DARUNAVIR KRKA 400mg tablets medication leaflet

Darunavir Krka 400 mg film-coated tablets

Darunavir Krka 800 mg film-coated tablets

Darunavir Krka 400 mg film-coated tablets

Each film-coated tablet contains 400 mg darunavir.

Darunavir Krka 800 mg film-coated tablets

Each film-coated tablet contains 800 mg darunavir.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Darunavir Krka 400 mg film-coated tablets

Yellowish brown, oval, biconvex film-coated tablets, engraved with a mark S1 on one side. Tabletdimension: 17 x 8.5 mm.

Darunavir Krka 800 mg film-coated tablets

Brownish red, oval, biconvex film-coated tablets, engraved with a mark S3 on one side. Tabletdimension: 20 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.

Darunavir Krka 400 mg and 800 mg tablets may be used to provide suitable dose regimens for thetreatment of HIV-1 infection in adult and paediatric patients from the age of 3 years and at least 40 kgbody weight who are:

- antiretroviral therapy (ART)-naïve (see section 4.2).

- ART-experienced with no darunavir resistance associated mutations (DRV-RAMs) and whohave plasma HIV-1 RNA < 100 000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l. Indeciding to initiate treatment with darunavir in such ART-experienced patients, genotypictesting should guide the use of darunavir (see sections 4.2, pct. 4.3, 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.

The interaction profile of darunavir depends on whether ritonavir is used as pharmacokinetic enhancer.

Darunavir may therefore have different contraindications and recommendations for concomitantmedicinal products depending on whether the compound is boosted with ritonavir (see sections pct. 4.3,4.4 and 4.5).

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 as appropriate, must therefore be consulted prior to initiation of therapy with darunavir.

This medicinal product is only available as film coated tablets and is thus not suitable for patients whoare unable to swallow intact tablets, for example young children. For use in these patients, moresuitable formulations containing darunavir should be checked for their availability.

ART-naïve adult patients

The recommended dose regimen is 800 mg once daily taken with ritonavir 100 mg once daily takenwith food. Darunavir Krka 400 mg and 800 mg tablets can be used to construct the once daily 800 mgregimen.

ART-experienced adult patients

The recommended dose regimens are as follows:

- In ART-experienced patients with no darunavir 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 4.1) a regimen of 800 mg once daily with ritonavir 100 mg oncedaily taken with food may be used. Darunavir Krka 400 mg and 800 mg tablets can be used toconstruct the once daily 800 mg regimen.

- In all other ART-experienced patients or if HIV-1 genotype testing is not available, therecommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily takenwith food. See the Summary of Product Characteristics for Darunavir Krka 600 mg tablets.

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

ART-naïve paediatric patients (3 to 17 years of age and weighing at least 40 kg)

The recommended dose regimen is 800 mg once daily with ritonavir 100 mg once daily taken withfood.

ART-experienced paediatric patients (3 to 17 years of age and weighing at least 40 kg)

The recommended dose regimens are as follows:

- In ART-experienced 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 4.1) aregimen of 800 mg once daily with ritonavir 100 mg once daily taken with food may be used.

Darunavir Krka 400 mg and 800 mg tablets can be used to construct the once daily 800 mgregimen. The dose of other pharmacokinetic enhancer to be used with darunavir in children lessthan 12 years of age has not been established.

- In all other ART-experienced patients or if HIV-1 genotype testing is not available, therecommended dose regimen is described in the Summary of Product Characteristics for

Darunavir Krka 600 mg tablets.

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

If a once daily dose of darunavir and/or ritonavir is missed within 12 hours of the time it is usuallytaken, patients should be instructed to take the prescribed dose of darunavir and ritonavir with food assoon as possible. If this is noticed later than 12 hours after the time it is usually taken, the missed doseshould not be taken and the patient should resume the usual dosing schedule.

This guidance is based on the half-life of darunavir in the presence of ritonavir and the recommendeddosing interval of approximately 24 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 for darunavir/ritonavir in patients with renal impairment (see sections4.4 and 5.2).

Darunavir Krka should not be used in children

- below 3 years of age, because of safety concerns (see sections 4.4 and 5.3), or,

- less than 15 kg body weight, as the dose for this population has not been established in asufficient number of patients (see section 5.1).

For dose recommendations in children see the Summary of Product Characteristics for Darunavir Krka600 mg tablets.

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).

Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure(see sections 4.4 and 5.2). Therefore, therapy with darunavir/cobicistat should not be initiated duringpregnancy, and women who become pregnant during therapy with darunavir/cobicistat should beswitched to an alternative regimen (see sections 4.4 and 4.6). Darunavir/ritonavir may be consideredas an alternative.

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.

Concomitant treatment with any of the following medicinal products given the expected decrease inplasma concentrations of darunavir, ritonavir and cobicistat and the potential for loss of therapeuticeffect (see sections 4.4 and 4.5).

Applicable to darunavir boosted with either ritonavir or cobicistat: The combination product lopinavir/ritonavir (see section 4.5). The strong CYP3A inducers rifampicin and herbal preparations containing St John’s wort(Hypericum perforatum). Co-administration is expected to reduce plasma concentrations ofdarunavir, ritonavir and cobicistat, which could lead to loss of therapeutic effect and possibledevelopment of resistance (see sections 4.4 and 4.5).

Applicable to darunavir boosted with cobicistat, not when boosted with ritonavir: Darunavir boosted with cobicistat is more sensitive for CYP3A induction than darunavirboosted with ritonavir. Concomitant use with strong CYP3A inducers is contraindicated, sincethese may reduce the exposure to cobicistat and darunavir leading to loss of therapeutic effect.

Strong CYP3A inducers include e.g. carbamazepine, phenobarbital and phenytoin (see sections4.4 and 4.5).

Darunavir boosted with either ritonavir or cobicistat inhibits the elimination of active substances thatare highly dependent on CYP3A for clearance, which results in increased exposure to the co-administered medicinal product. Therefore, concomitant treatment with such medicinal products forwhich elevated plasma concentrations are associated with serious and/or life-threatening events iscontraindicated (applies to darunavir boosted with either ritonavir or cobicistat). These activesubstances 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 cobicistat or low dose ritonavir as a pharmacokineticenhancer and in combination with other antiretroviral medicinal products (see section 5.2). The

Summary of Product Characteristics of cobicistat or ritonavir as appropriate, must therefore beconsulted prior to initiation of therapy with 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 cobicistat or ritonavir.

Darunavir binds predominantly to 1-acid glycoprotein. This protein binding is concentration-dependent indicative for saturation of binding. Therefore, protein displacement of medicinal productshighly bound to 1-acid glycoprotein cannot be ruled out (see section 4.5).

ART-experienced patients - once daily dosing

Darunavir Krka used in combination with cobicistat or low dose ritonavir once daily in ART-experienced patients should not be used in patients with one or more darunavir resistance associatedmutations (DRV-RAMs) or HIV-1 RNA ≥ 100 000 copies/ml or CD4+ cell count < 100 cells x 106/L(see section 4.2). Combinations with optimised background regimen (OBRs) other than ≥ 2 NRTIshave not been studied in this population. Limited data are available in patients with HIV-1 clades otherthan 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 may furtherdecrease darunavir exposure (see sections 4.5 and 5.2).

Treatment with darunavir/cobicistat 800/150 mg once daily during the second and third trimester hasbeen shown to result in low darunavir exposure, with a reduction of around 90% in Cmin levels (seesection 5.2). Cobicistat levels decrease and may not provide sufficient boosting. The substantialreduction in darunavir exposure may result in virological failure and an increased risk of mother tochild transmission of HIV infection. Therefore, therapy with darunavir/cobicistat should not beinitiated during pregnancy, and women who become pregnant during therapy with darunavir/cobicistatshould be switched to an alternative regimen (see sections 4.2 and 4.6). Darunavir given with low doseritonavir may be considered as an alternative.

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 used incombination with cobicistat or low dose ritonavir and patients should be monitored during treatment.

Increased aspartate aminotransferase/alanine aminotransferase (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 used incombination with cobicistat or low dose ritonavir treatment.

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 used in combination with cobicistat or low doseritonavir, interruption or discontinuation of treatment 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 to an increase in the unbound darunavir plasma concentrations, darunavir should be used withcaution in patients 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). Cobicistat hasnot been studied in patients receiving dialysis, therefore, no recommendation can be made for the useof darunavir/cobicistat in these patients (see section 4.2).

Cobicistat decreases the estimated creatinine clearance due to inhibition of tubular secretion ofcreatinine. This should be taken into consideration if darunavir with cobicistat is administered topatients in whom the estimated creatinine clearance is used to adjust doses of co-administeredmedicinal products (see section 4.2 and cobicistat SmPC).

There are currently inadequate data to determine whether co-administration of tenofovir disoproxil andcobicistat is associated with a greater risk of renal adverse reactions compared with regimens thatinclude tenofovir disoproxil without cobicistat.

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.

Pharmacokinetic enhancer and concomitant medicinal products

Darunavir has different interaction profiles depending on whether the compound is boosted withritonavir or cobicistat: Darunavir boosted with cobicistat is more sensitive for CYP3A induction: concomitant use ofdarunavir/cobicistat and strong CYP3A inducers is therefore contraindicated (see section 4.3),and concomitant use with weak to moderate CYP3A inducers is not recommended (see section4.5). Concomitant use of darunavir/ritonavir and darunavir/cobicistat with lopinavir/ritonavir,rifampicin and herbal products containing St John’s wort, Hypericum perforatum, iscontraindicated (see section 4.5).

 Unlike ritonavir, cobicistat does not have inducing effects on enzymes or transport proteins (seesection 4.5). If switching the pharmacoenhancer from ritonavir to cobicistat, caution is requiredduring the first two weeks of treatment with darunavir/cobicistat, particularly if doses of anyconcomitantly administered medicinal products have been titrated or adjusted during use ofritonavir as a pharmacoenhancer. A dose reduction of the co-administered medicinal productmay be needed in these cases.

Efavirenz in combination with boosted darunavir may result in sub-optimal darunavir Cmin. Ifefavirenz is to be used in combination with darunavir, the darunavir/ritonavir 600/100 mg twice dailyregimen should be used. See the Summary of Product Characteristics for Darunavir Krka 600 mgtablets (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).

The interaction profile of darunavir may differ depending on whether ritonavir or cobicistat is used aspharmacoenhancer. The recommendations given for concomitant use of darunavir and other medicinalproducts may therefore differ depending on whether darunavir is boosted with ritonavir or cobicistat(see sections 4.3 and 4.4), and caution is also required during the first time of treatment if switchingthe pharmacoenhancer from ritonavir to cobicistat (see section 4.4).

Medicinal products that affect darunavir exposure (ritonavir as pharmacoenhancer)

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 these compounds and consequently that of darunavir, leading to loss of therapeuticeffect and possible development of resistance (see sections 4.3 and 4.4). CYP3A inducers that arecontraindicated include rifampicin, St John’s wort and lopinavir.

Co-administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A maydecrease the clearance of darunavir and ritonavir, which may result in increased plasma concentrationsof darunavir and ritonavir. Co-administration with strong CYP3A4 inhibitors is not recommended andcaution is warranted, these interactions are described in the interaction table below (e.g. indinavir,azole antifungals like clotrimazole).

Medicinal products that affect darunavir exposure (cobicistat as pharmacoenhancer)

Darunavir and cobicistat are metabolised by CYP3A, and co-administration with CYP3A inducersmay therefore result in subtherapeutic plasma exposure to darunavir. Darunavir boosted withcobicistat is more sensitive to CYP3A induction than ritonavir-boosted darunavir: co-administration ofdarunavir/cobicistat with medicinal products that are strong inducers of CYP3A (e.g. St John’s wort,rifampicin, carbamazepine, phenobarbital, and phenytoin) is contraindicated (see section 4.3). Co-administration of darunavir/cobicistat with weak to moderate CYP3A inducers (e.g. efavirenz,etravirine, nevirapine, fluticasone, and bosentan) is not recommended (see interaction table below).

For co-administration with strong CYP3A4 inhibitors, the same recommendations apply independentof whether darunavir is boosted with ritonavir or with cobicistat (see section above).

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.

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).

Co-administration of boosted darunavir 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).

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 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 may be affected by darunavir boosted with cobicistat

The recommendations for darunavir boosted with ritonavir are similar to the recommendations fordarunavir boosted with cobicistat with regard to substrates of CYP3A4, CYP2D6, P-glycoprotein,

OATP1B1 and OATP1B3 (see contraindications and recommendations presented in the sectionabove). Cobicistat 150 mg given with darunavir 800 mg once daily enhances darunavirpharmacokinetic parameters in a comparable way to ritonavir (see section 5.2).

Unlike ritonavir, cobicistat does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or

UGT1A1. For further information on cobicistat, consult the cobicistat Summary of Product

Characteristics.

Interaction studies have only been performed in adults.

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 osafety may be indicated.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used aspharmacokinetic enhancer. Darunavir may therefore have different recommendations for concomitantmedicinal products depending on whether the compound is boosted with ritonavir or cobicistat. Nointeraction studies presented in the table have been performed with darunavir boosted with cobicistat.

The same recommendations apply, unless specifically indicated. For further information on cobicistat,consult the cobicistat Summary of Product Characteristics.

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”).

In the table below the specific pharmacokinetic enhancer is specified when recommendations differ.

When the recommendation is the same for darunavir when co-administered with a low dose ritonaviror cobicistat, the term “boosted darunavir” is used.

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 1. Interactions and dose recommendations with 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% Boosted darunavir and dolutegravirdolutegravir C24h ↓38% can be used without dose adjustment.dolutegravir Cmax ↓ 11%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.

Boosted darunavir and raltegravircan be used without doseadjustments.

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

Didanosine didanosine AUC ↓ 9% Boosted darunavir and didanosine400 mg once daily didanosine Cmin ND can be used without dosedidanosine Cmax ↓ 16% 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 boosted darunavir givenwith food.

Tenofovir disoproxil tenofovir AUC ↑ 22% Monitoring of renal function may be245 mg once daily tenofovir Cmin ↑ 37% indicated when boosted darunavir istenofovir Cmax ↑ 24% given in combination with tenofovir#darunavir AUC ↑ 21% disoproxil, particularly in patients#darunavir Cmin ↑ 24% with underlying systemic or renal#darunavir Cmax ↑ 16% disease, or in patients taking(↑ tenofovir from effect on MDR-1 nephrotoxic agents.transport in the renal tubules) Darunavir co-administered withcobicistat lowers the creatinineclearance. Refer to section 4.4 ifcreatinine clearance is used for doseadjustment of tenofovir disoproxil.

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

Abacavir Not studied. Based on the different Boosted darunavir can be used with

Emtricitabine elimination pathways of the other NRTIs these NRTIs without dose

Lamivudine zidovudine, emtricitabine, stavudine, adjustment.

Stavudine lamivudine, that are primarily renally Darunavir co-administered with

Zidovudine excreted, and abacavir for which cobicistat lowers the creatininemetabolism is not mediated by CYP450, clearance. Refer to section 4.4 ifno interactions are expected for these creatinine clearance is used for dosemedicinal compounds and boosted adjustment of emtricitabine ordarunavir. lamivudine.

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).

Co-administration with darunavir co-administered with cobicistat is notrecommended (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 ↔ Co-administration with darunavir co-darunavir Cmax ↔ administered with cobicistat is notrecommended (see section 4.4).

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 consistent Co-administration with darunavir co-with historical data administered with cobicistat is not(↑ nevirapine from CYP3A inhibition) recommended (see section 4.4).

Rilpivirine rilpivirine AUC ↑ 130% Boosted darunavir and rilpivirine can150 mg once daily rilpivirine Cmin ↑ 178% be used without dose adjustments.

rilpivirine Cmax ↑ 79%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 co-administered with#darunavir Cmin ↔ cobicistat should not be used in#darunavir Cmax ↔ combination with another

Atazanavir: comparison of antiretroviral agent that requiresatazanavir/ritonavir 300/100 mg once daily pharmacoenhancement by means ofvs. atazanavir 300 mg once daily in co-administration with an inhibitor ofcombination with darunavir/ritonavir CYP3A4 (see section 4.5).400/100 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 of Darunavir co-administered withindinavir/ritonavir 800/100 mg twice daily cobicistat should not be used invs. indinavir/darunavir/ritonavir combination with another800/400/100 mg twice daily. antiretroviral agent that requires

Darunavir: comparison of pharmacoenhancement by means ofdarunavir/ritonavir 400/100 mg twice daily co-administration with an inhibitor ofvs. darunavir/ritonavir 400/100 mg in CYP3A4 (see section 4.5).

combination 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% Darunavir co-administered withsaquinavir Cmin ↓ 18% cobicistat should not be used insaquinavir Cmax ↓ 6% combination with another

Saquinavir: comparison of antiretroviral agent that requiressaquinavir/ritonavir 1 000/100 mg twice pharmacoenhancement by means ofdaily vs. saquinavir/darunavir/ritonavir co-administration with an inhibitor of1 000/400/100 mg twice daily CYP3A4 (see section 4.5).

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,darunavir Cmin ↓ 51%‡ concomitant use of boosted darunavirdarunavir Cmax ↓ 21%‡ and the combination product

Lopinavir/ritonavir lopinavir AUC ↔ lopinavir/ritonavir is contraindicated533/133.3 mg twice daily lopinavir Cmin ↑ 13% (see section 4.3).lopinavir Cmax ↑ 11%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 boosted darunavir.darunavir, ritonavir concentrations wereconsistent with historical dataα1-ADRENORECEPTOR ANTAGONIST

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

ANAESTHETIC

Alfentanil Not studied. The metabolism of alfentanil The concomitant use with boostedis mediated via CYP3A, and may as such darunavir may require to lower thebe inhibited by boosted darunavir. dose of alfentanil and requiresmonitoring for risks of prolonged ordelayed respiratory depression.

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide I Not studied. Boosted darunavir is expected I Caution is warranted and therapeutic

Flecainide to 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 boosted darunavir.

Amiodarone Co-administration of boosted

Bepridil darunavir and amiodarone, bepridil,

Dronedarone dronedarone, ivabradine, quinidine,

Ivabradine or ranolazine is contraindicated (see

Quinidine 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 onboosted darunavir 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% boosted darunavir.#darunavir AUC ↓ 13% For patients with renal impairment#darunavir Cmin ↑ 1% the Summary of Product#darunavir Cmax ↓ 17% Characteristics for clarithromycin14-OH-clarithromycin concentrations were should be consulted for thenot detectable when combined with recommended dose.darunavir/ritonavir.(↑ clarithromycin from CYP3A inhibitionand possible P-gp inhibition)

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%

Darunavir/cobicistat:

darunavir/cobicistat 800/150 mg single Clinical monitoring and dosedose: reduction is required when a DOACdabigatran AUC ↑ 164% transported by P-gp but notdabigatran Cmax ↑ 164% metabolised by CYP3A4, includingdabigatran etexilate and edoxaban, isdarunavir/cobicistat 800/150 mg once co-administered with darunavir/cobi.

daily:

dabigatran AUC ↑ 88%dabigatran Cmax ↑ 99%

Concomitant administration of

Ticagrelor Based on theoretical considerations, boosted darunavir with ticagrelor isco-administration of boosted darunavir contraindicated (see section 4.3).

with ticagrelor may increaseconcentrations of ticagrelor (CYP3Aand/or P-glycoprotein inhibition).

Co-administration of clopidogrel

Clopidogrel Not studied. Co-administration of with boosted darunavir is notclopidogrel with boosted darunavir is recommended. Use of otherexpected to decrease clopidogrel active antiplatelets not affected by CYPmetabolite plasma concentration, which inhibition or induction (e.g.

may reduce the antiplatelet activity of prasugrel) is recommended.

clopidogrel

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

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. The use of these medicines with(induction of CYP450 enzymes) darunavir/cobicistat iscontraindicated (see section 4.3).

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.

The use of carbamazepine withdarunavir co-administered withcobicistat is contraindicated (seesection 4.3).

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 boosted darunavir,paroxetine Cmax ↓ 36% the recommended approach is a dose#darunavir AUC ↔ titration of the antidepressant based#darunavir Cmin ↔ on a clinical assessment of#darunavir Cmax ↔ antidepressant response. In addition,

Sertraline sertraline AUC ↓ 49% patients on a stable dose of these50 mg once daily sertraline Cmin ↓ 49% antidepressants who start treatmentsertraline Cmax ↓ 44% with boosted darunavir should be#darunavir AUC ↔ monitored for antidepressant#darunavir Cmin ↓ 6% response.

#darunavir Cmax ↔

In contrast to these data with darunavir/ritonavir, darunavir/cobicistat mayincrease these antidepressant plasmaconcentrations (CYP2D6 and/or CYP3A

Amitriptyline inhibition).

Desipramine Clinical monitoring is recommended

Imipramine Concomitant use of boosted darunavir and when co-administering boosted

Nortriptyline these antidepressants may increase darunavir with these antidepressants

Trazodone concentrations of the antidepressant. and a dose adjustment of the(CYP2D6 and/or CYP3A inhibition) antidepressant may be needed.

ANTI-DIABETICS

Metformin Not studied. Based on theoretical Careful patient monitoring and doseconsiderations darunavir co-administered adjustment of metformin iswith cobicistat is expected to increase recommended in patients who aremetformin plasma concentrations. taking darunavir co-administered(MATE1 inhibition) with cobicistat.

(not applicable for darunavir co-administered with ritonavir)

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 boosted darunavir(induction of CYP450 enzymes) unless an assessment of the

Concentrations of voriconazole may benefit/risk ratio justifies the use ofincrease or decrease when co-administered voriconazole.with darunavir co-administered withcobicistat.(inhibition of CYP450 enzymes)

Fluconazole Not studied. Boosted darunavir may Caution is warranted and clinical

Isavuconazole increase antifungal plasma concentrations monitoring is recommended.

Itraconazole and posaconazole, isavuconazole, When co-administration is required

Posaconazole itraconazole or fluconazole may increase the daily dose of itraconazole shoulddarunavir concentrations. not exceed 200 mg.(CYP3A and/or P-gp inhibition)

Clotrimazole Not studied. Concomitant systemic use ofclotrimazole and boosted darunavir mayincrease 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 boosted darunavir may increase the interruption of colchicine treatmentexposure to colchicine. is recommended in patients with(CYP3A and/ or P-gp inhibition) normal renal or hepatic function iftreatment with boosted darunavir isrequired. For patients with renal orhepatic impairment colchicine withboosted darunavir is contraindicated(see sections 4.3 and 4.4).

ANTIMALARIALS

Artemether/Lumefantrine I artemether AUC ↓ 16% I The combination of boosted80/480 mg, 6 doses at 0, 8, artemether Cmin ↔ darunavir and24, 36, 48, and 60 hours artemether Cmax ↓ 18% artemether/lumefantrine can be useddihydroartemisinin AUC ↓ 18% without dose adjustments; however,dihydroartemisinin Cmin ↔ due to the increase in lumefantrinedihydroartemisinin Cmax ↓ 18% exposure, the combination should belumefantrine AUC ↑ 175% used with caution.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 boosted darunavir is notshown to cause profound decreases in recommended.concentrations of other protease inhibitors, The combination of rifampicin andwhich can result in virological failure and boosted darunavir is contraindicatedresistance development (CYP450 enzyme (see section 4.3).induction). During attempts to overcomethe 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 (parent combination with darunavir co-drug + 25-O-desacetyl metabolite) administered with ritonavir. In caseof safety issues, a further increase of

The interaction study showed a the dosing interval for rifabutincomparable daily systemic exposure for and/or monitoring of rifabutin levelsrifabutin between treatment at 300 mg should be considered.once daily alone and 150 mg once every Consideration should be given toother day in combination with official guidance on the appropriatedarunavir/ritonavir (600/100 mg twice treatment of tuberculosis in HIVdaily) with an about 10-fold increase in the infected patients.daily exposure to the active metabolite 25- Based upon the safety profile of

O-desacetylrifabutin. Furthermore, AUC darunavir/ritonavir, the increase inof the sum of active moieties of rifabutin darunavir exposure in the presence of(parent drug + 25-O-desacetyl metabolite) rifabutin does not warrant a dosewas increased 1.6-fold, while Cmax adjustment for darunavir/ritonavir.remained comparable. Based on pharmacokinetic modeling,

Data on comparison with a 150 mg once this dose reduction of 75% is alsodaily reference dose is lacking. applicable if patients receiverifabutin at doses other than(Rifabutin is an inducer and substrate of 300 mg/day.

CYP3A.) An increase of systemicexposure to darunavir was observed when Co-administration of darunavir co-darunavir co-administered with 100 mg administered with cobicistat andritonavir was co-administered with rifabutin is not recommended.rifabutin (150 mg once every other day).

ANTINEOPLASTICS

Dasatinib Not studied. Boosted darunavir is expected Concentrations of these medicinal

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

Vinblastine concentrations. administered with boosted darunavir

Vincristine (CYP3A inhibition) resulting in the potential forincreased adverse events usuallyassociated with these agents.

Caution should be exercised whencombining one of theseantineoplastic agents with boosteddarunavir.

Irinotecan Concomitant use of everolimus oririnotecan and boosted darunavir isnot recommended.

ANTIPSYCHOTICS/NEUROLEPTICS

Quetiapine Not studied. Boosted darunavir is expected Concomitant administration ofto increase these antipsychotic plasma boosted darunavir and quetiapine isconcentrations. contraindicated as it may increase(CYP3A inhibition) quetiapine-related toxicity. Increasedconcentrations of quetiapine maylead to coma (see section 4.3).

Perphenazine Not studied. Boosted darunavir is expected A dose decrease may be needed for

Risperidone to increase these antipsychotic plasma these drugs when co-administered

Thioridazine concentrations. with boosted darunavir.

(CYP3A, CYP2D6 and/or P-gp inhibition)

Lurasidone Concomitant administration of

Pimozide boosted darunavir and lurasidone,

Sertindole pimozide or sertindole iscontraindicated (see section 4.3).

β-BLOCKERS

Carvedilol Not studied. Boosted darunavir is expected Clinical monitoring is recommended

Metoprolol to increase these β-blocker plasma when co-administering boosted

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

CALCIUM CHANNEL BLOCKERS

Amlodipine Not studied. Boosted darunavir can be Clinical monitoring of therapeutic

Diltiazem expected to increase the plasma and adverse reactions is

Felodipine concentrations of calcium channel recommended when these medicines

Nicardipine blockers. are concomitantly administered with

Nifedipine (CYP3A and/or CYP2D6 inhibition) boosted darunavir.

Verapamil

CORTICOSTEROIDS

Corticosteroids primarily Fluticasone: in a clinical study where Concomitant use of boostedmetabolised by CYP3A ritonavir 100 mg capsules twice daily were darunavir and corticosteroids (all(including betamethasone, co-administered with 50 μg intranasal routes of administration) that arebudesonide, fluticasone, fluticasone propionate (4 times daily) for metabolised by CYP3A may increasemometasone, prednisone, 7 days in healthy subjects, fluticasone the risk of development of systemictriamcinolone) propionate plasma concentrations corticosteroid effects, includingincreased significantly, whereas the Cushing's syndrome and adrenalintrinsic cortisol levels decreased by suppression.

approximately 86% (90% CI 82-89%).

Greater effects may be expected when Co-administration with CYP3A-fluticasone is inhaled. Systemic metabolised corticosteroids is notcorticosteroid effects including Cushing's recommended unless the potentialsyndrome and adrenal suppression have benefit to the patient outweighs thebeen reported in patients receiving risk, in which case patients should beritonavir and inhaled or intranasally monitored for systemic corticosteroidadministered fluticasone. The effects of effects.

high fluticasone systemic exposure onritonavir plasma levels are unknown. Alternative corticosteroids which are

Other corticosteroids: interaction not less dependent on CYP3Astudied. Plasma concentrations of these metabolism e.g. beclomethasonemedicinal products may be increased when should be considered, particularly forlong term use.

co-administered with boosted darunavir,resulting in reduced serum cortisolconcentrations.

Dexamethasone (systemic) Not studied. Dexamethasone may decrease Systemic dexamethasone should beplasma concentrations of darunavir. used with caution when combined(CYP3A induction) with boosted darunavir.

ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan Not studied. Concomitant use of bosentan When administered concomitantlyand boosted darunavir may increase with darunavir and low doseplasma concentrations of bosentan. ritonavir, the patient's tolerability of

Bosentan is expected to decrease plasma bosentan should be monitored.concentrations of darunavir and/or its Co administration of darunavir co-pharmacoenhancer. administered with cobicistat and(CYP3A induction) bosentan is not recommended.

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS

NS3-4A protease inhibitors

Elbasvir/grazoprevir Boosted darunavir may increase the Concomitant use of boostedexposure to grazoprevir. darunavir and elbasvir/grazoprevir is(CYP3A and OATP1B inhibition) contraindicated (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 Boosted darunavir must not be usedperforatum) decrease the plasma concentrations of concomitantly with productsdarunavir or its pharmacoenhancers. containing St John's wort(CYP450 induction) (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 boosted darunavir. rhabdomyolysis. Concomitant use of(CYP3A inhibition) boosted darunavir 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 boosted darunavir is desired, it isatorvastatin Cmax ↑ ≈2 fold recommended to start with an#darunavir/ritonavir atorvastatin dose of 10 mg oncedaily. A gradual dose increase ofatorvastatin may be tailored to theatorvastatin AUC ↑ 290% Ω clinical response.atorvastatin C ↑ 319% Ωmaxatorvastatin Cmin ND Ω

Ω with darunavir/cobicistat 800/150 mg

Pravastatin pravastatin AUC ↑ 81%¶ When administration of pravastatin40 mg single dose pravastatin Cmin ND and boosted darunavir is required, itpravastatin Cmax ↑ 63% is recommended to start with the¶ an up to five-fold increase was seen in a limited lowest possible dose of pravastatinsubset of subjects and titrate up to the desired clinicaleffect while monitoring for safety.

Rosuvastatin rosuvastatin AUC ↑ 48%║ When administration of rosuvastatin10 mg once daily rosuvastatin C ║max ↑ 144% and boosted darunavir is required, it║ based on published data with darunavir/ritonavir is recommended to start with the§ lowest possible dose of rosuvastatinrosuvastatin AUC ↑ 93% and titrate up to the desired clinicalrosuvastatin C §max ↑ 277% effect while monitoring for safety.rosuvastatin C §min ND§ with darunavir/cobicistat 800/150 mg

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 ↔ Boosted darunavir can be co-150 mg twice daily #darunavir Cmin ↔ administered with H2-receptor#darunavir Cmax ↔ antagonists without doseadjustments.

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 boosted done when co-administration occurs.

darunavir.(CYP3A inhibition) Concomitant use of everolimus and

Everolimus boosted darunavir is notrecommended.

INHALED BETA AGONISTS

Salmeterol Not studied. Concomitant use of Concomitant use of salmeterol andsalmeterol and boosted darunavir may boosted darunavir is notincrease plasma concentrations of recommended. The combination maysalmeterol. result in increased risk ofcardiovascular adverse event withsalmeterol, including QTprolongation, palpitations and sinustachycardia.

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 boosteddarunavir /cobicistat may, in contrast, darunavir. However, adjustment ofincrease methadone plasma concentrations the methadone dose may be(see cobicistat SmPC). necessary when concomitantlyadministered for a longer period oftime. Therefore, clinical monitoringis recommended, 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 ↔ boosted darunavir 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 drospirenone AUC ↑ 58%€ When darunavir is coadministered

Ethinylestradiol drospirenone Cmin ND€ with a drospirenone-containing(3 mg/0.02 mg once daily) drospirenone C €max ↑ 15% product, clinical monitoring isethinylestradiol AUC  30%€ recommended due to the potential forethinylestradiol Cmin ND€ hyperkalaemia.

ethinylestradiol Cmax  14%€€ with darunavir/cobicistat

Alternative or additional

Ethinylestradiol ethinylestradiol AUC ↓ 44% β contraceptive measures are

Norethindrone ethinylestradiol Cmin ↓ 62% β recommended when oestrogen-based35 μg/1 mg once daily ethinylestradiol C βmax ↓ 32% contraceptives are co-administerednorethindrone AUC ↓ 14% β with boosted darunavir. Patientsnorethindrone C βmin ↓ 30% using oestrogens as hormonenorethindrone Cmax ↔ β replacement therapy should beβ with darunavir/ritonavir clinically 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 boosted darunavir is contraindicated

Avanafil observed for a single intake of 100 mg (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 boosted darunavirshould be done with caution. Ifconcomitant use of boosted darunavirwith 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 boosted pulmonary arterial hypertension co-

Sildenafil darunavir may increase plasma administered with boosted darunavir

Tadalafil concentrations of sildenafil or tadalafil. has not been established. There is an(CYP3A inhibition) increased potential for sildenafil-associated adverse events (includingvisual disturbances, hypotension,prolonged erection and syncope).

Therefore, co-administration ofboosted darunavir and sildenafilwhen used for the treatment ofpulmonary arterial hypertension iscontraindicated (see section 4.3).

Co-administration of tadalafil for thetreatment of pulmonary arterialhypertension with boosted darunaviris not recommended.

PROTON PUMP INHIBITORS

Omeprazole #darunavir AUC ↔ Boosted darunavir can be co-20 mg once daily #darunavir Cmin ↔ administered with proton pump#darunavir Cmax ↔ inhibitors without dose adjustments.

SEDATIVES/HYPNOTICS

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

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

Diazepam administration with boosted darunavir may darunavir with these

Estazolam cause a large increase in the concentration sedatives/hypnotics and a lower dose

Flurazepam of these medicines. of the sedatives/hypnotics should be

Midazolam (parenteral) considered.

Zolpidem

If parenteral midazolam is co-administered If parenteral midazolam is co-with boosted darunavir it may cause a administered with boosted darunavir,large increase in the concentration of this it should be done in an intensive carebenzodiazepine. Data from concomitant unit (ICU) or similar setting, whichuse of parenteral midazolam with other ensures close clinical monitoring andprotease inhibitors suggest a possible 3- appropriate medical management in4 fold increase in midazolam plasma case of respiratory depression and/orlevels. prolonged sedation. Dose adjustmentfor midazolam should be considered,especially if more than a single doseof midazolam is administered.

Midazolam (oral) Boosted darunavir with triazolam or

Triazolam oral midazolam is contraindicated(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.

Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure(see section 5.2), which may be associated with an increased risk of treatment failure and an increasedrisk of HIV transmission to the child. Therapy with darunavir/cobicistat should not be initiated duringpregnancy, and women who become pregnant during therapy with darunavir/cobicistat should beswitched to an alternative regimen (see sections 4.2 and 4.4).

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 cobicistat or ritonavir has no or negligible influence on the ability todrive and use machines. However, dizziness has been reported in some patients during treatment withregimens containing darunavir co-administered with cobicistat or low dose ritonavir and should beborne in mind when considering 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.

During the Phase III clinical studies GS-US-216-130 with darunavir/cobicistat (N=313 treatment-naïve and treatment-experienced subjects), 66.5% of subjects experienced at least one adversereaction. The mean treatment duration was 58.4 weeks. The most frequent adverse reactions reportedwere diarrhoea (28%), nausea (23%), and rash (16%). Serious adverse reactions are diabetes mellitus,(drug) hypersensitivity, immune reconstitution inflammatory syndrome, rash and vomiting.

For information on cobicistat, consult the cobicistat Summary of Product Characteristics.

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 2. Adverse reactions observed with darunavir/ritonavir in clinical studies and post-marketing

MedDRA system organ class Adverse reaction

Frequency category

Infections and infestationsuncommon herpes simplex

Blood and lymphatic system disordersuncommon thrombocytopenia, neutropenia, anaemia,rare leukopeniaincreased eosinophil count

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

Endocrine disordersuncommon hypothyroidism, increased blood thyroidstimulating hormone

Metabolism and nutrition disorderscommon diabetes mellitus, hypertriglyceridaemia,uncommon hypercholesterolaemia, hyperlipidaemiagout, anorexia, decreased appetite, decreasedweight, increased weight, hyperglycaemia, insulinresistance, decreased high density lipoprotein,increased appetite, polydipsia, increased bloodlactate 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, increasedblood amylase, dyspepsia, abdominal distension,flatulenceuncommon pancreatitis, gastritis, gastrooesophageal refluxdisease, aphthous stomatitis, retching, dry mouth,abdominal discomfort, constipation, increasedlipase, 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 bloodbilirubin, increased blood alkaline phosphatase,increased gamma-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,skin lesion, 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 creatinephosphokinaserare 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,feeling hot, irritability, painrare chills, abnormal feeling, xerosis§adverse reaction identified in the post-marketing setting. Per the guideline on Summary of Product Characteristics(Revision 2, September 2009), the frequency of this adverse reaction in the post-marketing setting was determined using the'Rule of 3'.

Table 3. Adverse reactions observed with darunavir/cobicistat in adult patients

MedDRA system organ class Adverse reaction

Frequency category

Immune system disorderscommon (drug) hypersensitivityuncommon immune reconstitution inflammatory syndrome

Metabolism and nutrition disorderscommon anorexia, diabetes mellitus,hypercholesterolaemia, hypertriglyceridaemia,hyperlipidaemia

Psychiatric disorderscommon abnormal dreams

Nervous system disordersvery common headache

Gastrointestinal disordersvery common diarrhoea, nauseacommon vomiting, abdominal pain, abdominal distension,dyspepsia, flatulence, pancreatic enzymesincreaseduncommon pancreatitis acute

Hepatobiliary disorderscommon hepatic enzyme increaseduncommon hepatitis*, cytolytic hepatitis*

Skin and subcutaneous tissue disordersvery common rash (including macular, maculopapular, papular,erythematous, pruritic rash, generalised rash, andallergic dermatitis)common angioedema, pruritus, urticariarare drug reaction with eosinophilia and systemicsymptoms*, Stevens-Johnson syndrome*not known toxic epidermal necrolysis*, acute generalisedexanthematous pustulosis*

Musculoskeletal and connective tissue disorderscommon myalgiauncommon osteonecrosis*

Renal and urinary disordersrare crystal nephropathy*§

Reproductive system and breast disordersuncommon gynaecomastia*

General disorders and administration site conditionscommon fatigueuncommon asthenia

Investigationscommon increased blood creatinine

* these adverse drug reactions have not been reported in clinical study experience with darunavir/cobicistat but have beennoted with darunavir/ritonavir treatment and could be expected with darunavir/cobicistat too.§ 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. In a single arm study investigating darunavir 800 mg once daily in combination withcobicistat 150 mg once daily and other antiretrovirals 2.2% of patients discontinued treatment due torash.

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 of darunavir with ritonavir in paediatric patients is based on the 48-weekanalysis 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 cobicistat or low doseritonavir is limited. Single doses up to 3 200 mg of darunavir as oral solution alone and up to 1 600 mgof the tablet 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 > 40 are 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 4. The development of HIV-1 protease mutations and loss of susceptibility to PIs in virologicfailures at endpoint in the ARTEMIS, ODIN and TITAN studies

ARTEMIS ODIN TITAN

Week 192 Week 48 Week 48darunavir/ darunavir/ ritonavir darunavir/ darunavir/ ritonavirritonavir 800/100 mg ritonavir 600/100 mg800/100 mg once daily 600/100 mg twice dailyonce daily N=294 twice daily N=298

N=343 N=296

Total number of 55 (16.0%) 65 (22.1%) 54 (18.2%) 31 (10.4%)virologic 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, developingmutationsb at endpoint, 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 < 400copies/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.

In the virologic failures of the GS-US-216-130 study no cross-resistance with other HIV PIs wasobserved.

The pharmacokinetic enhancing effect of pharmacokinetic enhancer other than ritonavir on darunavirwas evaluated in a Phase I study in healthy subjects that were administered darunavir 800 mg withritonavir at 100 mg or other phrmacokinetic enhancer once daily. The steady-state pharmacokineticparameters of darunavir were comparable when boosted with ritonavir.

Adult patients

Efficacy of darunavir 800 mg once daily co-administered with 100 mg ritonavir once daily in ART-naïve patients

The evidence of efficacy of darunavir/ritonavir 800/100 mg once daily is based on the analyses of192 week data from the randomised, controlled, open-label Phase III study ARTEMIS in antiretroviraltreatment-naïve HIV-1 infected patients comparing darunavir/ritonavir 800/100 mg once daily withlopinavir/ritonavir 800/200 mg per day (given as a twice-daily or as a once-daily regimen). Both armsused a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily andemtricitabine 200 mg once daily.

The table below shows the efficacy data of the 48 week and 96 week analyses from the ARTEMISstudy:

Table 5. The efficacy data of the 48 week and 96 week analyses from the ARTEMIS study.

ARTEMIS

Week 48a Week 96b

Outcomes darunavir/ Lopinavir/ Treatment darunavir/ Lopinavir/ Treatmentritonavir ritonavir difference ritonavir ritonavir difference800/100 mg 800/200 mg (95% CI of 800/100 mg 800/200 mg (95% CI ofonce daily per day difference) once daily per day difference)

N=343 N=346 N=343 N=346

HIV-1 RNA < 50copies/mlc 83.7% 78.3% 5.3% 79.0% 70.8% 8.2%

All patients (287) (271) (-0.5; 11.2)d (271) (245) (1.7; 14.7)d

With baseline 85.8% 84.5% 1.3% 80.5% 75.2% 5.3%

HIV- (194/226) (191/226) (-5.2; 7.9)d (182/226) (170/226) (-2.3; 13.0)d

RNA < 100 000

With baseline 79.5% 66.7% 12.8% 76.1% 62.5% 13.6%

HIV- (93/117) (80/120) (1.6; 24.1)d (89/117) (75/120) (1.9; 25.3)d

RNA ≥ 100 000

With baseline 79.4% 70.3% 9.2% 78.7% 64.9% 13.9%

CD4+ cell count (112/141) (104/148) (-0.8; 19.2)d (111/141) (96/148) (3.5; 24.2)d< 200

With baseline 86.6% 84.3% 2.3% 79.2% 75.3% 4.0%

CD4+ cell count (175/202) (167/198) (-4.6; 9.2)d (160/202) (149/198) (-4.3; 12.2)d≥ 200median CD4+ cell 137 141 171 188count change frombaseline (x 106/L)ea Data based on analyses at week 48b Data based on analyses at week 96c Imputations according to the TLOVR algorithmd Based on normal approximation to the difference in % responsee Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0

Non-inferiority in virologic response to the darunavir/ritonavir treatment, defined as the percentage ofpatients with plasma HIV-1 RNA level < 50 copies/ml, was demonstrated (at the pre-defined 12%non-inferiority margin) for both Intent-To-Treat (ITT) and On Protocol (OP) populations in the48 week analysis. These results were confirmed in the analyses of data at 96 weeks of treatment in the

ARTEMIS study. These results were sustained up to 192 weeks of treatment in the ARTEMIS study.

Efficacy of darunavir 800 mg once daily co-administered with 100 mg ritonavir once daily in ART-experienced patients

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 6. The efficacy data from the 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 72.1% (212) 70.9% (210) 1.2% (-6.1; 8.5)bcopies/mla

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). Limiteddata is available in patients with HIV-1 clades other than B.

ART-naïve paediatric patients from the age of 12 years to < 18 years, and weighing at least 40 kg

DIONE is an open-label, Phase II study evaluating the pharmacokinetics, safety, tolerability, andefficacy of darunavir with low dose ritonavir in 12 ART-naïve HIV-1 infected paediatric patients aged12 to less than 18 years and weighing at least 40 kg. These patients received darunavir/ritonavir800/100 mg once daily in combination with other antiretroviral agents. Virologic response was definedas a decrease in plasma HIV-1 RNA viral load of at least 1.0 log10 versus baseline.

Table 7. The efficacy data from the DIONE study.

DIONEdarunavir/ritonavir

Outcomes at week 48

N=12

HIV-1 RNA < 50 copies/mla 83.3% (10)

CD4+ percent change from baselineb 14

CD4+ cell count mean change from baselineb 221≥ 1.0 log10 decrease from baseline in plasma viral load 100%a Imputations according to the TLOVR algorithm.b Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0.

For additional clinical study results in ART-experienced adults and paediatric patients, refer to the

Summary of Product Characteristics for Darunavir Krka 600 mg tablets.

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 cobicistat or ritonavir, have beenevaluated in healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higherin HIV-1 infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1infected patients compared to healthy subjects may be explained by the higher concentrations of α1-acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma

AAG and, therefore, higher plasma concentrations.

Darunavir is primarily metabolised by CYP3A. Cobicistat and ritonavir inhibit CYP3A, therebyincreasing the plasma concentrations of darunavir considerably.

For information on cobicistat pharmacokinetic properties, consult the cobicistat Summary of Product

Characteristics.

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 cobicistator low dose ritonavir is lower as compared to intake with food. Therefore, darunavir tablets should betaken with cobicistat or ritonavir and with food. The type of food does not affect exposure todarunavir.

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 000copies/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 8. 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 ofpregnancy, the third trimester of pregnancy and postpartum

Pharmacokinetics of Second trimester of Third trimester of Postpartum (6-total darunavir pregnancy pregnancy 12 weeks)(mean ± SD) (n=12)a (n=12) (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 9. 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 ofpregnancy, the third trimester of pregnancy and postpartum

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

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.

Treatment with darunavir/cobicistat 800/150 mg once daily during pregnancy results in low darunavirexposure. In women receiving darunavir/cobicistat during the second trimester of pregnancy, meanintra-individual values for total darunavir Cmax, AUC24h and Cmin were 49%, 56% and 92% lower,respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir

Cmax, AUC24h and Cmin values were 37%, 50% and 89% lower, respectively, as compared withpostpartum. The unbound fraction was also substantially reduced, including around 90% reductions of

Cmin levels. The main cause of these low exposures is a marked reduction in cobicistat exposure as aconsequence of pregnancy-associated enzyme induction (see below).

Table 10. Pharmacokinetic results of total darunavir after administration of darunavir/cobicistat800/150 mg once daily as part of an antiretroviral regimen, during the second trimester ofpregnancy, the third trimester of pregnancy, and postpartum

Pharmacokinetics of Second trimester Third trimester Postpartumtotal darunavir of pregnancy of pregnancy (6-12 weeks)(mean ± SD) (n=7) (n=6) (n=6)

Cmax, ng/mL 4 340 ± 1 616 4 910 ± 970 7 918 ± 2 199

AUC24h, ng.h/mL 47 293 ± 19 058 47 991 ± 9 879 99 613 ± 34 862

Cmin, ng/mL 168 ± 149 184 ± 99 1 538 ± 1 344

The exposure to cobicistat was lower during pregnancy, potentially leading to suboptimal boosting ofdarunavir. During the second trimester of pregnancy, cobicistat Cmax, AUC24h, and Cmin were 50%,63%, and 83% lower, respectively, as compared with postpartum. During the third trimester ofpregnancy, cobicistat Cmax, AUC24h, and Cmin, were 27%, 49%, and 83% lower, respectively, ascompared with 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 RBC parameters, liver and thyroid and increased incidence of islet fibrosis in thepancreas (in male rats only) compared to treatment with darunavir alone. In the dog, no major toxicityfindings or target organs were identified up to exposures equivalent to clinical exposure at therecommended 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) - only for 400 mg film-coated tablets

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.

400 mg film-coated tablets:

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.

800 mg film-coated tablets:

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

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

- 90 tablets. 3 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

400 mg film-coated tablets:30 film-coated tablets: EU/1/17/1249/00160 film-coated tablets: EU/1/17/1249/00290 film-coated tablets: EU/1/17/1249/003180 film-coated tablets: EU/1/17/1249/004800 mg film-coated tablets:30 film-coated tablets: EU/1/17/1249/00990 film-coated tablets: EU/1/17/1249/010

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.