DARUNAVIR MYLAN 600mg tablets medication leaflet

Darunavir Mylan 75 mg film-coated tablets

Darunavir Mylan 150 mg film-coated tablets

Darunavir Mylan 300 mg film-coated tablets

Darunavir Mylan 600 mg film-coated tablets

Darunavir Mylan 75 mg film-coated tablets

Each film-coated tablet contains 75 mg of darunavir.

Darunavir Mylan 150 mg film-coated tablets

Each film-coated tablet contains 150 mg of darunavir.

Darunavir Mylan 300 mg film-coated tablets

Each film-coated tablet contains 300 mg of darunavir.

Darunavir Mylan 600 mg film-coated tablets

Each film-coated tablet contains 600 mg of darunavir.

For the full list of excipients, see section 6.1.

Darunavir Mylan 75 mg film-coated tablets

Film-coated tablet.

White to off-white, oval shaped, biconvex film-coated tablets approximately 9.7 mm by 4.6 mm,debossed with ‘M’ on one side and ‘DV1' on the other side.

Darunavir Mylan 150 mg film-coated tablets

Film-coated tablet.

White to off-white, capsule shaped, biconvex film-coated tablets approximately 12.75 mm by 6.3 mmdebossed with ‘M’ on one side and ‘DV2’ on the other side.

Darunavir Mylan 300 mg film-coated tablets

Film-coated tablet.

White to off-white, oval shaped, biconvex film coated tablets approximately 16.5 mm by 8.2 mm,debossed with 'M' on one side of the tablet and 'DV3' on other side.

Darunavir Mylan 600 mg film-coated tablets

Film-coated tablet.

White to off-white, oval shaped, biconvex film-coated tablets approximately 21.2 mm by 10.6 mm,debossed with ‘M’ on one side and ‘DV5’ on the other side.

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

Darunavir Mylan 75 mg, 150 mg, 300 mg and 600 mg tablets may be used to provide suitable doseregimens (see section 4.2):● For the treatment of HIV-1 infection in antiretroviral treatment (ART)-experienced adultpatients, including those that have been highly pre-treated.● For the treatment of HIV-1 infection in paediatric patients from the age of 3 years and at least15 kg body weight.

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

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

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

Darunavir Mylan must always be given orally with low dose ritonavir as a pharmacokinetic enhancerand in combination with other antiretroviral medicinal products. The Summary of Product

Characteristics of ritonavir must, therefore, be consulted prior to initiation of therapy with darunavir.

ART-experienced adult patients

The recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily takenwith food. Darunavir Mylan 75 mg, 150 mg, 300 mg and 600 mg tablets can be used to construct thetwice daily 600 mg regimen.

The use of 75 mg and 150 mg tablets to achieve the recommended dose is appropriate when there is adifficulty in swallowing the 300 mg or 600 mg tablets. Before prescribing darunavir tablets, youngchildren should be assessed for the ability to swallow intact tablets. For young children unable toswallow tablets, more suitable formulations containing darunavir should be checked for theiravailability.

ART-naïve adult patients

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

Darunavir Mylan 400 mg and 800 mg tablets.

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

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

Recommended dose for treatment-naïve paediatric patients (3 to 17 years) with darunavirtablets and ritonavira

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

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

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

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

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

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

The recommended dose of darunavir with low dose ritonavir should not exceed the recommendedadult dose (600/100 mg twice daily or 800/100 mg once daily).

Recommended dose for treatment-experienced paediatric patients (3 to 17 years) with darunavirtablets and ritonavira

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

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

HIV protease inhibitor-naïve paediatric patients and the twice daily dosing regimen is recommended in

HIV protease inhibitor-experienced patients.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

- alfuzosin

- amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine

- astemizole, terfenadine

- colchicine when used in patients with renal and/or hepatic impairment (see section 4.5)

- ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)

- elbasvir/grazoprevir

- cisapride

- dapoxetine

- domperidone

- naloxegol

- lurasidone, pimozide, quetiapine, sertindole (see section 4.5)

- triazolam, midazolam administered orally (for caution on parenterally administered midazolam,see section 4.5)

- sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil

- simvastatin, lovastatin and lomitapide (see section 4.5)

- ticagrelor (see section 4.5).

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

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

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

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

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

ART-experienced patients - once daily dosing

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

B (see section 5.1).

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

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

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

Severe skin reactions

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

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

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

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

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

Patients with coexisting conditions

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

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

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

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

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported particularly in patients with advanced HIV disease and/or long-term exposure to combinationantiretroviral therapy (CART). Patients should be advised to seek medical advice if they experiencejoint aches and pain, joint stiffness or difficulty in movement.

Immune reconstitution inflammatory syndrome

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

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

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

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

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

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

Darunavir Mylan contains sodium

Darunavir Mylan 75 mg, 150 mg, 300 mg and 600 mg film-coated tablets contain less than 1 mmolsodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Interaction studies have only been performed in adults.

Medicinal products that may be affected by darunavir boosted with ritonavir

Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of darunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 or transported by

P-gp may result in increased systemic exposure to such medicinal products, which could increase orprolong their therapeutic effect and adverse reactions.

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

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

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

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

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

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

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

Medicinal products that affect darunavir/ritonavir exposure

Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activitywould be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasmaconcentrations of darunavir and ritonavir (e.g. rifampicin, St John’s wort, lopinavir).

Co-administration of darunavir and ritonavir and other medicinal products that inhibit CYP3A maydecrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations ofdarunavir and ritonavir (e.g. indinavir, azole antifungals like clotrimazole). These interactions aredescribed in the interaction table below.

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

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

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

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

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

HIV ANTIRETROVIRALS

Integrase strand transfer inhibitors

Dolutegravir dolutegravir AUC ↓ 22% dolutegravir Darunavir co-administered with low

C24h ↓ 38% dolutegravir Cmax ↓ 11% dose ritonavir and dolutegravir candarunavir ↔* be used without dose adjustment.

* Using cross-study comparisons tohistorical pharmacokinetic data

Raltegravir Some clinical studies suggest At present the effect of raltegravirraltegravir may cause a modest on darunavir plasma concentrationsdecrease in darunavir plasma does not appear to be clinicallyconcentrations. relevant. Darunavir co-administeredwith low dose ritonavir andraltegravir can be used without doseadjustments.

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

Didanosine didanosine AUC ↓ 9% Darunavir co-administered with low400 mg once daily didanosine Cmin ND dose ritonavir and didanosine candidanosine Cmax ↓ 16% be used without dose adjustments.darunavir AUC ↔ Didanosine is to be administered ondarunavir Cmin ↔ an empty stomach, thus it should bedarunavir Cmax ↔ administered 1 hour before or 2hours after darunavir/ritonavir givenwith food.

Tenofovir disoproxil tenofovir AUC ↑ 22% Monitoring of renal function may245 mg once daily‡ tenofovir Cmin ↑ 37% be indicated when darunavir co-tenofovir Cmax ↑ 24% administered with low dose#darunavir AUC ↑ 21% ritonavir is given in combination#darunavir Cmin ↑ 24% with tenofovir disoproxil,#darunavir Cmax ↑ 16% particularly in patients with(↑ tenofovir from effect on MDR-1 underlying systemic or renaltransport in the renal tubules) disease, or in patients takingnephrotoxic agents.

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

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

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

Lamivudine NRTIs zidovudine, emtricitabine, these NRTIs without dose

Stavudine stavudine, lamivudine, that are adjustment.

Zidovudine primarily renally excreted, andabacavir for which metabolism is notmediated by CYP450, no interactionsare expected for these medicinalcompounds and darunavir co-administered with low dose ritonavir.

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

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

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#darunavir AUC ↓ 13% efavirenz may be indicated when#darunavir Cmin ↓ 31% darunavir co-administered with low#darunavir Cmax ↓ 15% dose ritonavir is given in(↑ efavirenz from CYP3A inhibition) combination with efavirenz.(↓ darunavir from CYP3A induction)

Efavirenz in combination withdarunavir/ritonavir 800/100 mgonce daily may result in sub-optimal darunavir Cmin. If efavirenzis to be used in combination withdarunavir/ritonavir, thedarunavir/ritonavir 600/100 mgtwice daily regimen should be used(see section 4.4).

Etravirine etravirine AUC ↓ 37% Darunavir co-administered with low100 mg twice daily etravirine Cmin ↓ 49% dose ritonavir and etravirine 200 mgetravirine Cmax ↓ 32% twice daily can be used withoutdarunavir AUC ↑ 15% dose adjustments.darunavir Cmin ↔darunavir Cmax ↔

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

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

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

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

Atazanavir: comparison ofatazanavir/ritonavir 300/100 mg oncedaily vs. atazanavir 300 mg once dailyin combination with darunavir/ritonavir400/100 mg twice daily.

Darunavir: comparison ofdarunavir/ritonavir 400/100 mg twicedaily vs. darunavir/ritonavir400/100 mg twice daily in combinationwith atazanavir 300 mg once daily.

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

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

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#darunavir Cmin ↑ 44% to 600 mg twice daily may be#darunavir Cmax ↑ 11% warranted in case of intolerance.

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

Darunavir: comparison ofdarunavir/ritonavir 400/100 mg twicedaily vs. darunavir/ritonavir400/100 mg in combination withindinavir 800 mg twice daily.

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

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

Darunavir: comparison ofdarunavir/ritonavir 400/100 mg twicedaily vs. darunavir/ritonavir400/100 mg in combination withsaquinavir 1,000 mg twice daily.

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

Lopinavir/ritonavir 400/100 lopinavir AUC ↑ 9% Due to a decrease in the exposuremg twice daily lopinavir Cmin ↑ 23% (AUC) of darunavir by 40%,lopinavir Cmax ↓ 2% appropriate doses of thedarunavir AUC ↓ 38%‡ combination have not beendarunavir Cmin ↓ 51%‡ established. Hence, concomitant usedarunavir Cmax ↓ 21%‡ of darunavir co-administered with

Lopinavir/ritonavir lopinavir AUC ↔ low dose ritonavir and the533/133.3 mg twice daily lopinavir Cmin ↑ 13% combination productlopinavir Cmax ↑ 11% lopinavir/ritonavir isdarunavir AUC ↓ 41% contraindicated (see section 4.3).darunavir Cmin ↓ 55%darunavir Cmax ↓ 21%‡ based upon non dose normalisedvalues

CCR5 ANTAGONIST

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

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

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

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

ANAESTHETIC

Alfentanil Not studied. The metabolism of The concomitant use with darunaviralfentanil is mediated via CYP3A, and and low dose ritonavir may requiremay as such be inhibited by darunavir to lower the dose of alfentanil andco-administered with low dose requires monitoring for risks ofritonavir. prolonged or delayed respiratorydepression.

ANTIANGINA/ANTIARRHYTHMIC

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

Flecainide increase these antiarrhythmic plasma therapeutic concentration

Lidocaine concentrations. monitoring, if available, is(systemic) (CYP3A and/or CYP2D6 inhibition) recommended for these

Mexiletine antiarrhythmics when co-

Propafenone administered with darunavir withlow dose ritonavir.

Amiodarone Darunavir co-administered with low

Bepridil dose ritonavir and amiodarone,

Dronedarone bepridil, dronedarone, ivabradine,

Ivabradine, quinidine, or ranolazine is

Quinidine contraindicated (see section 4.3).

Ranolazine

Digoxin digoxin AUC ↑ 61% Given that digoxin has a narrow0.4 mg single dose digoxin Cmin ND therapeutic index, it isdigoxin Cmax ↑ 29% recommended that the lowest(↑ digoxin from probable inhibition of possible dose of digoxin should

P-gp) initially be prescribed in casedigoxin is given to patients ondarunavir/ritonavir therapy. Thedigoxin dose should be carefullytitrated to obtain the desired clinicaleffect while assessing the overallclinical state of the subject.

ANTIBIOTIC

Clarithromycin 500 mg clarithromycin AUC ↑ 57% Caution should be exercised whentwice daily clarithromycin Cmin ↑ 174% clarithromycin is combined withclarithromycin Cmax ↑ 26% darunavir co-administered with low#darunavir AUC ↓ 13% dose ritonavir.#darunavir Cmin ↑ 1%#darunavir Cmax ↓ 17% For patients with renal impairment14-OH-clarithromycin concentrations the Summary of Productwere not detectable when combined Characteristics for clarithromycinwith darunavir/ritonavir. should be consulted for the(↑ clarithromycin from CYP3A recommended dose.inhibition and possible P-gp inhibition)

ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR

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

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

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

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

Edoxaban darunavir/ritonavir 800/100 mg Clinical monitoring and/or dosesingle dose: 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 dabigatran etexilate and edoxaban,once daily: is co-administered withdabigatran AUC ↑ 18% Darunavir/rtv.dabigatran Cmax ↑ 22%

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

Clopidogrel Not studied. Co-administration of Co-administration of clopidogrelclopidogrel with boosted darunavir is with boosted darunavir is notexpected to decrease clopidogrel active recommended.metabolite plasma concentration,which may reduce the antiplatelet Use of other antiplatelets notactivity of clopidogrel. affected by CYP inhibition orinduction (e.g. prasugrel) isrecommended.

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

ANTICONVULSANTS

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

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

Carbamazepine carbamazepine AUC ↑ 45% No dose adjustment for200 mg twice daily carbamazepine Cmin ↑ 54% darunavir/ritonavir iscarbamazepine Cmax ↑ 43% recommended. If there is a need todarunavir AUC ↔ combine 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 the findings, thecarbamazepine dose may need to bereduced by 25% to 50% in thepresence of darunavir/ritonavir.

Clonazepam Not studied. Co-administration of Clinical monitoring isboosted darunavir with clonazepam recommended when co-may increase concentrations of administering boosted darunavirclonazepam. (CYP3A inhibition) with clonazepam.

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

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ANTIDEPRESSANTS

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

Sertraline sertraline AUC ↓ 49% antidepressant response. In addition,50 mg once daily sertraline Cmin ↓ 49% patients on a stable dose of thesesertraline Cmax ↓ 44% antidepressants who start treatment#darunavir AUC ↔ with darunavir with low dose#darunavir Cmin ↓ 6% ritonavir should be monitored for#darunavir Cmax ↔ antidepressant response.

Clinical monitoring is

Concomitant use of darunavir co- recommended when co-administered with low dose ritonavir administering darunavir with lowand these antidepressants may increase dose ritonavir with theseconcentrations of the antidepressant. antidepressants and a dose(CYP2D6 and/or CYP3A inhibition) adjustment of the antidepressant

Amitriptyline may be needed.

Desipramine

Imipramine

Nortriptyline

Trazodone

ANTIEMETICS

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

ANTIFUNGALS

Voriconazole Not studied. Ritonavir may decrease Voriconazole should not beplasma concentrations of voriconazole. combined with darunavir co-(induction of CYP450 enzymes) administered with low doseritonavir unless an assessment ofthe benefit/risk ratio justifies the useof voriconazole.

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

Isavuconazole antifungal plasma concentrations and monitoring is recommended. When

Itraconazole posaconazole, isavuconazole, co-administration is required the

Posaconazole itraconazole, or fluconazole may daily dose of itraconazole shouldincrease darunavir concentrations. not exceed 200 mg.

(CYP3A and/or P-gp inhibition)

Clotrimazole Not studied. Concomitant systemic useof clotrimazole and darunavir co-administered with low dose ritonavirmay increase plasma concentrations ofdarunavir and/or clotrimazole.

Darunavir AUC24h ↑ 33% (based onpopulation pharmacokinetic model)

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

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ANTIGOUT MEDICINES

Colchicine Not studied. Concomitant use of A reduction in colchicine dosage orcolchicine and darunavir co- an interruption of colchicineadministered with low dose ritonavir treatment is recommended inmay increase the exposure to patients with normal renal orcolchicine. hepatic function if treatment with(CYP3A and/ or P-gp inhibition) darunavir co-administered with lowdose ritonavir is required. Forpatients with renal or hepaticimpairment colchicine withdarunavir co-administered with lowdose ritonavir is contraindicated(see sections 4.3 and 4.4).

ANTIMALARIALS

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

ANTIMYCOBACTERIALS

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

Rifapentine are strong CYP3A inducers and have darunavir with concomitant lowbeen shown to cause profound dose ritonavir is not recommended.decreases in concentrations of otherprotease inhibitors, which can result in The combination of rifampicin andvirological failure and resistance darunavir with concomitant lowdevelopment (CYP450 enzyme dose ritonavir is contraindicatedinduction). During attempts to (see section 4.3).overcome the decreased exposure byincreasing the dose of other proteaseinhibitors with low dose ritonavir, ahigh frequency of liver reactions wasseen with rifampicin.

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

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Rifabutin rifabutin AUC** ↑ 55% A dosage reduction of rifabutin by150 mg once every other rifabutin C **min ↑ ND 75% of the usual dose ofday rifabutin C **max ↔ 300 mg/day (i.e. rifabutin 150 mgdarunavir AUC ↑ 53% once every other day) and increaseddarunavir Cmin ↑ 68% monitoring for rifabutin relateddarunavir Cmax ↑ 39% adverse events is warranted in

** sum of active moieties of rifabutin patients receiving the combination(parent drug + 25-O-desacetyl with darunavir co- administeredmetabolite) with ritonavir. In case of safetyissues, a further increase of the

The interaction trial showed a dosing interval for rifabutin and/orcomparable daily systemic exposure monitoring of rifabutin levelsfor rifabutin between treatment at 300 should be considered.mg once daily alone and 150 mg once Consideration should be given toevery other 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 infected patients.the daily exposure to the active Based upon the safety profile ofmetabolite 25-O-desacetylrifabutin. darunavir/ritonavir, the increase in

Furthermore, AUC of the sum of active darunavir exposure in the presencemoieties of rifabutin (parent drug + 25- of rifabutin does not warrant a dose

O- desacetyl metabolite) was increased adjustment for darunavir/ritonavir.1.6-fold, while Cmax remained Based on pharmacokineticcomparable. modeling, this dosage reduction of

Data on comparison with a 150 mg 75% is also applicable if patientsonce daily reference dose is lacking. receive rifabutin at doses other than300 mg/day.(Rifabutin is an inducer and substrateof CYP3A.) An increase of systemicexposure to darunavir was observedwhen darunavir co-administered with100 mg ritonavir was co-administeredwith rifabutin (150 mg once everyother day).

ANTINEOPLASTICS

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

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

Vinblastine concentrations. administered with darunavir with

Vincristine (CYP3A inhibition) low dose ritonavir resulting in thepotential for increased adverseevents usually associated with theseagents.

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

Everolimus Concomitant use of everolimus or

Irinotecan Irinotecan and darunavir co-administered with low doseritonavir is not recommended.

ANTIPSYCHOTICS/NEUROLEPTICS

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

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

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

Risperidone increase these antipsychotic plasma these drugs when co-administered

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

Lurasidone Pimozide Concomitant administration of

Sertindole darunavir with low dose ritonavirand lurasidone, pimozide orsertindole is contraindicated (seesection 4.3).

β-BLOCKERS

Carvedilol Not studied. Darunavir is expected to Clinical monitoring is

Metoprolol increase these β-blocker plasma recommended when co-

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

CALCIUM CHANNEL BLOCKERS

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

Diltiazem with low dose ritonavir can be and adverse effects is recommended

Felodipine expected to increase the plasma when these medicines are

Nicardipine concentrations of calcium channel concomitantly administered with

Nifedipine blockers. darunavir with low dose ritonavir.

Verapamil (CYP3A and/or CYP2D6 inhibition)

CORTICOSTEROIDS

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

CI 82-89%). Greater effects may beexpected when fluticasone is inhaled. Co-administration with CYP3A-

Systemic corticosteroid effects metabolised corticosteroids is notincluding Cushing’s syndrome and recommended unless the potentialadrenal suppression have been reported benefit to the patient outweighs thein patients receiving ritonavir and risk, in which case patients shouldinhaled or intranasally administered be monitored for systemicfluticasone. The effects of high corticosteroid effects.fluticasone systemic exposure onritonavir plasma levels are unknown. Alternative corticosteroids whichare less dependent on CYP3A

Other corticosteroids: interaction not metabolism e.g. beclomethasonestudied. Plasma concentrations of these should be considered, particularlymedicinal products may be increased for long term use.when co-administered with darunavirwith low dose ritonavir, resulting inreduced serum cortisol concentrations.

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

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

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ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan Not studied. Concomitant use of When administered concomitantlybosentan and darunavir co- with darunavir and low doseadministered with low dose ritonavir ritonavir, the patient’s tolerability ofmay increase plasma concentrations of bosentan should be monitored.bosentan.

Bosentan is expected to decreaseplasma concentrations of darunavirand/or its pharmacoenhancer. (CYP3Ainduction)

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS

NS3-4A protease inhibitors

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

Glecaprevir/pibrentasvir Based on theoretical considerations It is not recommended to co-boosted darunavir may increase the administer boosted darunavir withexposure to glecaprevir and glecaprevir/pibrentasvir.pibrentasvir.(P-gp, BCRP and/or OATP1B1/3inhibition)

HERBAL PRODUCTS

St John's wort Not studied. St John’s wort is expected Darunavir co-administered with low(Hypericum perforatum) to decrease the plasma concentrations dose ritonavir must not be usedof darunavir and ritonavir. concomitantly with products(CYP450 induction) containing St John’s wort(Hypericum perforatum) (seesection 4.3). If a patient is alreadytaking St John’s wort, stop St

John’s wort and if possible checkviral levels. Darunavir exposure(and also ritonavir exposure) mayincrease on stopping St John’s wort.

The inducing effect may persist forat least 2 weeks after cessation oftreatment with St John’s wort.

HMG CO-A REDUCTASE INHIBITORS

Lovastatin Not studied. Lovastatin and simvastatin Increased plasma concentrations of

Simvastatin are expected to have markedly lovastatin or simvastatin may causeincreased plasma concentrations when myopathy, includingco-administered with darunavir co- rhabdomyolysis. Concomitant useadministered with low dose ritonavir. of darunavir co-administered with(CYP3A inhibition) low dose ritonavir with lovastatinand simvastatin is thereforecontraindicated (see section 4.3).

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

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

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Pravastatin pravastatin AUC ↑ 81%¶ When administration of pravastatin40 mg single dose pravastatin Cmin ND and darunavir co-administered withpravastatin Cmax ↑ 63% low dose ritonavir is required, it is¶ an up to five-fold increase was seen in recommended to start with thea limited subset of subjects lowest possible dose of pravastatinand 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 darunavir co- administered with║ based on published data with low dose ritonavir is required, it isdarunavir/ritonavir recommended to start with thelowest possible dose of rosuvastatinand titrate up to the desired clinicaleffect while monitoring for safety.

OTHER LIPID MODIFYING AGENTS

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

H2-RECEPTOR ANTAGONISTS

Ranitidine #darunavir AUC ↔ Darunavir co-administered with low150 mg twice daily #darunavir Cmin ↔ dose ritonavir can be co-#darunavir Cmax ↔ administered with H2-receptorantagonists 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 darunavir done when co-administrationco-administered with low dose occurs.

ritonavir. (CYP3A inhibition)

Everolimus Concomitant use of everolimus anddarunavir co-administered with lowdose ritonavir is not recommended.

INHALED BETA AGONISTS

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

NARCOTIC ANALGESICS/TREATMENT OF OPIOID DEPENDENCE

Methadone R(-) methadone AUC ↓ 16% No adjustment of methadone dosageindividual dose ranging R(-) methadone Cmin ↓ 15% is required when initiating co-from 55 mg to 150 mg once R(-) methadone Cmax ↓ 24% administration withdaily darunavir/ritonavir. However,increased methadone dose may benecessary when concomitantlyadministered for a longer period oftime due to induction of metabolismby ritonavir.

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

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

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Buprenorphine/naloxone buprenorphine AUC ↓ 11% The clinical relevance of the8/2 mg-16/4 mg once daily buprenorphine Cmin ↔ increase 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- administerednaloxone AUC ↔ with darunavir/ritonavir but analoxone Cmin ND careful clinical monitoring for signsnaloxone Cmax ↔ of opiate toxicity is recommended.

Fentanyl Based on theoretical considerations Clinical monitoring is

Oxycodone boosted darunavir may increase plasma recommended when co-

Tramadol concentrations of these analgesics. administering boosted darunavir(CYP2D6 and/or CYP3A inhibition) with these analgesics.

OESTROGEN-BASED CONTRACEPTIVES

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

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

Ethinylestradiol ethinylestradiol AUC ↓ 44% β for hyperkalaemia.

Norethindrone ethinylestradiol Cmin ↓ 62% β35 μg/1 mg once daily ethinylestradiol Cmax ↓ 32% β Alternative or additionalnorethindrone AUC ↓ 14% β contraceptive measures arenorethindrone C βmin ↓ 30% recommended when oestrogen-norethindrone Cmax ↔ β based contraceptives are co-β with darunavir/ritonavir administered with darunavir andlow dose ritonavir.

Patients using oestrogens ashormone replacement therapyshould be clinically monitored forsigns of oestrogen deficiency.

OPIOID ANTAGONIST

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

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS

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

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

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

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

Vardenafil darunavir and low dose ritonavir. erectile dysfunction with darunavirco-administered with low doseritonavir should be done withcaution. If concomitant use ofdarunavir co-administered with lowdose ritonavir with sildenafil,vardenafil or tadalafil is indicated,sildenafil at a single dose notexceeding 25 mg in 48 hours,vardenafil at a single dose notexceeding 2.5 mg in 72 hours ortadalafil at a single dose notexceeding 10 mg in 72 hours isrecommended.

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

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

Sildenafil darunavir co-administered with low administered with darunavir and

Tadalafil dose ritonavir may increase plasma low dose ritonavir has not beenconcentrations of sildenafil or tadalafil. established. There is an increased(CYP3A inhibition) potential for sildenafil- associatedadverse events (including visualdisturbances, hypotension,prolonged erection and syncope).

Therefore, co- administration ofdarunavir with low dose ritonavirand sildenafil when used for thetreatment of pulmonary arterialhypertension is contraindicated (seesection 4.3). Co-administration oftadalafil for the treatment ofpulmonary arterial hypertensionwith darunavir and low doseritonavir is not recommended.

PROTON PUMP INHIBITORS

Omeprazole #darunavir AUC ↔ Darunavir co-administered with low20 mg once daily #darunavir Cmin ↔ dose ritonavir can be co-#darunavir Cmax ↔ administered with proton pumpinhibitors without dose adjustments.

SEDATIVES/HYPNOTICS

Buspirone Not studied. Sedative/hypnotics are Clinical monitoring is

Clorazepate extensively metabolised by CYP3A. recommended when co-

Diazepam Co-administration with administering darunavir with these

Estazolam darunavir/ritonavir may cause a large sedatives/hypnotics and a lower

Flurazepam increase in the concentration of these dose of the sedatives/hypnotics

Midazolam medicines. should be considered.(parenteral)

Zolpidem If parenteral midazolam is co- If parenteral midazolam is co-administered with darunavir co- administered with darunavir withadministered with low dose ritonavir it low dose ritonavir, it should bemay cause a large increase in the done in an intensive care unit (ICU)concentration of this benzodiazepine. or similar setting, which ensures

Data from concomitant use of close clinical monitoring andparenteral midazolam with other appropriate medical management inprotease inhibitors suggest a possible case of respiratory depression3-4 fold increase in midazolam plasma and/or prolonged sedation. Doselevels. adjustment for midazolam should beconsidered, especially if more thana single dose of midazolam isadministered.

Midazolam (oral) Triazolam Darunavir co-administered with lowdose ritonavir is contraindicatedwith triazolam or oral midazolam(see section 4.3).

TREATMENT FOR PREMATURE EJACULATION

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

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

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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 (seesection 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 andtipranavir) has not been established in HIV patients. According to current treatment guidelines, dual therapy withprotease inhibitors is generally not recommended.

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

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

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

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

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

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

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

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

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

During the clinical development program (N=2,613 treatment-experienced subjects who initiatedtherapy with darunavir/ ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least oneadverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequentadverse reactions reported in clinical trials 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 of darunavir/ritonavir 800/100 mg once daily was 162.5 weeks.

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

Adverse reactions observed with darunavir/ritonavir in clinical trials and post-marketing

MedDRA system organ class Frequency category Adverse reaction

Uncommon herpes simplex

Uncommon thrombocytopenia, neutropenia, anaemia,leucopenia

Rare increased eosinophil count

Uncommon immune reconstitution inflammatory syndrome,(drug) hypersensitivity

Uncommon hypothyroidism, increased blood thyroidstimulating hormone

Common diabetes mellitus, hypertriglyceridaemia,hypercholesterolaemia, hyperlipidaemia

Uncommon gout, anorexia, decreased appetite, decreasedweight, increased weight, hyperglycaemia,insulin resistance, decreased high densitylipoprotein, increased appetite, polydipsia,increased blood lactate dehydrogenase

MedDRA system organ class Frequency category Adverse reaction

Common insomnia

Uncommon depression, disorientation, anxiety, sleepdisorder, abnormal dreams, nightmare, decreasedlibido

Rare confusional state, altered mood, restlessness

Common headache, peripheral neuropathy, dizziness

Uncommon lethargy, paraesthesia, hypoaesthesia, dysgeusia,disturbance in attention, memory impairment,somnolence

Rare syncope, convulsion, ageusia, sleep phase rhythmdisturbance

Uncommon conjunctival hyperaemia, dry eye

Rare visual disturbance

Ear and labyrinth disorders

Uncommon vertigo

Uncommon myocardial infarction, angina pectoris, prolongedelectrocardiogram QT, tachycardia

Rare acute myocardial infarction, sinus bradycardia,palpitations

Uncommon hypertension, flushing

Uncommon dyspnoea, cough, epistaxis, throat irritation

Rare rhinorrhoea

Very common diarrhoea

Common vomiting, nausea, abdominal pain, increasedblood amylase, dyspepsia, abdominal distension,flatulence

Uncommon pancreatitis, gastritis, gastrooesophageal refluxdisease, aphthous stomatitis, retching, dry mouth,abdominal discomfort, constipation, increasedlipase, eructation, oral dysaesthesia

Rare stomatitis, haematemesis, cheilitis, dry lip, coatedtongue

MedDRA system organ class Frequency category Adverse reaction

Common increased alanine aminotransferase

Uncommon hepatitis, cytolytic hepatitis, hepatic steatosis,hepatomegaly, increased transaminase, increasedaspartate aminotransferase, increased bloodbilirubin, increased blood alkaline phosphatase,increased gamma-glutamyltransferase

Common rash (including macular, maculopapular, papular,erythematous and pruritic rash), pruritus

Uncommon angioedema, generalised rash, allergic dermatitis,urticaria, eczema, erythema, hyperhidrosis, nightsweats, alopecia, acne, dry skin, nailpigmentation

Rare DRESS, Stevens-Johnson syndrome, erythemamultiforme, dermatitis, seborrhoeic dermatitis,skin lesion, xeroderma

Not known toxic epidermal necrolysis, acute generalisedexanthematous pustulosis

Uncommon myalgia, osteonecrosis, muscle spasms, muscularweakness, arthralgia, pain in extremity,osteoporosis, increased blood creatinephosphokinase

Rare musculoskeletal stiffness, arthritis, joint stiffness

Uncommon acute renal failure, renal failure, nephrolithiasis,increased blood creatinine, proteinuria,bilirubinuria, dysuria, nocturia, pollakiuria

Rare decreased creatinine renal clearance

Rare crystal nephropathy§

Uncommon erectile dysfunction, gynaecomastia

Common asthenia, fatigue

Uncommon pyrexia, chest pain, peripheral oedema, malaise,feeling hot, irritability, pain

Rare 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 usingthe 'Rule of 3'.

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

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

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (seesection 4.4).

Musculoskeletal abnormalities

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

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

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

Immune reconstitution inflammatory syndrome

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

Bleeding in haemophiliac patients

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

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

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

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

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

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

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

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

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

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

There is no specific antidote for overdose with darunavir. Treatment of overdose with darunavirconsists of general supportive measures including monitoring of vital signs and observation of theclinical status of the patient. Since darunavir is highly protein bound, dialysis is unlikely to bebeneficial in significant removal of the 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 and humanmonocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 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). The selectedviruses 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 trial data from ART-experienced patients (TITAN trial and the pooled analysis of the

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

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

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

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

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

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

ARTEMIS ODIN TITAN

Week 192 Week 48 Week 48

Darunavir/ Darunavir/ Darunavir/ ritonavir Darunavir/ritonavir ritonavir 600/100 mg twice ritonavir800/100 mg 800/100 mg once daily N=296 600/100 mgonce daily daily twice daily

N=343 N=294 N=298

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

Rebounders

Never suppressed 39 (11.4%) 11 (3.7%) 11 (3.7%) 16 (5.4%)subjects 16 (4.7%) 54 (18.4%) 43 (14.5%) 15 (5.0%)

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

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

Mutations

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 trial no cross-resistance with other PIs was observed.

Adult patients

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

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

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

ART-experienced patients is based on the 96 weeks analysis of the Phase III trial TITAN in

ART-experienced lopinavir naïve patients, on the 48 week analysis of the Phase III trial ODIN in

ART-experienced patients with no DRV-RAMs, and on the analyses of 96 weeks data from the Phase

IIb trials POWER 1 and 2 in ART-experienced patients with high level of PI resistance.

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

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

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

TITAN

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

N=298 N=297

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

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

ODIN is a Phase III, randomised, open-label trial 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.

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 72.1% (212) 70.9% (210) 1.2% (-6.1; 8.5)b< 50 copies/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 be non-inferior (at the pre-defined 12% non-inferiority margin) compared to darunavir/ritonavir 600/100 mgtwice 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 ≥ 100,000copies/ml or CD4+ cell count < 100 cells x 106/L (see sections 4.2 and 4.4). Limited data is availablein patients with HIV-1 clades other than B.

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

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

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

POWER 1 and POWER 2 trials.

POWER 1 and POWER 2 pooled data

Week 48 Week 96

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

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

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

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

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

Baseline genotype or phenotype and virologic outcome

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

Proportion (%) of patients with response (HIV-1 RNA < 50 copies/ml at week 24) to darunavir co-administered with ritonavir (600/100 mg twice daily) by baseline genotypea, and baseline darunavir

FC and by use of enfuvirtide (ENF): As treated analysis of the POWER and DUET trials.

Number of baseline mutationsa Baseline DRV FCb

Response (HIV-1

RNA < 50 copies/ml All 0-2 3 ≥ 4 All ≤ 10 10-40 > 40at week 24) ranges ranges%, n/N

All patients 45% 54% 39% 12% 45% 55% 29% 8%455/1,014 359/660 67/172 20/171 455/1,014 364/659 59/203 9/118

Patients withno/non-naïve use of 39% 50% 29% 7% 39% 51% 17% 5%

ENFc 290/741 238/477 35/120 10/135 290/741 244/477 25/147 5/94

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

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

For clinical trial results in ART-naïve paediatric patients aged 12 to 17 years, refer to the Summary of

Product Characteristics for Darunavir Mylan 400 mg and 800 mg tablets.

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

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

RNA viral load of at least 1.0 log10 versus baseline.

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

DELPHI

Outcomes at week 48 Darunavir/ritonavir

N=80

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

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

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

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

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

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

ARIEL

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

N=5 N=16

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

CD4+ percent change from baselineb 4 4

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

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

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

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

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

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

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

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

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

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

In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarilyundergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system andalmost exclusively by isozyme CYP3A4. A 14C-darunavir trial 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 dosages resulted in darunavir exposure that was comparable to that achieved inadults receiving 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 dosage may beused in 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 dosages resulted in darunavir exposure that was comparable to that achieved inadults receiving darunavir/ritonavir 800/100 mg once daily (see section 4.2). In addition,pharmacokinetic modeling and simulation of darunavir exposures in paediatric patients across the agesof 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and allowedthe identification of weight-based darunavir/ritonavir once daily dosing regimens for paediatricpatients weighing at least 15 kg that are either ART-naïve or treatment-experienced paediatric patientswithout DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count≥ 100 cells x 106/L (see section 4.2).

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

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

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

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

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

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

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

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

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

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 Postpartumtotal darunavir pregnancy pregnancy (6-12 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

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 Postpartumtotal darunavir pregnancy pregnancy (6-12 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.

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 including bacterialreverse mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleustest in mice.

Silica, colloidal anhydrous

Cellulose microcrystalline

Crospovidone

Sodium starch glycolate

Hypromellose

Magnesium stearate

Tablet film-coat

Polyvinyl alcohol, partially hydrolysed

Titanium dioxide (E171)

Macrogol

Talc

Not applicable.

3 years

In-use shelf life after first opening HDPE bottle: 100 days

This medicinal product does not require any special storage conditions.

Darunavir Mylan 75 mg film-coated tablets

PVC/PE/PVDC-Al blister pack containing 480 tablets and 480x1 tablets.

Cold form PVC/Al/OPA-Al blister pack containing 480 tablets and 480x1 tablets.

HDPE bottle pack with a PP screw cap containing 480 tablets.

Darunavir Mylan 150 mg film-coated tablets

PVC/PE/PVDC-Al blister pack containing 240 tablets and 240x1 tablets.

Cold form PVC/Al/OPA-Al blister pack containing 240 tablets and 240x1 tablets.

HDPE bottle pack with a PP screw cap containing 60 and 240 tablets.

Darunavir Mylan 300 mg film-coated tablets

PVC/PE/PVDC-Al blister pack containing 30, 60 and 120 tablets and 120x1 tablets.

Cold form PVC/Al/OPA-Al blister pack containing 30, 60 and 120 tablets and 120x1 tablets.

HDPE bottle pack with a PP screw cap containing 30 and 120 tablets.

Darunavir Mylan 600 mg film-coated tablets

PVC/PE/PVDC-Al blister pack containing 30 and 60 tablets and 60x1 tablets.

Cold form PVC/Al/OPA-Al blister pack containing 30 and 60 tablets and 60x1 tablets.

HDPE bottle pack with a PP screw cap containing 30, 60, 90 tablets.

Not all pack sizes may be marketed.

No special requirements for disposal.

Mylan Pharmaceuticals Limited

Damastown Industrial Park,

Mulhuddart, Dublin 15,

DUBLIN

Ireland

Darunavir Mylan 75 mg film-coated tablets

EU/1/16/1140/001

EU/1/16/1140/002

EU/1/16/1140/003

EU/1/16/1140/004

EU/1/16/1140/005

Darunavir Mylan 150 mg film-coated tablets

EU/1/16/1140/006

EU/1/16/1140/007

EU/1/16/1140/008

EU/1/16/1140/009

EU/1/16/1140/010

EU/1/16/1140/011

Darunavir Mylan 300 mg film-coated tablets

EU/1/16/1140/012

EU/1/16/1140/013

EU/1/16/1140/014

EU/1/16/1140/015

EU/1/16/1140/016

EU/1/16/1140/017

EU/1/16/1140/018

EU/1/16/1140/019

EU/1/16/1140/020

EU/1/16/1140/021

Darunavir Mylan 600 mg film-coated tablets

EU/1/16/1140/030

EU/1/16/1140/031

EU/1/16/1140/032

EU/1/16/1140/033

EU/1/16/1140/034

EU/1/16/1140/035

EU/1/16/1140/036

EU/1/16/1140/037

EU/1/16/1140/038

Date of first authorisation: 04 January 2017

Date of latest renewal: 16 September 2021

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

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