PREZISTA 400 mg film-coated tablets

PREZISTA 800 mg film-coated tablets

400 mg film-coated tablet:

Each film-coated tablet contains 400 mg of darunavir (as ethanolate).

Excipient with known effect: Each tablet contains 0.834 mg sunset yellow FCF (E110).

800 mg film-coated tablet:

Each film-coated tablet contains 800 mg of darunavir (as ethanolate).

For the full list of excipients, see section 6.1.

Film-coated tablets

400 mg tablets

Light orange oval shaped tablet of 19.1 mm, debossed with “400MG” on one side and “TMC” on the other side.

800 mg tablest.

Dark red oval shaped tablet of 20.0 mm, debossed with “800” on one side and “T” on the other side.

PREZISTA, co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection.

PREZISTA, co-administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients (see section 4.2).

PREZISTA 400mg and 800 mg tablets may be used to provide suitable dose regimens for the treatment of HIV-1 infection in adult and paediatric patients from the age of 12 years and at least 40 kg body weight who are:

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

● ART-experienced with no darunavir resistance associated mutations (DRV-RAMs) and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/l. In deciding to initiate treatment with PREZISTA in such ART-experienced patients, genotypic testing should guide the use of PREZISTA (see sections 4.2, 4.3, 4.4 and 5.1).

Therapy should be initiated by a health care provider experienced in the management of HIV infection. After therapy with PREZISTA has been initiated, patients should be advised not to alter the dosage, dose form or discontinue therapy without discussing with their health care provider.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as pharmacokinetic enhancer. Darunavir may therefore have different contraindications and recommendations for concomitant medications depending on whether the compound is boosted with ritonavir or cobicistat (see sections 4.3, 4.4 and 4.5).

Posology

PREZISTA must always be given orally with cobicistat or low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of cobicistat or ritonavir as appropriate, must therefore be consulted prior to initiation of therapy with PREZISTA. Cobicistat is not indicated for use in twice daily regimens or for use in the pediatric population.

PREZISTA is also available as an oral suspension for use in patients who are unable to swallow PREZISTA tablets (please refer to the Summary of Product Characteristics for PREZISTA oral suspension).

ART-naïve adult patients

The recommended dose regimen is 800 mg once daily with cobicistat 150 mg once daily or ritonavir 100 mg once daily taken with food. PREZISTA 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.

ART-experienced adult patients

The recommended dose regimens are as follows:

● In ART-experienced patients with no darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/l (see section 4.1) a regimen of 800 mg once daily with cobicistat 150 mg once daily or ritonavir 100 mg once daily taken with food may be used. PREZISTA 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.

● In all other ART-experienced patients or if HIV-1 genotype testing is not available, the recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food. See the Summary of Product Characteristics for PREZISTA 100 mg/ml oral suspension, 75 mg, 150 mg, 300 mg or 600 mg tablets.

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

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

The recommended dose regimen is 800 mg once daily with ritonavir 100 mg once daily taken with food. The dose of cobicistat to be used with PREZISTA in children less than 18 years of age has not been established.

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

The dose of cobicistat to be used with PREZISTA in children less than 18 years of age has not been established.

The recommended dose regimens are as follows:

● In ART-experienced patients without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/l (see section 4.1) a regimen of 800 mg once daily with ritonavir 100 mg once daily taken with food may be used. PREZISTA 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.

● In all other ART-experienced patients or if HIV-1 genotype testing is not available, the recommended dose regimen described in the Summary of Product Characteristics for PREZISTA 100 mg/ml oral suspension, 75 mg, 150 mg, 300 mg or 600 mg tablets.

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

Advice on missed doses

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

This guidance is based on the half-life of darunavir in the presence of cobicistat or ritonavir and the recommended dosing interval of approximately 24 hours.

Special populations

Elderly

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

Hepatic impairment

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

Renal impairment

No dose adjustment is required for darunavir/ritonavir in patients with renal impairment (see sections 4.4 and 5.2). Cobicistat has not been studied in patients receiving dialysis, and, therefore, no recommendation can be made for the use of darunavir/cobicistat in these patients.

Cobicistat inhibits the tubular secretion of creatinine and may cause modest increases in serum creatinine and modest declines in creatinine clearance. Hence, the use of creatinine clearance as an estimate of renal elimination capacity may be misleading. Cobicistat as a pharmacokinetic enhancer of darunavir should, therefore, not be initiated in patients with creatine clearance less than 70 ml/min if any co-administered agent requires dose adjustment based on creatinine clearance: e.g. emtricitabine, lamivudine, tenofovir disoproxil fumarate or adefovir dipovoxil.

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

Paediatric population

PREZISTA should not be used in paediatric patients below 3 years of age or less than 15 kg body weight (see sections 4.4 and 5.3).

ART-naïve paediatric patients (less than 3 years of age or less than 15 kg body weight)

No recommendations on posology can be made in this population.

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

Darunavir exposures in treatment-naïve adolescents 12 to 17 years weighing at least 40 kg receiving PREZISTA/ritonavir 800/100 mg once daily have been determined and were found to be within the therapeutic range as has been established in adults receiving PREZISTA/ritonavir 800/100 mg once daily. As a consequence, since PREZISTA/ritonavir 800/100 mg once daily has also been registered for use in treatment-experienced adults without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/l, the same indication of PREZISTA 800 mg once daily applies to treatment-experienced children 3 to 17 years weighing at least 40 kg. The dose of darunavir with cobicistat has not been established in this patient population.

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

For dosage recommendations in children see the Summary of Product Characteristics for PREZISTA 75 mg, 150 mg, 300 mg, 600 mg tablets and 100 mg/ml oral suspension.

PREZISTA should not be used in children less than 15 kg body weight as the dose for this population has not been established in a sufficient number of patients. PREZISTA should not be used in children below 3 years of age because of safety concerns.

Method of administration

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

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

Use in patients with severe (Child-Pugh Class C) hepatic impairment.

Concomitant treatment with any of the following medicinal products is contraindicated given the expected decrease in plasma concentrations of darunavir, ritonavir and cobicistat and the potential for loss of therapeutic effect (see sections 4.4 and 4.5).

Applicable to darunavir boosted with either ritonavir or cobicistat:

- The combination product lopinavir/ritonavir (see section 4.5).

- The strong CYP3A inducers rifampicin and herbal preparations containing St John's wort (Hypericum perforatum). Co-administration is expected to reduce plasma concentrations of darunavir, ritonavir and cobicistat, which could lead to loss of therapeutic effect and possible development of resistance (see sections 4.4 and 4.5).

Applicable to darunavir boosted with cobicistat, not when boosted with ritonavir:

- Darunavir boosted with cobicistat is more sensitive for CYP3A induction than darunavir boosted with ritonavir. Concomitant use with strong CYP3A inducers is contraindicated, since these may reduce the exposure to cobicistat and darunavir leading to loss of therapeutic effect. Strong CYP3A inducers include e.g. carbamazepine, phenobarbital and phenytoin (see sections 4.4 and 4.5).

Darunavir boosted with either ritonavir or cobicistat inhibits the elimination of active substances that are highly dependent on CYP3A for clearance, which results in increased exposure to the co-administered medicinal product. Therefore, concomitant treatment with such medicinal products for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated (applies to darunavir boosted with either ritonavir or cobicistat). These active substances include e.g.:

- alfuzosin (alpha 1-adrenoreceptor antagonist)

- amiodarone, bepridil, dronedarone, quinidine, ranolazine, systemic lidocaine (antiarrhythmics/antianginals)

- astemizole, terfenadine (antihistamines)

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

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

- cisapride (gastrointestinal motility agents)

- pimozide, quetiapine, sertindole (antipsychotics/neuroleptics) (see section 4.5)

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

- sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil (PDE-5 inhibitors)

- simvastatin and lovastatin (HMG-CoA reductase inhibitors) (see section 4.5)

- ticagrelor (antiplatelets) (see section 4.5).

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

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

PREZISTA must always be given orally with cobicistat or low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products (see section 5.2). The Summary of Product Characteristics of cobicistat or ritonavir as appropriate, must therefore be consulted prior to initiation of therapy with PREZISTA.

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

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

ART-experienced patients – once daily dosing

PREZISTA used in combination with cobicistat or low dose ritonavir once daily in ART-experienced patients should not be used in patients with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA ≥ 100,000 copies/ml or CD4+ cell count < 100 cells x 10⁶/l (see section 4.2). Combinations with optimised background regimen (OBRs) other than ≥ 2 NRTIs have not been studied in this population. Limited data are available in patients with HIV-1 clades other than B (see section 5.1).

Paediatric population

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

Elderly

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

Severe skin reactions

During the darunavir/ritonavir clinical development program (N=3,063), severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermal necrolysis and acute generalised exanthematous pustulosis have been reported. PREZISTA should be discontinued 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 or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.

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

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

Hepatotoxicity

Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA. During the darunavir/ritonavir clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving combination antiretroviral therapy with PREZISTA/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.

Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA used in combination with cobicistat or low dose ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of PREZISTA used in combination with cobicistat or low dose ritonavir treatment.

If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients using PREZISTA used in combination with cobicistat or low dose ritonavir, interruption or discontinuation of treatment should be considered promptly.

Patients with coexisting conditions

Hepatic impairment

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

Renal impairment

No special precautions or dose adjustments for darunavir/ritonavir are required in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis. Therefore, no special precautions or dose adjustments are required in these patients (see sections 4.2 and 5.2). Cobicistat has not been studied in patients receiving dialysis, therefore, no recommendation can be made for the use of darunavir/cobicistat in these patients (see section 4.2).

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

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

Haemophiliac patients

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

Diabetes mellitus/hyperglycaemia

New onset diabetes mellitus, hyperglycaemia, or exacerbation of existing diabetes mellitus has been reported in patients receiving antiretroviral therapy, including PIs. In some of these patients the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many patients had confounding medical conditions some of which required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycaemia.

Fat redistribution and metabolic disorders

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include eva luation for physical signs of fat redistribution. Consideration should be given to measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint 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 combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens 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. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be eva luated and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical studies with PREZISTA co-administered with low dose ritonavir.

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

Interactions with medicinal products

Pharmacokinetic enhancer and concomitant medications

Darunavir has different interaction profiles depending on whether the compound is boosted with ritonavir or cobicistat:

- Darunavir boosted with cobicistat is more sensitive for CYP3A induction: concomitant use of darunavir/cobicistat and strong CYP3A inducers is therefore contraindicated (see section 4.3), and concomitant use with weak to moderate CYP3A inducers is not recommended (see section 4.5). Concomitant use of darunavir/ritonavir and darunavir/cobicistat with lopinavir/ritonavir, rifampicin and herbal products containing St John's wort, Hypericum perforatum, is contraindicated (see section 4.5).

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

Efavirenz in combination with PREZISTA/ritonavir 800/100 mg once daily may result in sub-optimal darunavir C_min. If efavirenz is to be used in combination with PREZISTA/ritonavir, the PREZISTA/ritonavir 600/100 mg twice daily regimen should be used. See the Summary of Product Characteristics for PREZISTA 75 mg, 150 mg, 300 mg or 600 mg tablets (see section 4.5).

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

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

Medicinal products that affect darunavir exposure (ritonavir as pharmacoenhancer)

Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of these compounds and consequently that of darunavir, leading to loss of therapeutic effect and possible development of resistance (see sections 4.3 and 4.4). CYP3A inducers that are contraindicated include rifampicin, St John's wort and lopinavir.

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

Medicinal products that affect darunavir exposure (cobicistat as pharmacoenhancer)

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

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

Medicinal products that may be affected by darunavir boosted with ritonavir

Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration 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 or prolong their therapeutic effect and adverse reactions.

Darunavir co-administered with low dose ritonavir must not be combined with medicinal products that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with 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 in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily. Cobicistat 150 mg given with darunavir 800 mg once daily enhances darunavir pharmacokinetic parameters in a comparable way to ritonavir (see section 5.2).Therefore, darunavir must only be used in combination with a pharmacokinetic enhancer (see section 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 and inhibition of CYP2D6 activity in the presence of darunavir/ritonavir, which may be attributed to the presence of low dose ritonavir. Co-administration of darunavir and ritonavir with medicinal products which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result in increased plasma concentrations of these medicinal products, which could increase or prolong their therapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir and medicinal products 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 or shorten their therapeutic effect.

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

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

Medicinal products that may be affected by darunavir boosted with cobicistat

The recommendations for darunavir boosted with ritonavir are adequate also for darunavir boosted with cobicistat with regard to substrates of CYP3A4, CYP2D6, P-glycoprotein, OATP1B1 and OATP1B3 (see contraindications and recommendations presented in the section above). Cobicistat 150 mg given with darunavir 800 mg once daily enhances darunavir pharmacokinetic parameters in a comparable way to ritonavir (see section 5.2).

Unlike ritonavir, cobicistat does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or UGT1A1. For further information on cobicistat, consult the cobicistat Summary of Product Characteristics.

Interaction table

Interaction studies have only been performed in adults.

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

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as pharmacokinetic enhancer. Darunavir may therefore have different recommendations for concomitant medications depending on whether the compound is boosted with ritonavir or cobicistat. No interaction studies presented in the table have been performed with darunavir boosted with cobicistat. The same recommendations apply, unless specifically indicated. For further information on cobicistat, consult the cobicistat Summary of Product Characteristics.

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

In the table below the specific pharmacokinetic enhancer is specified when recommendeations differ. When the recommendation is the same for PREZISTA when co-administered with a low dose ritonavir or cobicistat, the term “boosted PREZISTA” is used.

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