease darunavir exposure (see sections 4.5 and 5.2).

As limited information is available on the use of darunavir in patients aged 65 and over, cautionshould be exercised in the administration of darunavir in elderly patients, reflecting the greaterfrequency of decreased hepatic function and of concomitant disease or other therapy (see sections 4.2and 5.2).

Severe skin reactions

During the darunavir/ritonavir clinical development program (N=3 063), severe skin reactions, whichmay be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% ofpatients. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson

Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermalnecrolysis and acute generalised exanthematous pustulosis have been reported. Darunavir should bediscontinued immediately if signs or symptoms of severe skin reactions develop. These can include,but are not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle orjoint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.

Rash occurred more commonly in treatment-experienced patients receiving regimens containingdarunavir/ritonavir + raltegravir compared to patients receiving darunavir/ritonavir without raltegraviror raltegravir without darunavir (see section 4.8).

Darunavir contains a sulphonamide moiety. Darunavir should be used with caution in patients with aknown sulphonamide allergy.

Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with darunavir.

During the darunavir/ritonavir clinical development program (N=3 063), hepatitis was reported in0.5% of patients receiving combination antiretroviral therapy with darunavir/ritonavir. Patients withpre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk forliver function abnormalities including severe and potentially fatal hepatic adverse reactions. In case ofconcomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information forthese medicinal products.

Appropriate laboratory testing should be conducted prior to initiating therapy with darunavir/ritonavirand patients should be monitored during treatment. Increased AST/ALT monitoring should beconsidered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of darunavir/ritonavirtreatment.

If there is evidence of new or worsening liver dysfunction (including clinically significant elevation ofliver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, livertenderness, hepatomegaly) in patients using darunavir/ritonavir, interruption or discontinuation oftreatment should be considered promptly.

Patients with coexisting conditions

The safety and efficacy of darunavir have not been established in patients with severe underlying liverdisorders and darunavir is therefore contraindicated in patients with severe hepatic impairment. Due toan increase in the unbound darunavir plasma concentrations, darunavir should be used with caution inpatients with mild or moderate hepatic impairment (see sections 4.2, pct. 4.3 and 5.2).

No special precautions or dose adjustments for darunavir/ritonavir are required in patients with renalimpairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that theywill be significantly removed by haemodialysis or peritoneal dialysis. Therefore, no specialprecautions or dose adjustments are required in these patients (see sections 4.2 and 5.2).

There have been reports of increased bleeding, including spontaneous skin haematomas andhaemarthrosis in patients with haemophilia type A and B treated with PIs. In some patients additionalfactor VIII was given. In more than half of the reported cases, treatment with PIs was continued orreintroduced if treatment had been discontinued. A causal relationship has been suggested, althoughthe mechanism of action has not been elucidated. Haemophiliac patients should, therefore, be madeaware 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.

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported particularly 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.

Immune reconstitution inflammatory syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticpathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically,such reactions have been observed within the first weeks or months of initiation of CART. Relevantexamples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections andpneumonia caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii). Anyinflammatory symptoms should be evaluated and treatment instituted when necessary. In addition,reactivation of herpes simplex and herpes zoster has been observed in clinical studies with darunavirco-administered with low dose ritonavir.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported tooccur in the setting of immune reactivation; however, the reported time to onset is more variable andthese events can occur many months after initiation of treatment (see section 4.8).

Several of the interaction studies have been performed with darunavir at lower than recommendeddoses. The effects on co-administered medicinal products may thus be underestimated and clinicalmonitoring of safety may be indicated. For full information on interactions with other medicinalproducts see section 4.5.

Efavirenz in combination with boosted darunavir once daily may result in sub-optimal darunavir Cmin.

If efavirenz is to be used in combination with darunavir, the darunavir/ritonavir 600/100 mg twicedaily regimen should be used (see section 4.5).

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine andstrong inhibitors of CYP3A and P-glycoprotein (P-gp; see sections 4.3 and 4.5).

Interaction studies have only been performed in adults.

Medicinal products that may be affected by darunavir boosted with ritonavir

Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration ofdarunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 ortransported by P-gp may result in increased systemic exposure to such medicinal products, whichcould increase or prolong their therapeutic effect and adverse reactions.

Co-administration of darunavir/ritonavir with drugs that have active metabolite(s) formed by CYP3Amay result in reduced plasma concentrations of these active metabolite(s), potentially leading to lossof their therapeutic effect (see the Interaction table below).

Darunavir co-administered with low dose ritonavir must not be combined with medicinal products thatare highly dependent on CYP3A for clearance and for which increased systemic exposure is associatedwith serious and/or life-threatening events (narrow therapeutic index) (see section 4.3).

The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase inthe systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally incombination with ritonavir at 100 mg twice daily. Therefore, darunavir must only be used incombination with low dose ritonavir as a pharmacokinetic enhancer (see sections 4.4 and 5.2).

A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes

CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity andinhibition of CYP2D6 activity in the presence of darunavir/ritonavir, which may be attributed to thepresence of low dose ritonavir. Co-administration of darunavir and ritonavir with medicinal productswhich are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may resultin increased plasma concentrations of these medicinal products, which could increase or prolong theirtherapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir with medicinalproducts primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone)may result in decreased systemic exposure to such medicinal products, which could decrease orshorten their therapeutic effect.

Although the effect on CYP2C8 has only been studied in vitro, co-administration of darunavir andritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone,repaglinide) may result in decreased systemic exposure to such medicinal products, which coulddecrease or shorten their therapeutic effect.

Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administrationwith substrates of these transporters can result in increased plasma concentrations of these compounds(e.g. dabigatran etexilate, digoxin, statins and bosentan; see the Interaction table below).

Medicinal products that affect darunavir/ritonavir exposure

Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activitywould be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasmaconcentrations of darunavir and ritonavir (e.g. rifampicin, St John's wort, lopinavir). Co-administrationof darunavir and ritonavir and other medicinal products that inhibit CYP3A may decrease theclearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavirand ritonavir (e.g. indinavir, azole antifungals like clotrimazole). These interactions are described inthe interaction table below.

Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal productsare listed in the table below. The direction of the arrow for each pharmacokinetic parameter is basedon the 90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑)the 80-125% range (not determined as “ND”).

Several of the interaction studies (indicated by # in the table below) have been performed at lower thanrecommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology). Theeffects on co-administered medicinal products may thus be underestimated and clinical monitoring ofsafety may be indicated.

The below list of examples of drug-drug interactions is not comprehensive and therefore the label ofeach drug that is co-administered with darunavir should be consulted for information related to theroute of metabolism, interaction pathways, potential risks, and specific actions to be taken withregards to co-administration.

Table 3. Interactions and dose recommendations with other medicinal products

Medicinal products by Interaction Recommendations concerning co-therapeutic areas Geometric mean change (%) administration

HIV ANTIRETROVIRALS

Integrase strand transfer inhibitors

Dolutegravir dolutegravir AUC ↓ 22% Darunavir co-administered with lowdolutegravir C24h ↓38% dose ritonavir and dolutegravir candolutegravir Cmax ↓ 11% be used without dose adjustment.darunavir ↔*

* Using cross-study comparisons to historicalpharmacokinetic data

Raltegravir Some clinical studies suggest raltegravir At present the effect of raltegravir onmay cause a modest decrease in darunavir darunavir plasma concentrations doesplasma concentrations. not appear to be clinically relevant.

Darunavir co-administered with lowdose ritonavir and raltegravir can beused without dose adjustments.

Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)

Didanosine didanosine AUC ↓ 9% Darunavir co-administered with low400 mg once daily didanosine Cmin ND dose ritonavir and didanosine can bedidanosine Cmax ↓ 16% used without dose adjustments.darunavir AUC ↔ Didanosine is to be administered ondarunavir Cmin ↔ an empty stomach, thus it should bedarunavir Cmax ↔ administered 1 hour before or2 hours after darunavir/ritonavirgiven with food.

Tenofovir disoproxil tenofovir AUC ↑ 22% Monitoring of renal function may be245 mg once daily tenofovir Cmin ↑ 37% indicated when darunavir co-tenofovir Cmax ↑ 24% administered with low dose ritonavir#darunavir AUC ↑ 21% is given in combination with#darunavir Cmin ↑ 24% tenofovir disoproxil, particularly in#darunavir Cmax ↑ 16% patients with underlying systemic or(↑ tenofovir from effect on MDR-1 renal disease, or in patients takingtransport in the renal tubules) nephrotoxic agents.

Emtricitabine/tenofovir Tenofovir alafenamide ↔ The recommended dose ofalafenamide Tenofovir ↑ emtricitabine/tenofovir alafenamideis 200/10 mg once daily when usedwith darunavir with low doseritonavir.

Abacavir Not studied. Based on the different Darunavir co-administered with low

Emtricitabine elimination pathways of the other NRTIs dose ritonavir can be used with these

Lamivudine zidovudine, emtricitabine, stavudine, NRTIs without dose adjustment.

Stavudine lamivudine, that are primarily renally

Zidovudine excreted, and abacavir for whichmetabolism is not mediated by CYP450,no interactions are expected for thesemedicinal compounds and darunavir co-administered with low dose ritonavir.

Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)

Efavirenz efavirenz AUC ↑ 21% Clinical monitoring for central600 mg once daily efavirenz Cmin ↑ 17% nervous system toxicity associatedefavirenz Cmax ↑ 15% with increased exposure to efavirenz#darunavir AUC ↓ 13% may be indicated when darunavir co-#darunavir Cmin ↓ 31% administered with low dose ritonavir#darunavir Cmax ↓ 15% is given in combination with(↑ efavirenz from CYP3A inhibition) efavirenz.(↓ darunavir from CYP3A induction) Efavirenz in combination withdarunavir /ritonavir 800/100 mg oncedaily may result in sub-optimaldarunavir Cmin. If efavirenz is to beused in combination with darunavir/ritonavir, the darunavir/ritonavir600/100 mg twice daily regimenshould be used (see section 4.4).

Etravirine etravirine AUC ↓ 37% Darunavir co-administered with low100 mg twice daily etravirine Cmin ↓ 49% dose ritonavir and etravirine 200 mgetravirine Cmax ↓ 32% twice daily can be used without dosedarunavir AUC ↑ 15% adjustments.darunavir Cmin ↔darunavir Cmax ↔

Nevirapine nevirapine AUC ↑ 27% Darunavir co-administered with low200 mg twice daily nevirapine Cmin ↑ 47% dose ritonavir and nevirapine can benevirapine Cmax ↑ 18% used without dose adjustments.#darunavir: concentrations were consistentwith historical data(↑ nevirapine from CYP3A inhibition)

Rilpivirine rilpivirine AUC ↑ 130% Darunavir co-administered with low150 mg once daily rilpivirine Cmin ↑ 178% dose ritonavir and rilpivirine can berilpivirine Cmax ↑ 79% used without dose adjustments.darunavir AUC ↔darunavir Cmin ↓ 11%darunavir Cmax ↔

HIV Protease inhibitors (PIs) - without additional co-administration of low dose ritonavir†

Atazanavir atazanavir AUC ↔ Darunavir co-administered with low300 mg once daily atazanavir Cmin ↑ 52% dose ritonavir and atazanavir can beatazanavir Cmax ↓ 11% used without dose adjustments.#darunavir AUC ↔#darunavir Cmin ↔#darunavir Cmax ↔

Atazanavir: comparison ofatazanavir/ritonavir 300/100 mg once dailyvs. atazanavir 300 mg once daily incombination with darunavir/ritonavir400/100 mg twice daily.

Darunavir: comparison ofdarunavir/ritonavir 400/100 mg twice dailyvs. darunavir/ritonavir 400/100 mg twicedaily in combination with atazanavir300 mg once daily.

Indinavir indinavir AUC ↑ 23% When used in combination with800 mg twice daily indinavir Cmin ↑ 125% darunavir co-administered with lowindinavir Cmax ↔ dose ritonavir, dose adjustment of#darunavir AUC ↑ 24% indinavir from 800 mg twice daily to#darunavir Cmin ↑ 44% 600 mg twice daily may be#darunavir Cmax ↑ 11% warranted in case of intolerance.

Indinavir: comparison ofindinavir/ritonavir 800/100 mg twice dailyvs. indinavir/darunavir/ritonavir800/400/100 mg twice daily.

Darunavir: comparison ofdarunavir/ritonavir 400/100 mg twice dailyvs. darunavir/ritonavir 400/100 mg incombination with indinavir 800 mg twicedaily.

Saquinavir #darunavir AUC ↓ 26% It is not recommended to combine1 000 mg twice daily #darunavir Cmin ↓ 42% darunavir co-administered with low#darunavir Cmax ↓ 17% dose ritonavir with saquinavir.saquinavir AUC ↓ 6%saquinavir Cmin ↓ 18%saquinavir Cmax ↓ 6%

Saquinavir: comparison ofsaquinavir/ritonavir 1 000/100 mg twicedaily vs. saquinavir/darunavir/ritonavir1 000/400/100 mg twice daily

Darunavir: comparison ofdarunavir/ritonavir 400/100 mg twice dailyvs. darunavir/ritonavir 400/100 mg incombination with saquinavir 1 000 mgtwice daily.

HIV Protease inhibitors (PIs) - with co-administration of low dose ritonavir†

Lopinavir/ritonavir lopinavir AUC ↑ 9% Due to a decrease in the exposure400/100 mg twice daily lopinavir Cmin ↑ 23% (AUC) of darunavir by 40%,lopinavir Cmax ↓ 2% appropriate doses of the combinationdarunavir AUC ↓ 38%‡ have not been established. Hence,

Lopinavir/ritonavir darunavir C ‡min ↓ 51% concomitant use of darunavir co-533/133.3 mg twice daily darunavir Cmax ↓ 21%‡ administered with low dose ritonavirlopinavir AUC ↔ and the combination productlopinavir Cmin ↑ 13% lopinavir/ritonavir is contraindicatedlopinavir Cmax ↑ 11% (see section 4.3).darunavir AUC ↓ 41%darunavir Cmin ↓ 55%darunavir Cmax ↓ 21%‡ based upon non dose normalised values

CCR5 ANTAGONIST

Maraviroc maraviroc AUC ↑ 305% The maraviroc dose should be150 mg twice daily maraviroc Cmin ND 150 mg twice daily when co-maraviroc Cmax ↑ 129% administered with darunavir with lowdarunavir, ritonavir concentrations were dose ritonavir.consistent with historical dataα1-ADRENORECEPTOR ANTAGONIST

Alfuzosin Based on theoretical considerations Co-administration of darunavir withdarunavir is expected to increase alfuzosin low dose ritonavir and alfuzosin isplasma concentrations. contraindicated (see section 4.3).(CYP3A inhibition)

ANAESTHETIC

Alfentanil Not studied. The metabolism of alfentanil The concomitant use with darunaviris mediated via CYP3A, and may as such and low dose ritonavir may require tobe inhibited by darunavir co-administered lower the dose of alfentanil andwith low dose ritonavir. requires monitoring for risks ofprolonged or delayed respiratorydepression.

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide Not studied. Darunavir is expected to Caution is warranted and therapeutic

Flecainide increase these antiarrhythmic plasma concentration monitoring, if

Lidocaine (systemic) concentrations. available, is recommended for these

Mexiletine (CYP3A and/or CYP2D6 inhibition) antiarrhythmics when co-

Propafenone administered with darunavir with lowdose ritonavir.

Amiodarone Darunavir co-administered with low

Bepridil dose ritonavir and amiodarone,

Dronedarone bepridil, dronedarone, ivabradine,

Ivabradine quinidine, or ranolazine is

Quinidine contraindicated (see section 4.3).

Ranolazine

Digoxin digoxin AUC ↑ 61% Given that digoxin has a narrow0.4 mg single dose digoxin Cmin ND therapeutic index, it is recommendeddigoxin Cmax ↑ 29% that the lowest possible dose of(↑ digoxin from probable inhibition of P- digoxin should initially be prescribedgp) in case digoxin is given to patients ondarunavir/ritonavir therapy. Thedigoxin dose should be carefullytitrated to obtain the desired clinicaleffect while assessing the overallclinical state of the subject.

ANTIBIOTIC

Clarithromycin clarithromycin AUC ↑ 57% Caution should be exercised when500 mg twice daily clarithromycin Cmin ↑ 174% clarithromycin is combined withclarithromycin Cmax ↑ 26% darunavir co-administered with low#darunavir AUC ↓ 13% dose ritonavir.#darunavir Cmin ↑ 1%#darunavir Cmax ↓ 17%14-OH-clarithromycin concentrations were For patients with renal impairmentnot detectable when combined with the Summary of Productdarunavir/ritonavir. Characteristics for clarithromycin(↑ clarithromycin from CYP3A inhibition should be consulted for theand possible P-gp inhibition) recommended dose.

ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR

Apixaban Not studied. Co-administration of boosted The use of boosted darunavir with a

Rivaroxaban darunavir with these anticoagulants may direct oral anticoagulant (DOAC)increase concentrations of the that is metabolised by CYP3A4 andanticoagulant. transported by P-gp is not(CYP3A and/or P-gp inhibition). recommended as this may lead to anincreased bleeding risk.

Dabigatran etexilate dabigatran etexilate (150 mg): Darunavir/ritonavir:

Edoxaban darunavir/ritonavir 800/100 mg single Clinical monitoring and/or dosedose: reduction of the DOAC should bedabigatran AUC ↑ 72% considered when a DOACdabigatran Cmax ↑ 64% transported by P-gp but notmetabolised by CYP3A4, includingdarunavir/ritonavir 800/100 mg once daily: dabigatran etexilate and edoxaban, isdabigatran AUC ↑ 18% co-administered with darunavir/rtv.

dabigatran Cmax ↑ 22%

Ticagrelor Based on theoretical considerations, Concomitant administration ofco-administration of boosted darunavir boosted darunavir with ticagrelor iswith ticagrelor may increase contraindicated (see section 4.3).concentrations of ticagrelor (CYP3Aand/or P-glycoprotein inhibition).

Clopidogrel Not studied. Co-administration ofclopidogrel with boosted darunavir is Co-administration of clopidogrelexpected to decrease clopidogrel active with boosted darunavir is notmetabolite plasma concentration, which recommended. Use of othermay reduce the antiplatelet activity of antiplatelets not affected by CYPclopidogrel. inhibition or induction (e.g.

prasugrel) is recommended.

Warfarin Not studied. Warfarin concentrations may It is recommended that thebe affected when co-administered with international normalised ratio (INR)darunavir with low dose ritonavir. be monitored when warfarin iscombined with darunavir co-administered with low dose ritonavir.

ANTICONVULSANTS

Phenobarbital Not studied. Phenobarbital and phenytoin Darunavir co-administered with low

Phenytoin are expected to decrease plasma dose ritonavir should not be used inconcentrations of darunavir and its combination with these medicines.pharmacoenhancer.(induction of CYP450 enzymes)

Carbamazepine carbamazepine AUC ↑ 45% No dose adjustment for darunavir200 mg twice daily carbamazepine Cmin ↑ 54% /ritonavir is recommended. If there iscarbamazepine Cmax ↑ 43% a need to combinedarunavir AUC ↔ darunavir/ritonavir anddarunavir Cmin ↓ 15% carbamazepine, patients should bedarunavir Cmax ↔ monitored for potentialcarbamazepine-related adverseevents. Carbamazepineconcentrations should be monitoredand its dose should be titrated foradequate response. Based upon thefindings, the carbamazepine dosemay need to be reduced by 25% to50% in the presence ofdarunavir/ritonavir.

Clonazepam Not studied. Co-administration of boosted Clinical monitoring is recommendeddarunavir with clonazepam may increase when co-administering boostedconcentrations of clonazepam. (CYP3A darunavir with clonazepam.inhibition)

ANTIDEPRESSANTS

Paroxetine paroxetine AUC ↓ 39% If antidepressants are co-20 mg once daily paroxetine Cmin ↓ 37% administered with darunavir with lowparoxetine Cmax ↓ 36% dose ritonavir, the recommended#darunavir AUC ↔ approach is a dose titration of the#darunavir Cmin ↔ antidepressant based on a clinical#darunavir Cmax ↔ assessment of antidepressant

Sertraline sertraline AUC ↓ 49% response. In addition, patients on a50 mg once daily sertraline Cmin ↓ 49% stable dose of these antidepressantssertraline Cmax ↓ 44% who start treatment with darunavir#darunavir AUC ↔ with low dose ritonavir should be#darunavir Cmin ↓ 6% monitored for antidepressant#darunavir Cmax ↔ response.

Concomitant use of darunavir co-administered wirth low dose ritonavir andthese antidepressants may increase Clinical monitoring is recommendedconcentrations of the antidepressant. when co-administering darunavir(CYP2D6 and/or CYP3A inhibition). with low dose ritonavir with theseantidepressants and a doseadjustment of the antidepressant may

Amitriptyline be needed.

Desipramine

Imipramine

Nortriptyline

Trazodone

ANTIEMETICS

Domperidone Not studied. Co-administration of domperidonewith boosted darunavir iscontraindicated.

ANTIFUNGALS

Voriconazole Not studied. Ritonavir may decrease Voriconazole should not beplasma concentrations of voriconazole. combined with darunavir co-(induction of CYP450 enzymes) administered with low dose ritonavirunless an assessment of thebenefit/risk ratio justifies the use ofvoriconazole.

Fluconazole Not studied. Darunavir may increase Caution is warranted and clinical

Isavuconazole antifungal plasma concentrations and monitoring is recommended. When

Itraconazole posaconazole, isavuconazole, itraconazole, co-administration is required the

Posaconazole or fluconazole may increase darunavir daily dose of itraconazole should notconcentrations. exceed 200 mg.(CYP3A and/or P-gp inhibition)

Not studied. Concomitant systemic use of

Clotrimazole clotrimazole and darunavirco-administered with low dose ritonavirmay increase plasma concentrations ofdarunavir and/or clotrimazole.darunavir AUC24h ↑ 33% (based onpopulation pharmacokinetic model)

ANTIGOUT MEDICINES

Colchicine Not studied. Concomitant use of colchicine A reduction in colchicine dose or anand darunavir co-administered with low interruption of colchicine treatmentdose ritonavir may increase the exposure is recommended in patients withto colchicine. normal renal or hepatic function if(CYP3A and/ or P-gp inhibition) treatment with darunavir co-administered with low dose ritonaviris required. For patients with renal orhepatic impairment colchicine withdarunavir co-administered with lowdose ritonavir is contraindicated (seesections 4.3 and 4.4).

ANTIMALARIALS

Artemether/Lumefantrine artemether AUC ↓ 16% The combination of darunavir and80/480 mg, 6 doses at 0, 8, artemether Cmin ↔ artemether/lumefantrine can be used24, 36, 48, and 60 hours artemether Cmax ↓ 18% without dose adjustments; however,dihydroartemisinin AUC ↓ 18% due to the increase in lumefantrinedihydroartemisinin Cmin ↔ exposure, the combination should bedihydroartemisinin Cmax ↓ 18% used with caution.lumefantrine AUC ↑ 175%lumefantrine Cmin ↑ 126%lumefantrine Cmax ↑ 65%darunavir AUC ↔darunavir Cmin ↓ 13%darunavir Cmax ↔

ANTIMYCOBACTERIALS

Rifampicin Not studied. Rifapentine and rifampicin The combination of rifapentine and

Rifapentine are strong CYP3A inducers and have been darunavir with concomitant low doseshown to cause profound decreases in ritonavir is not recommended.concentrations of other protease inhibitors, The combination of rifampicin andwhich can result in virological failure and darunavir with concomitant low doseresistance development (CYP450 enzyme ritonavir is contraindicated (seeinduction). During attempts to overcome section 4.3).the decreased exposure by increasing thedose of other protease inhibitors with lowdose ritonavir, a high frequency of liverreactions was seen with rifampicin.

Rifabutin rifabutin AUC** ↑ 55% A dose reduction of rifabutin by 75%150 mg once every other day rifabutin C **min ↑ ND of the usual dose of 300 mg/day (i.e.

rifabutin C **max ↔ rifabutin 150 mg once every otherdarunavir AUC ↑ 53% day) and increased monitoring fordarunavir Cmin ↑ 68% rifabutin related adverse events isdarunavir Cmax ↑ 39% warranted in patients receiving the

** sum of active moieties of rifabutin combination with darunavir(parent drug + 25-O-desacetyl metabolite) co-administered with ritonavir. In

The interaction study showed a case of safety issues, a furthercomparable daily systemic exposure for increase of the dosing interval forrifabutin between treatment at 300 mg rifabutin and/or monitoring ofonce daily alone and 150 mg once every rifabutin levels should be considered.other day in combination with Consideration should be given todarunavir/ritonavir (600/100 mg twice official guidance on the appropriatedaily) with an about 10-fold increase in the treatment of tuberculosis in HIVdaily exposure to the active metabolite 25- infected patients.

O-desacetylrifabutin. Furthermore, AUC Based upon the safety profile ofof the sum of active moieties of rifabutin darunavir/ritonavir, the increase in(parent drug + 25-O-desacetyl metabolite) darunavir exposure in the presence ofwas increased 1.6-fold, while Cmax rifabutin does not warrant a doseremained comparable. adjustment for darunavir/ritonavir.

Data on comparison with a 150 mg once Based on pharmacokinetic modeling,daily reference dose is lacking. this dose reduction of 75% is also(Rifabutin is an inducer and substrate of applicable if patients receive

CYP3A.) An increase of systemic rifabutin at doses other thanexposure to darunavir was observed when 300 mg/day.darunavir co-administered with 100 mgritonavir was co-administered withrifabutin (150 mg once every other day).

ANTINEOPLASTICS

Dasatinib Not studied. Darunavir is expected to Concentrations of these medicinal

Nilotinib increase these antineoplastic plasma products may be increased when co-

Vinblastine concentrations. administered with darunavir with low

Vincristine (CYP3A inhibition) dose ritonavir resulting in thepotential for increased adverse eventsusually associated with these agents.

Caution should be exercised whencombining one of theseantineoplastic agents with darunavirwith low dose ritonavir.

Everolimus Concomitant use of everolimus or

Irinotecan irinotecan and darunavir co-administered with low dose ritonaviris not recommended.

ANTIPSYCHOTICS/NEUROLEPTICS

Quetiapine Not studied. Darunavir is expected to Concomitant administration ofincrease these antipsychotic plasma darunavir with low dose ritonavir andconcentrations. quetiapine is contraindicated as it(CYP3A inhibition) may increase quetiapine-relatedtoxicity. Increased concentrations ofquetiapine may lead to coma (seesection 4.3).

Perphenazine Not studied. Darunavir is expected to A dose decrease may be needed for

Risperidone increase these antipsychotic plasma these drugs when co-administered

Thioridazine concentrations. with darunavir co-administered with(CYP3A, CYP2D6 and/or P-gp inhibition) low dose ritonavir.

Concomitant administration of

Lurasidone darunavir with low dose ritonavir and

Pimozide lurasidone, pimozide or sertindole is

Sertindole contraindicated (see section 4.3).

β-BLOCKERS

Carvedilol Not studied. Darunavir is expected to Clinical monitoring is recommended

Metoprolol increase these β-blocker plasma when co-administering darunavir

Timolol concentrations. with β-blockers. A lower dose of the(CYP2D6 inhibition) β-blocker should be considered.

CALCIUM CHANNEL BLOCKERS

Amlodipine Not studied. Darunavir co-administered Clinical monitoring of therapeutic

Diltiazem with low dose ritonavir can be expected to and adverse reactions is

Felodipine increase the plasma concentrations of recommended when these medicines

Nicardipine calcium channel blockers. are concomitantly administered with

Nifedipine (CYP3A and/or CYP2D6 inhibition) darunavir with low dose ritonavir.

Verapamil

CORTICOSTEROIDS

Corticosteroids primarily Fluticasone: in a clinical study where Concomitant use of darunavir withmetabolised by CYP3A ritonavir 100 mg capsules twice daily were low dose ritonavir and(including betamethasone, co-administered with 50 μg intranasal corticosteroids (all routes ofbudesonide, fluticasone, fluticasone propionate (4 times daily) for administration) that are metabolisedmometasone, prednisone, 7 days in healthy subjects, fluticasone by CYP3A may increase the risk oftriamcinolone) propionate plasma concentrations development of systemicincreased significantly, whereas the corticosteroid effects, includingintrinsic cortisol levels decreased by Cushing's syndrome and adrenalapproximately 86% (90% CI 82-89%). suppression.

Greater effects may be expected whenfluticasone is inhaled. Systemic Co-administration with CYP3A-corticosteroid effects including Cushing's metabolised corticosteroids is notsyndrome and adrenal suppression have recommended unless the potentialbeen reported in patients receiving benefit to the patient outweighs theritonavir and inhaled or intranasally risk, in which case patients should beadministered fluticasone. The effects of monitored for systemic corticosteroidhigh fluticasone systemic exposure on effects.ritonavir plasma levels are unknown.

Other corticosteroids: interaction not Alternative corticosteroids which arestudied. Plasma concentrations of these less dependent on CYP3Amedicinal products may be increased when metabolism e.g. beclomethasoneco-administered with darunavir with low should be considered, particularly fordose ritonavir, resulting in reduced serum long term use.cortisol concentrations.

Dexamethasone (systemic) Not studied. Dexamethasone may decrease Systemic dexamethasone should beplasma concentrations of darunavir. used with caution when combined(CYP3A induction) with darunavir co-administered withlow dose ritonavir.

ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan Not studied. Concomitant use of bosentan When administered concomitantlyand darunavir co-administered with low with darunavir A and low dosedose ritonavir may increase plasma ritonavir, the patient's tolerability ofconcentrations of bosentan. bosentan should be monitored.

Bosentan is expected to decrease plasmaconcentrations of darunavir and/or itspharmacoenhancer.(CYP3A induction)

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS

NS3-4A protease inhibitors

Elbasvir/grazoprevir Darunavir with low dose ritonavir may Concomitant use of darunavir withincrease the exposure to grazoprevir. low dose ritonavir and(CYP3A and OATP1B inhibition) elbasvir/grazoprevir iscontraindicated (see section 4.3).

Glecaprevir/pibrentasvir Based on theoretical considerations It is not recommended toboosted darunavir may increase the co-administer boosted darunavir withexposure to glecaprevir and pibrentasvir. glecaprevir/pibrentasvir.

(P-gp, BCRP and/or OATP1B1/3inhibition)

HERBAL PRODUCTS

St John's wort (Hypericum Not studied. St John's wort is expected to Darunavir co-administered with lowperforatum) decrease the plasma concentrations of dose ritonavir must not be useddarunavir and ritonavir. concomitantly with products(CYP450 induction) containing St John's wort(Hypericum perforatum) (see section4.3). If a patient is already taking St

John's wort, stop St John's wort andif possible check viral levels.

Darunavir exposure (and alsoritonavir exposure) may increase onstopping St John's wort. Theinducing effect may persist for atleast 2 weeks after cessation oftreatment with St John's wort.

HMG CO-A REDUCTASE INHIBITORS

Lovastatin Not studied. Lovastatin and simvastatin are Increased plasma concentrations of

Simvastatin expected to have markedly increased lovastatin or simvastatin may causeplasma concentrations when co- myopathy, includingadministered with darunavir co- rhabdomyolysis. Concomitant use ofadministered with low dose ritonavir. darunavir co-administered with low(CYP3A inhibition) dose ritonavir with lovastatin andsimvastatin is thereforecontraindicated (see section 4.3).

Atorvastatin atorvastatin AUC ↑ 3-4 fold When administration of atorvastatin10 mg once daily atorvastatin Cmin ↑ ≈5.5-10 fold and darunavir co-administered withatorvastatin Cmax ↑ ≈2 fold low dose ritonavir is desired, it is#darunavir/ritonavir recommended to start with anatorvastatin dose of 10 mg oncedaily. A gradual dose increase ofatorvastatin may be tailored to theclinical response.

Pravastatin pravastatin AUC ↑ 81%¶ When administration of pravastatin40 mg single dose pravastatin Cmin ND and darunavir co-administered withpravastatin Cmax ↑ 63% low dose ritonavir is required, it is¶ an up to five-fold increase was seen in a recommended to start with the lowestlimited subset of subjects possible dose of pravastatin andtitrate up to the desired clinical effectwhile monitoring for safety.

Rosuvastatin rosuvastatin AUC ↑ 48%║ When administration of rosuvastatin10 mg once daily rosuvastatin C ║max ↑ 144% and darunavir co-administered with║ based on published data with darunavir/ritonavir low dose ritonavir is required, it isrecommended to start with the lowestpossible dose of rosuvastatin andtitrate up to the desired clinical effectwhile monitoring for safety.

OTHER LIPID MODIFYING AGENTS

Lomitapide Based on theoretical considerations Co-administration is contraindicatedboosted darunavir is expected to increase (see section 4.3).the exposure of lomitapide when co-administered.(CYP3A inhibition)

H2-RECEPTOR ANTAGONISTS

Ranitidine #darunavir AUC ↔ Darunavir co-administered with low150 mg twice daily #darunavir Cmin ↔ dose ritonavir can be co-administered#darunavir Cmax ↔ with H2-receptor antagonists withoutdose adjustments.

IMMUNOSUPPRESSANTS

Ciclosporin Not studied. Exposure to these Therapeutic drug monitoring of the

Sirolimus immunosuppressants will be increased immunosuppressive agent must be

Tacrolimus when co-administered with darunavir co- done when co-administration occurs.

Everolimus administered with low dose ritonavir. Concomitant use of everolimus and(CYP3A inhibition) darunavir co-administered with lowdose ritonavir is not recommended.

INHALED BETA AGONISTS

Salmeterol Not studied. Concomitant use of Concomitant use of salmeterol andsalmeterol and darunavir co-administered darunavir co-administered with lowwith low dose ritonavir may increase dose ritonavir is not recommended.plasma concentrations of salmeterol. The combination may result inincreased risk of cardiovascularadverse event with salmeterol,including QT prolongation,palpitations and sinus tachycardia.

NARCOTIC ANALGESICS/TREATMENT OF OPIOID DEPENDENCE

Methadone R(-) methadone AUC ↓ 16% No adjustment of methadone dose isindividual dose ranging from R(-) methadone Cmin ↓ 15% required when initiating co-55 mg to 150 mg once daily R(-) methadone Cmax ↓ 24% administration with darunavir/ritonavir. However, increasedmethadone dose may be necessarywhen concomitantly administered fora longer period of time due toinduction of metabolism by ritonavir.

Therefore, clinical monitoring isrecommended, as maintenancetherapy may need to be adjusted insome patients.

Buprenorphine/naloxone buprenorphine AUC ↓ 11% The clinical relevance of the increase8/2 mg-16/4 mg once daily buprenorphine Cmin ↔ in norbuprenorphinebuprenorphine Cmax ↓ 8% pharmacokinetic parameters has notnorbuprenorphine AUC ↑ 46% been established. Dose adjustmentnorbuprenorphine Cmin ↑ 71% for buprenorphine may not benorbuprenorphine Cmax ↑ 36% necessary when co-administered withnaloxone AUC ↔ darunavir/ritonavir but a carefulnaloxone Cmin ND clinical monitoring for signs ofnaloxone Cmax ↔ opiate toxicity is recommended.

Fentanyl Based on theoretical considerations Clinical monitoring is recommended

Oxycodone boosted darunavir may increase plasma when co-administering boosted

Tramadol concentrations of these analgesics. darunavir with these analgesics.

(CYP2D6 and/or CYP3A inhibition)

OESTROGEN-BASED CONTRACEPTIVES

Drospirenone Not studied with darunavir/ritonavir. When darunavir is coadministered

Ethinylestradiol with a drospirenone-containing(3 mg/0.02 mg once daily) product, clinical monitoring isrecommended due to the potential forhyperkalaemia.

Alternative or additionalethinylestradiol AUC ↓ 44% β contraceptive measures are

Ethinylestradiol ethinylestradiol Cmin ↓ 62% β recommended when oestrogen-based

Norethindrone ethinylestradiol C βmax ↓ 32% contraceptives are co-administered35 μg/1 mg once daily norethindrone AUC ↓ 14% β with darunavir and low dosenorethindrone Cmin ↓ 30% β ritonavir.norethindrone C βmax ↔β with darunavir/ritonavir Patients using oestrogens as hormonereplacement therapy should beclinically monitored for signs ofoestrogen deficiency.

OPIOID ANTAGONIST

Naloxegol Not studied. Co-administration of boosteddarunavir and naloxegol iscontraindicated.

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS

For the treatment of erectile In an interaction study #, a comparable The combination of avanafil anddysfunction systemic exposure to sildenafil was darunavir with low dose ritonavir is

Avanafil observed for a single intake of 100 mg contraindicated (see section 4.3).

Sildenafil sildenafil alone and a single intake of Concomitant use of other PDE-5

Tadalafil 25 mg sildenafil co-administered with inhibitors for the treatment of erectile

Vardenafil darunavir and low dose ritonavir. dysfunction with darunavir co-administered with low dose ritonavirshould be done with caution. Ifconcomitant use of darunavir co-administered with low dose ritonavirwith sildenafil, vardenafil or tadalafilis indicated, sildenafil at a singledose not exceeding 25 mg in48 hours, vardenafil at a single dosenot exceeding 2.5 mg in 72 hours ortadalafil at a single dose notexceeding 10 mg in 72 hours isrecommended.

For the treatment of Not studied. Concomitant use of sildenafil A safe and effective dose ofpulmonary arterial or tadalafil for the treatment of pulmonary sildenafil for the treatment ofhypertension arterial hypertension and darunavir co- pulmonary arterial hypertension co-

Sildenafil administered with low dose ritonavir may administered with darunavir and low

Tadalafil increase plasma concentrations of dose ritonavir has not beensildenafil or tadalafil. established. There is an increased(CYP3A inhibition) potential for sildenafil-associatedadverse events (including visualdisturbances, hypotension, prolongederection and syncope). Therefore, co-administration of darunavir with lowdose ritonavir and sildenafil whenused for the treatment of pulmonaryarterial hypertension iscontraindicated (see section 4.3).

Co-administration of tadalafil for thetreatment of pulmonary arterialhypertension with darunavir and lowdose ritonavir is not recommended.

PROTON PUMP INHIBITORS

Omeprazole #darunavir AUC ↔ Darunavir co-administered with low20 mg once daily #darunavir Cmin ↔ dose ritonavir can be co-administered#darunavir Cmax ↔ with proton pump inhibitors withoutdose adjustments.

SEDATIVES/HYPNOTICS

Buspirone Not studied. Sedative/hypnotics are Clinical monitoring is recommended

Clorazepate extensively metabolised by CYP3A. Co- when co-administering darunavir

Diazepam administration with darunavir/ritonavir with these sedatives/hypnotics and a

Estazolam may cause a large increase in the lower dose of the sedatives/hypnotics

Flurazepam concentration of these medicines. should be considered.

Midazolam (parenteral)

Zolpidem

If parenteral midazolam is co-administered If parenteral midazolam is co-with darunavir co-administered with low administered with darunavir with lowdose ritonavir it may cause a large increase dose ritonavir, it should be done inin the concentration of this an intensive care unit (ICU) orbenzodiazepine. Data from concomitant similar setting, which ensures closeuse of parenteral midazolam with other clinical monitoring and appropriateprotease inhibitors suggest a possible 3- medical management in case of4 fold increase in midazolam plasma respiratory depression and/orlevels. prolonged sedation. Dose adjustmentfor midazolam should be considered,especially if more than a single doseof midazolam is administered.

Midazolam(oral) Darunavir with low dose ritonavir

Triazolam with triazolam or oral midazolam iscontraindicated (see section 4.3).

TREATMENT FOR PREMATURE EJACULATION

Dapoxetine Not studied. Co-administration of boosteddarunavir with dapoxetine iscontraindicated.

UROLOGICAL DRUGS

Fesoterodine Not studied. Use with caution. Monitor for

Solifenacin fesoterodine or solifenacin adversereactions, dose reduction offesoterodine or solifenacin may benecessary.

# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2

Posology).

† The efficacy and safety of the use of darunavir with 100 mg ritonavir and any other HIV PI (e.g. (fos)amprenavir and tipranavir) has notbeen established in HIV patients. According to current treatment guidelines, dual therapy with protease inhibitors is generally notrecommended.

‡ Study was conducted with tenofovir disoproxil fumarate 300 mg once daily.

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection inpregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn,the animal data as well as the clinical experience in pregnant women should be taken into account.

There are no adequate and well controlled studies on pregnancy outcome with darunavir in pregnantwomen. Studies in animals do not indicate direct harmful effects with respect to pregnancy,embryonal/foetal development, parturition or postnatal development (see section 5.3).

Darunavir co-administered with low dose ritonavir should be used during pregnancy only if thepotential benefit justifies the potential risk.

It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated thatdarunavir is excreted in milk and at high levels (1 000 mg/kg/day) resulted in toxicity of the offspring.

Because of the potential for adverse reactions in breast-fed infants, women should be instructed not tobreast-feed if they are receiving Darunavir Krka.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV donot breast-feed.

No human data on the effect of darunavir on fertility are available. There was no effect on mating orfertility with darunavir treatment in rats (see section 5.3).

Darunavir in combination with ritonavir has no or negligible influence on the ability to drive and usemachines. However, dizziness has been reported in some patients during treatment with regimenscontaining darunavir co-administered with low dose ritonavir and should be borne in mind whenconsidering a patient's ability to drive or operate machinery (see section 4.8).

During the clinical development program (N=2 613 treatment-experienced subjects who initiatedtherapy with darunavir/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least oneadverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequentadverse reactions reported in clinical studies and as spontaneous reports are diarrhoea, nausea, rash,headache and vomiting. The most frequent serious reactions are acute renal failure, myocardialinfarction, immune reconstitution inflammatory syndrome, thrombocytopenia, osteonecrosis,diarrhoea, hepatitis and pyrexia.

In the 96 week analysis, the safety profile of darunavir/ritonavir 800/100 mg once daily in treatment-naïve subjects was similar to that seen with darunavir/ritonavir 600/100 mg twice daily in treatment-experienced subjects except for nausea which was observed more frequently in treatment-naïvesubjects. This was driven by mild intensity nausea. No new safety findings were identified in the192 week analysis of the treatment-naïve subjects in which the mean treatment duration ofdarunavir/ritonavir 800/100 mg once daily was 162.5 weeks.

Adverse reactions are listed by system organ class (SOC) and frequency category. Within eachfrequency category, adverse reactions are presented in order of decreasing seriousness. Frequencycategories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon(≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000) and not known (frequency cannot be estimatedfrom the available data).

Table 4. Adverse reactions observed with darunavir/ritonavir in clinical study and post-marketing

MedDRA system organ class Adverse reaction

Frequency category

Infections and infestationsuncommon herpes simplex

Blood and lymphatic system disordersuncommon thrombocytopenia, neutropenia, anaemia, leukopeniarare increased eosinophil count

Immune system disordersuncommon immune reconstitution inflammatory syndrome, (drug)hypersensitivity

Endocrine disordersuncommon hypothyroidism, increased blood thyroid stimulatinghormone

Metabolism and nutrition disorderscommon diabetes mellitus, hypertriglyceridaemia,hypercholesterolaemia, hyperlipidaemiauncommon gout, anorexia, decreased appetite, decreased weight,increased weight, hyperglycaemia, insulin resistance,decreased high density lipoprotein, increased appetite,polydipsia, increased blood lactate dehydrogenase

Psychiatric disorderscommon insomniauncommon depression, disorientation, anxiety, sleep disorder,abnormal dreams, nightmare, decreased libidorare confusional state, altered mood, restlessness

Nervous system disorderscommon headache, peripheral neuropathy, dizzinessuncommon lethargy, paraesthesia, hypoaesthesia, dysgeusia,disturbance in attention, memory impairment,somnolencerare syncope, convulsion, ageusia, sleep phase rhythmdisturbance

Eye disordersuncommon conjunctival hyperaemia, dry eyerare visual disturbance

Ear and labyrinth disordersuncommon vertigo

Cardiac disordersuncommon myocardial infarction, angina pectoris, prolongedelectrocardiogram QT, tachycardiarare acute myocardial infarction, sinus bradycardia,palpitations

Vascular disordersuncommon hypertension, flushing

Respiratory, thoracic and mediastinal disordersuncommon dyspnoea, cough, epistaxis, throat irritationrare rhinorrhoea

Gastrointestinal disordersvery common diarrhoeacommon vomiting, nausea, abdominal pain, increased bloodamylase, dyspepsia, abdominal distension, flatulenceuncommon pancreatitis, gastritis, gastrooesophageal reflux disease,aphthous stomatitis, retching, dry mouth, abdominaldiscomfort, constipation, increased lipase, eructation,oral dysaesthesiarare stomatitis, haematemesis, cheilitis, dry lip, coatedtongue

Hepatobiliary disorderscommon increased alanine aminotransferaseuncommon hepatitis, cytolytic hepatitis, hepatic steatosis,hepatomegaly, increased transaminase, increasedaspartate aminotransferase, increased blood bilirubin,increased blood alkaline phosphatase, increasedgamma-glutamyltransferase

Skin and subcutaneous tissue disorderscommon rash (including macular, maculopapular, papular,erythematous and pruritic rash), pruritusuncommon angioedema, generalised rash, allergic dermatitis,urticaria, eczema, erythema, hyperhidrosis, nightsweats, alopecia, acne, dry skin, nail pigmentationrare DRESS, Stevens-Johnson syndrome, erythemamultiforme, dermatitis, seborrhoeic dermatitis, skinlesion, xerodermanot known toxic epidermal necrolysis, acute generalisedexanthematous pustulosis

Musculoskeletal and connective tissue disordersuncommon myalgia, osteonecrosis, muscle spasms, muscularweakness, arthralgia, pain in extremity, osteoporosis,increased blood creatine phosphokinaserare musculoskeletal stiffness, arthritis, joint stiffness

Renal and urinary disordersuncommon acute renal failure, renal failure, nephrolithiasis,increased blood creatinine, proteinuria, bilirubinuria,dysuria, nocturia, pollakiuriarare decreased creatinine renal clearancerare crystal nephropathy§

Reproductive system and breast disordersuncommon erectile dysfunction, gynaecomastia

General disorders and administration site conditionscommon asthenia, fatigueuncommon pyrexia, chest pain, peripheral oedema, malaise, feelinghot, irritability, painrare chills, abnormal feeling, xerosis§ adverse reaction identified in the post-marketing setting. Per the guideline on Summary of Product Characteristics (Revision2, September 2009), the frequency of this adverse reaction in the post-marketing setting was determined using the 'Rule of3'.

In clinical studies, rash was mostly mild to moderate, often occurring within the first four weeks oftreatment and resolving with continued dosing. In cases of severe skin reaction see the warning insection 4.4.

During the clinical development program of raltegravir in treatment-experienced patients, rash,irrespective of causality, was more commonly observed with regimens containing darunavir/ritonavir+ raltegravir compared to those containing darunavir/ritonavir without raltegravir or raltegravirwithout darunavir/ritonavir. Rash considered by the investigator to be drug-related occurred at similarrates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years(PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. Therashes observed in clinical studies were mild to moderate in severity and did not result indiscontinuation of therapy (see section 4.4).

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

Musculoskeletal abnormalities

Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use ofprotease inhibitors, particularly in combination with NRTIs.

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).

Immune reconstitution inflammatory syndrome

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 these events can occurmany months after initiation of treatment (see section 4.4).

Bleeding in haemophiliac patients

There have been reports of increased spontaneous bleeding in haemophiliac patients receivingantiretroviral protease inhibitors (see section 4.4).

The safety assessment in paediatric patients is based on the 48-week analysis of safety data from three

Phase II studies. The following patient populations were evaluated (see section 5.1): 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing atleast 20 kg who received darunavir tablets with low dose ritonavir twice daily in combinationwith other antiretroviral agents.

 21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received darunavir oral suspensionwith low dose ritonavir twice daily in combination with other antiretroviral agents.

 12 ART-naïve HIV-1 infected paediatric patients aged from 12 to 17 years and weighing at least40 kg who received darunavir tablets with low dose ritonavir once daily in combination withother antiretroviral agents (see section 5.1).

Overall, the safety profile in these paediatric patients was similar to that observed in the adultpopulation.

Patients co-infected with hepatitis B and/or hepatitis C virus

Among 1 968 treatment-experienced patients receiving darunavir co-administered with ritonavir600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients weremore likely to have baseline and treatment emergent hepatic transaminase elevations than thosewithout chronic viral hepatitis (see section 4.4).

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 darunavir co-administered with low dose ritonavir islimited. Single doses up to 3 200 mg of darunavir as oral solution alone and up to 1 600 mg of thetablet formulation of darunavir in combination with ritonavir have been administered to healthyvolunteers without untoward symptomatic effects.

There is no specific antidote for overdose with darunavir. Treatment of overdose with darunavirconsists of general supportive measures including monitoring of vital signs and observation of theclinical status of the patient.

Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal ofthe active substance.

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE10.

Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease (KD of4.5 x 10-12M). It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virusinfected cells, thereby preventing the formation of mature infectious virus particles.

Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratorystrains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells andhuman monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to5.0 ng/ml). Darunavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M(A, B, C, D, E, F, G) and group O primary isolates with EC50 values ranging from < 0.1 to 4.3 nM.

These EC50 values are well below the 50% cellular toxicity concentration range of 87 µM to> 100 µM.

In vitro selection of darunavir-resistant virus from wild type HIV-1 was lengthy (> 3 years). Theselected viruses were unable to grow in the presence of darunavir concentrations above 400 nM.

Viruses selected in these conditions and showing decreased susceptibility to darunavir (range: 23-50-fold) harboured 2 to 4 amino acid substitutions in the protease gene. The decreased susceptibility todarunavir of the emerging viruses in the selection experiment could not be explained by the emergenceof these protease mutations.

The clinical study data from ART-experienced patients (TITAN study and the pooled analysis of the

POWER 1, 2 and 3 and DUET 1 and 2 studies) showed that virologic response to darunavir co-administered with low dose ritonavir was decreased when 3 or more darunavir RAMs (V11I, V32I,

L33F, I47V, I50V, I54L or M, T74P, L76V, I84V and L89V) were present at baseline or when thesemutations developed during treatment.

Increasing baseline darunavir fold change in EC50 (FC) was associated with decreasing virologicresponse. A lower and upper clinical cut-off of 10 and 40 were identified. Isolates with baseline FC≤ 10 are susceptible; isolates with FC > 10 to 40 have decreased susceptibility; isolates with FC > 40are resistant (see Clinical results).

Viruses isolated from patients on darunavir /ritonavir 600/100 mg twice daily experiencing virologicfailure by rebound that were susceptible to tipranavir at baseline remained susceptible to tipranavirafter treatment in the vast majority of cases.

The lowest rates of developing resistant HIV virus are observed in ART-naïve patients who are treatedfor the first time with darunavir in combination with other ART.

The table below shows the development of HIV-1 protease mutations and loss of susceptibility to PIsin virologic failures at endpoint in the ARTEMIS, ODIN and TITAN studies.

Table 5. The development of HIV-1 protease mutations and loss of susceptibility to PIs invirologic failures at endpoint in the ARTEMIS, ODIN and TITAN studies.

ARTEMIS ODIN TITAN

Week 192 Week 48 Week 48darunavir/ ritonavir darunavir/ ritonavir darunavir/ ritonavir darunavir/ ritonavir800/100 mg 800/100 mg 600/100 mg 600/100 mgonce daily once daily twice daily twice daily

N=343 N=294 N=296 N=298

Total number of virologic 55 (16.0%) 65 (22.1%) 54 (18.2%) 31 (10.4%)failuresa, n (%)

Rebounders 39 (11.4%) 11 (3.7%) 11 (3.7%) 16 (5.4%)

Never suppressed 16 (4.7%) 54 (18.4%) 43 (14.5%) 15 (5.0%)subjects

Number of subjects with virologic failure and paired baseline/endpoint genotypes, developing mutationsb atendpoint, n/N

Primary (major) PI 0/43 1/60 0/42 6/28mutations

PI RAMs 4/43 7/60 4/42 10/28

Number of subjects with virologic failure and paired baseline/endpoint phenotypes, showing loss ofsusceptibility to PIs at endpoint compared to baseline, n/N

PIdarunavir 0/39 1/58 0/41 3/26amprenavir 0/39 1/58 0/40 0/22atazanavir 0/39 2/56 0/40 0/22indinavir 0/39 2/57 0/40 1/24lopinavir 0/39 1/58 0/40 0/23saquinavir 0/39 0/56 0/40 0/22tipranavir 0/39 0/58 0/41 1/25a TLOVR non-VF censored algorithm based on HIV-1 RNA < 50 copies/ml, except for TITAN (HIV-1 RNA< 400 copies/ml)b IAS-USA lists

Darunavir FC was less than 10 for 90% of 3 309 clinical isolates resistant to amprenavir, atazanavir,indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant tomost PIs remain susceptible to darunavir.

In the virologic failures of the ARTEMIS study no cross-resistance with other PIs was observed.

Adult patients

For clinical study results in ART-naïve adult patients, refer to the Summary of Product Characteristicsfor Darunavir Krka 400 mg and 800 mg tablets.

Efficacy of darunavir 600 mg twice daily co-administered with 100 mg ritonavir twice daily in ART-experienced patients

The evidence of efficacy of darunavir co-administered with ritonavir (600/100 mg twice daily) in

ART-experienced patients is based on the 96 weeks analysis of the Phase III study TITAN in ART-experienced lopinavir naïve patients, on the 48 week analysis of the Phase III study ODIN in ART-experienced patients with no DRV-RAMs, and on the analyses of 96 weeks data from the Phase IIbstudies POWER 1 and 2 in ART-experienced patients with high level of PI resistance.

TITAN is a randomised, controlled, open-label Phase III study comparing darunavir co-administeredwith ritonavir (600/100 mg twice daily) versus lopinavir/ritonavir (400/100 mg twice daily) in ART-experienced, lopinavir naïve HIV-1 infected adult patients. Both arms used an Optimised Background

Regimen (OBR) consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs).

The table below shows the efficacy data of the 48 week analysis from the TITAN study.

Table 6. The efficacy data of the 48 week analysis from the TITAN study

TITAN

Outcomes darunavir/ritonavir Lopinavir/ritonavir Treatment difference600/100 mg twice daily + 400/100 mg twice daily + (95% CI of difference)

OBR OBR

N=298 N=297

HIV-1 RNA 70.8% (211) 60.3% (179) 10.5% (2.9; 18.1)b< 50 copies/mlamedian CD4+ cell 88 81count change frombaseline (x 106/L)ca Imputations according to the TLOVR algorithmb Based on a normal approximation of the difference in % responsec NC=F

At 48 weeks non-inferiority in virologic response to the darunavir/ritonavir treatment, defined as thepercentage of patients with plasma HIV-1 RNA level < 400 and < 50 copies/ml, was demonstrated (atthe pre-defined 12% non-inferiority margin) for both ITT and OP populations. These results wereconfirmed in the analysis of data at 96 weeks of treatment in the TITAN study, with 60.4% of patientsin the darunavir/ritonavir arm having HIV-1 RNA < 50 copies/ml at week 96 compared to 55.2% inthe lopinavir/ritonavir arm [difference: 5.2%, 95% CI (-2.8; 13.1)].

ODIN is a Phase III, randomised, open-label study comparing darunavir/ritonavir 800/100 mg oncedaily versus darunavir/ritonavir 600/100 mg twice daily in ART-experienced HIV-1 infected patientswith screening genotype resistance testing showing no darunavir RAMs (i.e. V11I, V32I, L33F, I47V,

I50V, I54M, I54L, T74P, L76V, I84V, L89V) and a screening HIV-1 RNA > 1 000 copies/ml.

Efficacy analysis is based on 48 weeks of treatment (see table below). Both arms used an optimisedbackground regimen (OBR) of ≥ 2 NRTIs.

Table 7. Efficacy analysis of ODIN study.

ODIN

Outcomes darunavir/ritonavir darunavir/ritonavir Treatment difference800/100 mg once daily + 600/100 mg twice daily (95% CI of difference)

OBR + OBR

N=294 N=296

HIV-1 RNA< 50 copies/mla 72.1% (212) 70.9% (210) 1.2% (-6.1; 8.5)b

With Baseline HIV-1

RNA (copies/ml)< 100 000 77.6% (198/255) 73.2% (194/265) 4.4% (-3.0; 11.9)≥ 100 000 35.9% (14/39) 51.6% (16/31) -15.7% (-39.2; 7.7)

With Baseline CD4+cell count (x 106/L)≥ 100 75.1% (184/245) 72.5% (187/258) 2.6% (-5.1; 10.3)< 100 57.1% (28/49) 60.5% (23/38) -3.4% (-24.5; 17.8)

With HIV-1 clade

Type B 70.4% (126/179) 64.3% (128/199) 6.1% (-3.4; 15.6)

Type AE 90.5% (38/42) 91.2% (31/34) -0.7% (-14.0; 12.6)

Type C 72.7% (32/44) 78.8% (26/33) -6.1% (-2.6; 13.7)

Otherc 55.2% (16/29) 83.3% (25/30) -28.2% (-51.0; -5.3)mean CD4+ cell count 108 112 -5d (-25; 16)change from baseline(x 106/L)ea Imputations according to the TLOVR algorithmb Based on a normal approximation of the difference in % responsec Clades A1, D, F1, G, K, CRF02_AG, CRF12_BF, and CRF06_CPXd Difference in meanse Last Observation Carried Forward imputation

At 48 weeks, virologic response, defined as the percentage of patients with plasma HIV-1 RNA level< 50 copies/ml, with darunavir/ritonavir 800/100 mg once daily treatment was demonstrated to benon-inferior (at the pre-defined 12% non-inferiority margin) compared to darunavir/ritonavir600/100 mg twice daily for both ITT and OP populations.

Darunavir/ritonavir 800/100 mg once daily in ART-experienced patients should not be used in patientswith one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA≥ 100 000 copies/ml or CD4+ cell count < 100 cells x 106/L (see section 4.2 and 4.4). Limited data isavailable in patients with HIV-1 clades other than B.

POWER 1 and POWER 2 are randomised, controlled studies comparing darunavir co-administeredwith ritonavir (600/100 mg twice daily) with a control group receiving an investigator-selected PI(s)regimen in HIV-1 infected patients who had previously failed more than 1 PI containing regimen. An

OBR consisting of at least 2 NRTIs with or without enfuvirtide (ENF) was used in both studies.

The table below shows the efficacy data of the 48-week and 96-week analyses from the pooled

POWER 1 and POWER 2 studies.

Table 8. POWER 1 and POWER 2 pooled data

Week 48 Week 96

Outcomes darunavir/Control Treatment darunavir/Control Treatmentritonavir n=124 difference ritonavir n=124 difference600/100 mg 600/100 mgtwice daily twice dailyn=131 n=131

HIV RNA 45.0% 11.3% 33.7% 38.9% 8.9% 30.1%< 50 copies/mla (59) (14) (23.4%; 44.1%)c (51) (11) (20.1; 40.0)c

CD4+ cell count 103 17 86 133 15 118mean change from (57; 114)c (83.9; 153.4)cbaseline (x 106/L)ba Imputations according to the TLOVR algorithmb Last Observation Carried Forward imputationc 95% confidence intervals.

Analyses of data through 96 weeks of treatment in the POWER studies demonstrated sustainedantiretroviral efficacy and immunologic benefit.

Out of the 59 patients who responded with complete viral suppression (< 50 copies/ml) at week 48,47 patients (80% of the responders at week 48) remained responders at week 96.

Baseline genotype or phenotype and virologic outcome

Baseline genotype and darunavir FC (shift in susceptibility relative to reference) were shown to be apredictive factor of virologic outcome.

Table 9. Proportion (%) of patients with response (HIV-1 RNA < 50 copies/ml at week 24) todarunavir co-administered with ritonavir (600/100 mg twice daily) by baseline genotypea, andbaseline darunavir FC and by use of enfuvirtide (ENF): As treated analysis of the POWER and

DUET studies.

I I Number of baseline mutationsa I Baseline DRV FCb I

Response (HIV-1

RNA < 50 copies/ml

All ranges 0-2 3 ≥ 4 All ranges ≤ 10 10-40 > 40at week 24)%, n/N45% 54% 39% 12% 45% 55% 29% 8%

All patients455/1 014 359/660 67/172 20/171 455/1 014 364/659 59/203 9/118

Patients with no/non- 39% 50% 29% 7% 39% 51% 17% 5%naïve use of ENFc 290/741 238/477 35/120 10/135 290/741 244/477 25/147 5/94

Patients with naïve 60% 66% 62% 28% 60% 66% 61% 17%use of ENFd 165/273 121/183 32/52 10/36 165/273 120/182 34/56 4/24a Number of mutations from the list of mutations associated with a diminished response to darunavir/ritonavir (V11I, V32I,

L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V)b fold change in EC50c “Patients with no/non-naïve use of ENF” are patients who did not use ENF or who used ENF but not for the first timed “Patients with naïve use of ENF” are patients who used ENF for the first time

For clinical study results in ART-naïve paediatric patients aged 12 to 17 years, refer to the Summaryof Product Characteristics for Darunavir Krka 400 mg and 800 mg tablets.

ART-experienced paediatric patients from the age of 6 to < 18 years and weighing at least 20 kg

DELPHI is an open-label, Phase II study evaluating the pharmacokinetics, safety, tolerability, andefficacy of darunavir with low dose ritonavir in 80 ART-experienced HIV-1 infected paediatricpatients aged 6 to 17 years and weighing at least 20 kg. These patients received darunavir/ritonavirtwice daily in combination with other antiretroviral agents (see section 4.2 for dose recommendationsper body weight). Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of atleast 1.0 log10 versus baseline.

In the study, patients who were at risk of discontinuing therapy due to intolerance of ritonavir oralsolution (e.g. taste aversion) were allowed to switch to the capsule formulation. Of the 44 patientstaking ritonavir oral solution, 27 switched to the 100 mg capsule formulation and exceeded the weight-based ritonavir dose without changes in observed safety.

Table 10. Outcomes at week 48 in Delphi studydarunavir/ritonavir

Outcomes at week 48

N=80

HIV-1 RNA < 50 copies/mla 47.5% (38)

CD4+ cell count mean change from baselineb 147a Imputations according to the TLOVR algorithm.b Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0.

According to the TLOVR non-virologic failure censored algorithm 24 (30.0%) patients experiencedvirological failure, of which 17 (21.3%) patients were rebounders and 7 (8.8%) patients were non-responders.

ART-experienced paediatric patients from the age of 3 to < 6 years

The pharmacokinetics, safety, tolerability and efficacy of darunavir/ritonavir twice daily incombination with other antiretroviral agents in 21 ART-experienced HIV-1 infected paediatric patientsaged 3 to < 6 years and weighing 10 kg to < 20 kg was evaluated in an open-label, Phase II study,

ARIEL. Patients received a weight-based twice daily treatment regimen, patients weighing 10 kg to< 15 kg received darunavir/ritonavir 25/3 mg/kg twice daily, and patients weighing 15 kg to < 20 kgreceived darunavir/ritonavir 375/50 mg twice daily. At week 48, the virologic response, defined as thepercentage of patients with confirmed plasma viral load < 50 HIV-1 RNA copies/ml, was evaluated in16 paediatric patients 15 kg to < 20 kg and 5 paediatric patients 10 kg to < 15 kg receivingdarunavir/ritonavir in combination with other antiretroviral agents (see section 4.2 for doserecommendations per body weight).

Table 11. Outcomes at week 48 in Ariel study

Outcomes at week 48 darunavir /ritonavir10 kg to < 15 kg 15 kg to < 20 kg

N=5 N=16

HIV-1 RNA < 50 copies/mla 80.0% (4) 81.3% (13)

CD4+ percent change from baselineb 4 4

CD4+ cell count mean change from baselineb 16 241a Imputations according to the TLOVR algorithm.b NC=F

Limited efficacy data are available in paediatric patients below 15 kg and no recommendation on aposology can be made.

Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with abackground regimen was evaluated in a clinical study of 36 pregnant women (18 in each arm) duringthe second and third trimesters, and postpartum. Virologic response was preserved throughout thestudy period in both arms. No mother to child transmission occurred in the infants born to the31 subjects who stayed on the antiretroviral treatment through delivery. There were no new clinicallyrelevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV-1infected adults (see sections 4.2, pct. 4.4 and 5.2).

The pharmacokinetic properties of darunavir, co-administered with ritonavir, have been evaluated inhealthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1 infectedpatients compared to healthy subjects may be explained by the higher concentrations of α1-acidglycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAGand, therefore, higher plasma concentrations.

Darunavir is primarily metabolised by CYP3A. Ritonavir inhibits CYP3A, thereby increasing theplasma concentrations of darunavir considerably.

Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration ofdarunavir in the presence of low dose ritonavir is generally achieved within 2.5-4.0 hours.

The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37%and increased to approximately 82% in the presence of 100 mg twice daily ritonavir. The overallpharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemicexposure of darunavir when a single dose of 600 mg darunavir was given orally in combination withritonavir at 100 mg twice daily (see section 4.4).

When administered without food, the relative bioavailability of darunavir in the presence of low doseritonavir is 30% lower as compared to intake with food. Therefore, darunavir tablets should be takenwith ritonavir and with food. The type of food does not affect exposure to darunavir.

Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma α1-acidglycoprotein.

Following intravenous administration, the volume of distribution of darunavir alone was 88.1 ± 59.0 l(Mean ± SD) and increased to 131 ± 49.9 l (Mean ± SD) in the presence of 100 mg twice-dailyritonavir.

In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarilyundergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system andalmost exclusively by isozyme CYP3A4. A 14C-darunavir study in healthy volunteers showed that amajority of the radioactivity in plasma after a single 400/100 mg darunavir with ritonavir dose was dueto the parent active substance. At least 3 oxidative metabolites of darunavir have been identified inhumans; all showed activity that was at least 10-fold less than the activity of darunavir against wildtype HIV.

After a 400/100 mg 14C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of theadministered dose of 14C-darunavir could be retrieved in faeces and urine, respectively. Unchangeddarunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine,respectively. The terminal elimination half-life of darunavir was approximately 15 hours whencombined with ritonavir.

The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was32.8 l/h and 5.9 l/h, respectively.

The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 74 treatment-experienced paediatric patients, aged 6 to 17 years and weighing at least 20 kg, showed that theadministered weight-based doses of darunavir/ritonavir resulted in darunavir exposure comparable tothat in adults receiving darunavir/ritonavir 600/100 mg twice daily (see section 4.2).

The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 14 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 15 kg to < 20 kg, showedthat weight-based doses resulted in darunavir exposure that was comparable to that achieved in adultsreceiving darunavir/ritonavir 600/100 mg twice daily (see section 4.2).

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART-naïvepaediatric patients, aged 12 to < 18 years and weighing at least 40 kg, showed that darunavir/ritonavir800/100 mg once daily results in darunavir exposure that was comparable to that achieved in adultsreceiving darunavir/ritonavir 800/100 mg once daily. Therefore the same once daily dose may be usedin treatment-experienced adolescents aged 12 to < 18 years and weighing at least 40 kg withoutdarunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100 000 copies/ml and CD4+ cell count ≥ 100 cells x 106/L (see section 4.2).

* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 10 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 14 kg to < 20 kg, showedthat weight-based doses resulted in darunavir exposure that was comparable to that achieved in adultsreceiving darunavir/ritonavir 800/100 mg once daily (see section 4.2). In addition, pharmacokineticmodeling and simulation of darunavir exposures in paediatric patients across the ages of 3 to< 18 years confirmed the darunavir exposures as observed in the clinical studies and allowed theidentification of weight-based darunavir/ritonavir once daily dosing regimens for paediatric patientsweighing at least 15 kg that are either ART-naïve or treatment-experienced paediatric patients without

DRV-RAMs* and who have plasma HIV-1 RNA < 100 000 copies/ml and CD4+ cell count≥ 100 cells x 106/L (see section 4.2).

* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokineticsare not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients(n=12, age ≥ 65) (see section 4.4). However, only limited data were available in patients above the ageof 65 year.

Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIVinfected females compared to males. This difference is not clinically relevant.

Results from a mass balance study with 14C-darunavir with ritonavir showed that approximately 7.7%of the administered dose of darunavir is excreted in the urine unchanged.

Although darunavir has not been studied in patients with renal impairment, populationpharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantlyaffected in HIV infected patients with moderate renal impairment (CrCl between 30-60 ml/min, n=20)(see sections 4.2 and 4.4).

Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose study with darunavirco-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the total plasmaconcentrations of darunavir in subjects with mild (Child-Pugh Class A, n=8) and moderate (Child-

Pugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects. However,unbound darunavir concentrations were approximately 55% (Child-Pugh Class A) and 100% (Child-

Pugh Class B) higher, respectively. The clinical relevance of this increase is unknown therefore,darunavir should be used with caution. The effect of severe hepatic impairment on thepharmacokinetics of darunavir has not been studied (see sections 4.2, pct. 4.3 and 4.4).

The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twicedaily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generallylower during pregnancy compared with postpartum. However, for unbound (i.e. active) darunavir, thepharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to anincrease in the unbound fraction of darunavir during pregnancy compared to postpartum.

Table 12. Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at600/100 mg twice daily as part of an antiretroviral regimen, during the second trimester of pregnancy, thethird trimester of pregnancy and postpartum

Pharmacokinetics of total Second trimester of Third trimester of Postpartum (6-12 weeks)darunavir pregnancy pregnancy (n=12)(mean ± SD) (n=12)a (n=12)

Cmax, ng/ml 4 668 ± 1 097 5 328 ± 1 631 6 659 ± 2 364

AUC12h, ng.h/ml 39 370 ± 9 597 45 880 ± 17 360 56 890 ± 26 340

Cmin, ng/ml 1 922 ± 825 2 661 ± 1 269 2 851 ± 2 216a n=11 for AUC12h

Table 13. Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at800/100 mg once daily as part of an antiretroviral regimen, during the second trimester of pregnancy, thethird trimester of pregnancy and postpartum

Pharmacokinetics of total Second trimester of Third Trimester of Postpartum (6-12 weeks)darunavir pregnancy pregnancy (n=16)(mean ± SD) (n=17) (n=15)

Cmax, ng/ml 4 964 ± 1 505 5 132 ± 1 198 7 310 ± 1 704

AUC24h, ng.h/ml 62 289 ± 16 234 61 112 ± 13 790 92 116 ± 29 241

Cmin, ng/ml 1 248 ± 542 1 075 ± 594 1 473 ± 1 141

In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester ofpregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 26% and26% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, totaldarunavir Cmax, AUC12h and Cmin values were 18%, 16% lower and 2% higher, respectively, ascompared with postpartum.

In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester ofpregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 33%, 31% and30% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, totaldarunavir Cmax, AUC24h and Cmin values were 29%, 32% and 50% lower, respectively, as comparedwith postpartum.

Animal toxicology studies have been conducted at exposures up to clinical exposure levels withdarunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.

In repeated-dose toxicology studies in mice, rats and dogs, there were only limited effects of treatmentwith darunavir. In rodents the target organs identified were the haematopoietic system, the bloodcoagulation system, liver and thyroid. A variable but limited decrease in red blood cell-relatedparameters was observed, together with increases in activated partial thromboplastin time.

Changes were observed in liver (hepatocyte hypertrophy, vacuolation, increased liver enzymes) andthyroid (follicular hypertrophy). In the rat, the combination of darunavir with ritonavir lead to a smallincrease in effect on red blood cell (RBC) parameters, liver and thyroid and increased incidence ofislet fibrosis in the pancreas (in male rats only) compared to treatment with darunavir alone. In thedog, no major toxicity findings or target organs were identified up to exposures equivalent to clinicalexposure at the recommended dose.

In a study conducted in rats, the number of corpora lutea and implantations were decreased in thepresence of maternal toxicity. Otherwise, there were no effects on mating or fertility with darunavirtreatment up to 1 000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at theclinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir inrats and rabbits when treated alone nor in mice when treated in combination with ritonavir. Theexposure levels were lower than those with the recommended clinical dose in humans. In a pre- andpostnatal development assessment in rats, darunavir with and without ritonavir, caused a transientreduction in body weight gain of the offspring pre-weaning and there was a slight delay in the openingof eyes and ears. Darunavir in combination with ritonavir caused a reduction in the number of pupsthat exhibited the startle response on day 15 of lactation and a reduced pup survival during lactation.

These effects may be secondary to pup exposure to the active substance via the milk and/or maternaltoxicity. No post weaning functions were affected with darunavir alone or in combination withritonavir. In juvenile rats receiving darunavir up to days 23-26, increased mortality was observed withconvulsions in some animals. Exposure in plasma, liver and brain was considerably higher than inadult rats after comparable doses in mg/kg between days 5 and 11 of age. After day 23 of life, theexposure was comparable to that in adult rats. The increased exposure was likely at least partly due toimmaturity of the drug-metabolising enzymes in juvenile animals. No treatment related mortalitieswere noted in juvenile rats dosed at 1 000 mg/kg darunavir (single dose) on day 26 of age or at500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile werecomparable to those observed in adult rats.

Due to uncertainties regarding the rate of development of the human blood brain barrier and liverenzymes, darunavir with low dose ritonavir should not be used in paediatric patients below 3 years ofage.

Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats upto 104 weeks. Daily doses of 150, 450 and 1 000 mg/kg were administered to mice and doses of 50,150 and 500 mg/kg were administered to rats. Dose-related increases in the incidences ofhepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroidfollicular cell adenomas were noted in male rats. Administration of darunavir did not cause astatistically significant increase in the incidence of any other benign or malignant neoplasm in mice orrats. The observed hepatocellular and thyroid tumours in rodents are considered to be of limitedrelevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzymeinduction and increased thyroid hormone elimination, which predispose rats, but not humans, tothyroid neoplasms. At the highest tested doses, the systemic exposures (based on AUC) to darunavirwere between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humansat the recommended therapeutic doses.

After 2 years administration of darunavir at exposures at or below the human exposure, kidneychanges were observed in mice (nephrosis) and rats (chronic progressive nephropathy).

Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays includingbacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes and in vivomicronucleus test in mice.

Cellulose, microcrystalline

Crospovidone

Hydroxypropylcellulose

Silica, colloidal anhydrous

Silicified microcrystalline cellulose (Cellulose, microcrystalline; Silica, colloidal anhydrous)

Magnesium stearate (E470b)

Poly(vinyl alcohol)

Macrogol

Titanium dioxide (E171)

Talc (E553b)

Iron oxide, yellow (E172)

Iron oxide, red (E172)

Not applicable.

3 years

Shelf life after first opening: 3 months.

Keep the bottle tightly closed in order to protect from moisture.

For storage conditions after first opening of the medicinal product, see section 6.3.

Bottle (HDPE), child resistant tamper evident PP closure with a desiccant:

- 30 tablets: 1 bottle of 30 film-coated tablets,

- 60 tablets: 2 bottles of 30 film-coated tablets,

- 90 tablets: 3 bottles of 30 film-coated tablets,

- 180 tablets: 6 bottles of 30 film-coated tablets.

Not all pack sizes may be marketed.

No special requirements for disposal.

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

30 film-coated tablets: EU/1/17/1249/00560 film-coated tablets: EU/1/17/1249/00690 film-coated tablets: EU/1/17/1249/007180 film-coated tablets: EU/1/17/1249/008

Date of first authorisation: 26 January 2018

Date of latest renewal: 9 November 2022

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

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