4.1. Therapeutic indications

PREZISTA, co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adult and paediatric patients from the age of 3 years and at least 15 kg body weight (see section 4.2).

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 adults and adolescents (aged 12 years and older, weighing at least 40 kg) (see section 4.2).

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

4.2. Posology and method of administration

Therapy should be initiated by a healthcare 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 healthcare 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 paediatric population less than 12 years of age and weighing less than 40 kg.

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.

ART-experienced adult patients

The recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food.

A dose regimen of 800 mg once daily with cobicistat 150 mg once daily or ritonavir 100 mg once daily taken with food may be used in patients with prior exposure to antiretroviral medicinal products but 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.

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

If HIV-1 genotype testing is not available, the recommended dose regimen is PREZISTA 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food.

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

The weight-based dose of PREZISTA taken with ritonavir or cobicistat taken with food in paediatric patients is provided in the table below. The dose of cobicistat to be used with PREZISTA in children less than 12 years of age has not been established.

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

Body weight (kg)

Dose (once daily with food)

≥ 15 kg to < 30 kg

600 mg (6 ml) PREZISTA/100 mg (1.2 ml) ritonavir once daily

≥ 30 kg to < 40 kg

675 mg (6.8 ml)c PREZISTA/100 mg (1.2 ml) ritonavir once daily

≥ 40 kg

800 mg (8 ml) PREZISTA/100 mg (1.2 ml) ritonavir once daily or

800 mg (8 ml) PREZISTA/150 mg (tablet) cobicistatb once daily

a ritonavir oral solution: 80 mg/ml

b adolescents 12 years and older

c rounded up for suspension dosing convenience

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

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

A once daily dose regimen of PREZISTA taken with ritonavir or cobicistat taken with food may be used in patients with prior exposure to antiretroviral medicinal products but 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.

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

The weight-based dose of PREZISTA taken with ritonavir or cobicistat in paediatric patients is provided in the table below. The recommended dose of PREZISTA with low dose ritonavir should not exceed the recommended adult dose (600/100 mg twice daily or 800/100 mg once daily). The dose of PREZISTA with cobicistat in adolescent patients 12 years of age and older weighing at least 40 kg is 800/150 mg once daily taken with food. The dose of cobicistat to be used with PREZISTA in children less than 12 years of age has not been established.

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

Body weight (kg)

Dose (once daily with food)

Dose (twice daily with food)

≥ 15 kg to < 30 kg

600 mg (6 ml) PREZISTA/100 mg (1.2 ml) ritonavir once daily

380 mg (3.8 ml) PREZISTA/50 mg (0.6 ml) ritonavir twice daily

≥ 30 kg to < 40 kg

675 mg (6.8 ml)c PREZISTA/100 mg (1.2 ml) ritonavir once daily

460 mg (4.6 ml) PREZISTA/60 mg (0.8 ml) ritonavir twice daily

≥ 40 kg

800 mg (8 ml) PREZISTA/100 mg (1.2 ml) ritonavir once daily or

800 mg (8 ml) PREZISTA/150 mg (tablet) cobicistatb once daily

600 mg (6 ml) PREZISTA/100 mg (1.2 ml) ritonavir twice daily

a ritonavir oral solution: 80 mg/ml

b adolescents 12 years and older

c rounded up for suspension dosing convenience

For ART-experienced paediatric patients HIV genotypic testing is recommended. However, when HIV genotypic testing is not feasible, the PREZISTA (taken with ritonavir or cobicistat) once daily dosing regimen is recommended in HIV protease inhibitor-naïve paediatric patients and the PREZISTA taken with ritonavir twice daily dosing regimen is recommended in HIV protease inhibitor-experienced patients.

PREZISTA oral suspension can be used in patients unable to swallow PREZISTA tablets. PREZISTA is also available as 75 mg, 150 mg, 400 mg, 600 mg and 800 mg film-coated tablets.

Advice on missed doses

The following guidance is based on the half-life of darunavir in the presence of cobicistat or ritonavir and the recommended dosing interval of approximately 12 hours (twice daily regimen) or approximately 24 hours (once daily regimen).

• If using the twice daily regimen: in case a dose of PREZISTA 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 PREZISTA and ritonavir with food as soon as possible. If this is noticed later than 6 hours after the time it is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.

• If using the once daily regimen: in case a 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.

If a patient vomits within 4 hours of taking the medicine, another dose of PREZISTA with cobicistat or ritonavir should be taken with food as soon as possible. If a patient vomits more than 4 hours after taking the medicine, the patient does not need to take another dose of PREZISTA with cobicistat or ritonavir until the next regularly scheduled time.

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 (as fumarate, phosphate or succinate) or adefovir dipovoxil.

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

Paediatric population

PREZISTA should not be used in children

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

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

PREZISTA taken with cobicistat should not be used in children aged 3 to 11 years of age weighing < 40 kg as the dose of cobicistat to be used in these children has not been established (see sections 4.4 and 5.3).

Pregnancy and postpartum

No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. PREZISTA/ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk (see sections 4.4, 4.6 and 5.2).

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

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).

PREZISTA suspension is administered orally. Shake the bottle vigorously prior to each dose. The supplied oral dosing pipette should not be used for any other medicinal products.

4.3. Contraindications

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

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

Concomitant treatment with any of the following medicinal products given the expected decrease 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).

- Strong CYP3A inducers such as 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

- 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, lomitapide (see section 4.5)

- ticagrelor (see section 4.5).

4.4. Special warnings and precautions for use

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).

Pregnancy

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

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

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 and cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that include tenofovir disoproxil 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.

Weight and metabolic parameters

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

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 evaluated 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 and autoimmune hepatitis) 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

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

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 strong CYP3A inducers such as 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 boosted PREZISTA may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with PREZISTA, the PREZISTA/ritonavir 600/100 mg twice daily regimen should be used. See the Summary of Product Characteristics for PREZISTA 75 mg, 150 mg and 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).

PREZISTA oral suspension contains sodium methyl parahydroxybenzoate (E219) which may cause allergic reactions (possibly delayed).

PREZISTA oral suspension contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially 'sodium free'.

4.5. Interaction with other medicinal products and other forms of interaction

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, azole antifungals such as 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, 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.

Co administration of boosted darunavir with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see the Interaction table below).

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. Therefore, darunavir must only be used in combination with a pharmacokinetic enhancer (see sections 4.4 and 5.2).

A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity 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 with 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 similar to the recommendations 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. 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. 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 (not determined as “ND”).

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

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

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

Medicinal product examples by therapeutic area

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

HIV ANTIRETROVIRALS

Integrase strand transfer inhibitors

Dolutegravir

dolutegravir AUC ↓ 22%

dolutegravir C24h ↓ 38%

dolutegravir Cmax ↓ 11%

darunavir ↔*

* Using cross-study comparisons to historical pharmacokinetic data

Boosted PREZISTA and dolutegravir can be used without dose adjustment.

Raltegravir

Some clinical studies suggest raltegravir may cause a modest decrease in darunavir plasma concentrations.

At present the effect of raltegravir on darunavir plasma concentrations does not appear to be clinically relevant. Boosted PREZISTA and raltegravir can be used without dose adjustments.

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

Didanosine

400 mg once daily

didanosine AUC ↓ 9%

didanosine Cmin ND

didanosine Cmax ↓ 16%

darunavir AUC ↔

darunavir Cmin ↔

darunavir Cmax ↔

Boosted PREZISTA and didanosine can be used without dose adjustments.

Didanosine is to be administered on an empty stomach, thus it should be administered 1 hour before or 2 hours after boosted PREZISTA given with food.

Tenofovir disoproxil

245 mg once daily‡

tenofovir AUC ↑ 22%

tenofovir Cmin ↑ 37%

tenofovir Cmax ↑ 24%

#darunavir AUC ↑ 21%

#darunavir Cmin ↑ 24%

#darunavir Cmax ↑ 16%

(↑ tenofovir from effect on MDR-1 transport in the renal tubules)

Monitoring of renal function may be indicated when boosted PREZISTA is given in combination with tenofovir disoproxil, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.

PREZISTA co-administered with cobicistat lowers the creatinine clearance. Refer to section 4.4 if creatinine clearance is used for dose adjustment of tenofovir disoproxil.

Emtricitabine/tenofovir alafenamide

Tenofovir alafenamide ↔

Tenofovir ↑

The recommended dose of emtricitabine/tenofovir alafenamide is 200/10 mg once daily when used with boosted PREZISTA.

Abacavir

Emtricitabine

Lamivudine

Stavudine

Zidovudine

Not studied. Based on the different elimination pathways of the other NRTIs zidovudine, emtricitabine, stavudine, lamivudine, that are primarily renally excreted, and abacavir for which metabolism is not mediated by CYP450, no interactions are expected for these medicinal compounds and boosted PREZISTA.

Boosted PREZISTA can be used with these NRTIs without dose adjustment.

PREZISTA co-administered with cobicistat lowers the creatinine clearance. Refer to section 4.4 if creatinine clearance is used for dose adjustment of emtricitabine or lamivudine.

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

Efavirenz

600 mg once daily

efavirenz AUC ↑ 21%

efavirenz Cmin ↑ 17%

efavirenz Cmax ↑ 15%

#darunavir AUC ↓ 13%

#darunavir Cmin ↓ 31%

#darunavir Cmax ↓ 15%

(↑ efavirenz from CYP3A inhibition)

(↓ darunavir from CYP3A induction)

Clinical monitoring for central nervous system toxicity associated with increased exposure to efavirenz may be indicated when PREZISTA co-administered with low dose ritonavir is given in combination with efavirenz.

Efavirenz in combination with PREZISTA/ritonavir 800/100 mg once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with PREZISTA/ritonavir, the PREZISTA/ritonavir 600/100 mg twice daily regimen should be used (see section 4.4).

Co-administration with PREZISTA co-administered with cobicistat is not recommended (see section 4.4).

Etravirine

100 mg twice daily

etravirine AUC ↓ 37%

etravirine Cmin ↓ 49%

etravirine Cmax ↓ 32%

darunavir AUC ↑ 15%

darunavir Cmin ↔

darunavir Cmax ↔

PREZISTA co-administered with low dose ritonavir and etravirine 200 mg twice daily can be used without dose adjustments.

Co-administration with PREZISTA co-administered with cobicistat is not recommended (see section 4.4).

Nevirapine

200 mg twice daily

nevirapine AUC ↑ 27%

nevirapine Cmin ↑ 47%

nevirapine Cmax ↑ 18%

#darunavir: concentrations were consistent with historical data

(↑ nevirapine from CYP3A inhibition)

PREZISTA co-administered with low dose ritonavir and nevirapine can be used without dose adjustments.

Co-administration with PREZISTA co-administered with cobicistat is not recommended (see section 4.4).

Rilpivirine

150 mg once daily

rilpivirine AUC ↑ 130%

rilpivirine Cmin ↑ 178%

rilpivirine Cmax ↑ 79%

darunavir AUC ↔

darunavir Cmin ↓ 11%

darunavir Cmax ↔

Boosted PREZISTA and rilpivirine can be used without dose adjustments.

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

Atazanavir

300 mg once daily

atazanavir AUC ↔

atazanavir Cmin ↑ 52%

atazanavir Cmax ↓ 11%

#darunavir AUC ↔

#darunavir Cmin ↔

#darunavir Cmax ↔

Atazanavir: comparison of atazanavir/ritonavir 300/100 mg once daily vs. atazanavir 300 mg once daily in combination with darunavir/ritonavir 400/100 mg twice daily.

Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg twice daily in combination with atazanavir 300 mg once daily.

PREZISTA co-administered with low dose ritonavir and atazanavir can be used without dose adjustments.

PREZISTA co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4 (see section 4.5).

Indinavir

800 mg twice daily

indinavir AUC ↑ 23%

indinavir Cmin ↑ 125%

indinavir Cmax ↔

#darunavir AUC ↑ 24%

#darunavir Cmin ↑ 44%

#darunavir Cmax ↑ 11%

Indinavir: comparison of indinavir/ritonavir 800/100 mg twice daily vs. indinavir/darunavir/ritonavir 800/400/100 mg twice daily.

Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg in combination with indinavir 800 mg twice daily.

When used in combination with PREZISTA co-administered with low dose ritonavir, dose adjustment of indinavir from 800 mg twice daily to 600 mg twice daily may be warranted in case of intolerance.

PREZISTA co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4 (see section 4.5).

Saquinavir

1,000 mg twice daily

#darunavir AUC ↓ 26%

#darunavir Cmin ↓ 42%

#darunavir Cmax ↓ 17%

saquinavir AUC ↓ 6%

saquinavir Cmin ↓ 18%

saquinavir Cmax ↓ 6%

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

Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg in combination with saquinavir 1,000 mg twice daily.

It is not recommended to combine PREZISTA co-administered with low dose ritonavir with saquinavir.

PREZISTA co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4 (see section 4.5).

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

Lopinavir/ritonavir

400/100 mg twice daily

Lopinavir/ritonavir

533/133.3 mg twice daily

lopinavir AUC ↑ 9%

lopinavir Cmin ↑ 23%

lopinavir Cmax ↓ 2%

darunavir AUC ↓ 38%‡

darunavir Cmin ↓ 51%‡

darunavir Cmax ↓ 21%‡

lopinavir AUC ↔

lopinavir Cmin ↑ 13%

lopinavir Cmax ↑ 11%

darunavir AUC ↓ 41%

darunavir Cmin ↓ 55%

darunavir Cmax ↓ 21%

‡ based upon non dose normalised values

Due to a decrease in the exposure (AUC) of darunavir by 40%, appropriate doses of the combination have not been established. Hence, concomitant use of boosted PREZISTA and the combination product lopinavir/ritonavir is contraindicated (see section 4.3).

CCR5 ANTAGONIST

Maraviroc

150 mg twice daily

maraviroc AUC ↑ 305%

maraviroc Cmin ND

maraviroc Cmax ↑ 129%

darunavir, ritonavir concentrations were consistent with historical data

The maraviroc dose should be 150 mg twice daily when co-administered with boosted PREZISTA.

α1-ADRENORECEPTOR ANTAGONIST

Alfuzosin

Based on theoretical considerations PREZISTA is expected to increase alfuzosin plasma concentrations.

(CYP3A inhibition)

Co-administration of boosted PREZISTA and alfuzosin is contraindicated (see section 4.3).

ANAESTHETIC

Alfentanil

Not studied. The metabolism of alfentanil is mediated via CYP3A, and may as such be inhibited by boosted PREZISTA.

The concomitant use with boosted PREZISTA may require to lower the dose of alfentanil and requires monitoring for risks of prolonged or delayed respiratory depression.

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide

Flecainide

Lidocaine (systemic)

Mexiletine

Propafenone

Amiodarone

Bepridil

Dronedarone

Ivabradine

Quinidine

Ranolazine

Not studied. Boosted PREZISTA is expected to increase these antiarrhythmic plasma concentrations.

(CYP3A and/or CYP2D6 inhibition)

Caution is warranted and therapeutic concentration monitoring, if available, is recommended for these antiarrhythmics when co-administered with boosted PREZISTA.

Co-administration of boosted PREZISTA and amiodarone, bepridil, dronedarone, ivabradine, quinidine, or ranolazine is contraindicated (see section 4.3).

Digoxin

0.4 mg single dose

digoxin AUC ↑ 61%

digoxin Cmin ND

digoxin Cmax ↑ 29%

(↑ digoxin from probable inhibition of P-gp)

Given that digoxin has a narrow therapeutic index, it is recommended that the lowest possible dose of digoxin should initially be prescribed in case digoxin is given to patients on boosted PREZISTA therapy. The digoxin dose should be carefully titrated to obtain the desired clinical effect while assessing the overall clinical state of the subject.

ANTIBIOTIC

Clarithromycin

500 mg twice daily

clarithromycin AUC ↑ 57%

clarithromycin Cmin ↑ 174%

clarithromycin Cmax ↑ 26%

#darunavir AUC ↓ 13%

#darunavir Cmin ↑ 1%

#darunavir Cmax ↓ 17%

14-OH-clarithromycin concentrations were not detectable when combined with PREZISTA/ritonavir.

(↑ clarithromycin from CYP3A inhibition and possible P-gp inhibition)

Caution should be exercised when clarithromycin is combined with boosted PREZISTA.

For patients with renal impairment the Summary of Product Characteristics for clarithromycin should be consulted for the recommended dose.

ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR

Apixaban

Rivaroxaban

Not studied. Co administration of boosted PREZISTA with these anticoagulants may increase concentrations of the anticoagulant (CYP3A and/or P gp inhibition)

The use of boosted PREZISTA with a direct oral anticoagulant (DOAC) that is metabolised by CYP3A4 and transported by P gp is not recommended as this may lead to an increased bleeding risk..

Dabigatran etexilate

Edoxaban

Ticagrelor

Clopidogrel

dabigatran etexilate (150 mg):

darunavir/ritonavir 800/100 mg single dose:

dabigatran AUC ↑ 72%

dabigatran Cmax ↑ 64%

darunavir/ritonavir 800/100 mg once daily:

dabigatran AUC ↑ 18%

dabigatran Cmax ↑ 22%

darunavir/cobicistat 800/150 mg single dose:

dabigatran AUC ↑ 164%

dabigatran Cmax ↑ 164%

darunavir/cobicistat 800/150 mg once daily:

dabigatran AUC ↑ 88%

dabigatran Cmax ↑ 99%

Based on theoretical considerations, co administration of boosted PREZISTA with ticagrelor may increase concentrations of ticagrelor (CYP3A and/or P glycoprotein inhibition).

Not studied. Co administration of clopidogrel with boosted PREZISTA is expected to decrease clopidogrel active metabolite plasma concentration, which may reduce the antiplatelet activity of clopidogrel.

Darunavir/ritonavir:

Clinical monitoring and/or dose reduction of the DOAC should be considered when a DOAC transported by P gp but not metabolised by CYP3A4, including dabigatran etexilate and edoxaban, is co administered with PREZISTA/rtv.

Darunavir/cobicistat:

Clinical monitoring and dose reduction is required when a DOAC transported by P gp but not metabolised by CYP3A4, including dabigatran etexilate and edoxaban, is co administered with PREZISTA/cobi.

Concomitant administration of boosted PREZISTA with ticagrelor is contraindicated (see section 4.3).

Co administration of clopidogrel with boosted PREZISTA is not recommended. Use of other antiplatelets not affected by CYP inhibition or induction (e.g. prasugrel) is recommended.

Warfarin

Not studied. Warfarin concentrations may be affected when co-administered with boosted PREZISTA.

It is recommended that the international normalised ratio (INR) be monitored when warfarin is combined with boosted PREZISTA.

ANTICONVULSANTS

Phenobarbital

Phenytoin

Not studied. Phenobarbital and phenytoin are expected to decrease plasma concentrations of darunavir and its pharmacoenhancer.

(induction of CYP450 enzymes)

PREZISTA co-administered with low dose ritonavir should not be used in combination with these medicines.

The use of these medicines with PREZISTA/cobicistat is contraindicated (see section 4.3).

Carbamazepine

200 mg twice daily

carbamazepine AUC ↑ 45%

carbamazepine Cmin ↑ 54%

carbamazepine Cmax ↑ 43%

darunavir AUC ↔

darunavir Cmin ↓ 15%

darunavir Cmax ↔

No dose adjustment for PREZISTA/ritonavir is recommended. If there is a need to combine PREZISTA/ritonavir and carbamazepine, patients should be monitored for potential carbamazepine-related adverse events. Carbamazepine concentrations should be monitored and its dose should be titrated for adequate response. Based upon the findings, the carbamazepine dose may need to be reduced by 25% to 50% in the presence of PREZISTA/ritonavir.

The use of carbamazepine with PREZISTA co-administered with cobicistat is contraindicated (see section 4.3).

Clonazepam

Not studied. Co-administration of boosted PREZISTA with clonazepam may increase concentrations of clonazepam. (CYP3A inhibition)

Clinical monitoring is recommended when co-administering boosted PREZISTA with clonazepam.

ANTIDEPRESSANTS

Paroxetine

20 mg once daily

Sertraline

50 mg once daily

Amitriptyline

Desipramine

Imipramine

Nortriptyline

Trazodone

paroxetine AUC ↓ 39%

paroxetine Cmin ↓ 37%

paroxetine Cmax ↓ 36%

#darunavir AUC ↔

#darunavir Cmin ↔

#darunavir Cmax ↔

sertraline AUC ↓ 49%

sertraline Cmin ↓ 49%

sertraline Cmax ↓ 44%

#darunavir AUC ↔

#darunavir Cmin ↓ 6%

#darunavir Cmax ↔

In contrast to these data with PREZISTA/ritonavir, PREZISTA/cobicistat may increase these antidepressant plasma concentrations (CYP2D6 and/or CYP3A inhibition).

Concomitant use of boosted PREZISTA and these antidepressants may increase concentrations of the antidepressant.

(CYP2D6 and/or CYP3A inhibition)

If antidepressants are co-administered with boosted PREZISTA, the recommended approach is a dose titration of the antidepressant based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of these antidepressants who start treatment with boosted PREZISTA should be monitored for antidepressant response.

Clinical monitoring is recommended when co-administering boosted PREZISTA with these antidepressants and a dose adjustment of the antidepressant may be needed.

ANTI-DIABETICS

Metformin

Not studied. Based on theoretical considerations PREZISTA co-administered with cobicistat is expected to increase metformin plasma concentrations.

(MATE1 inhibition)

Careful patient monitoring and dose adjustment of metformin is recommended in patients who are taking PREZISTA co-administered with cobicistat.

(not applicable for PREZISTA co-administered with ritonavir)

ANTIEMETICS

Domperidone

Not studied.

Co-administration of domperidone with boosted PREZISTA is contraindicated.

ANTIFUNGALS

Voriconazole

Not studied. Ritonavir may decrease plasma concentrations of voriconazole.

(induction of CYP450 enzymes)

Concentrations of voriconazole may increase or decrease when co-administered with PREZISTA co-administered with cobicistat.

(inhibition of CYP450 enzymes)

Voriconazole should not be combined with boosted PREZISTA unless an assessment of the benefit/risk ratio justifies the use of voriconazole.

Fluconazole

Isavuconazole

Itraconazole

Posaconazole

Clotrimazole

Not studied. Boosted PREZISTA may increase antifungal plasma concentrations and posaconazole, isavuconazole, itraconazole or fluconazole may increase darunavir concentrations.

(CYP3A and/or P-gp inhibition)

Not Studied. Concomitant systemic use of clotrimazole and boosted PREZISTA may increase plasma concentrations of darunavir and/or clotrimazole.

darunavir AUC24h ↑ 33% (based on population pharmacokinetic model)

Caution is warranted and clinical monitoring is recommended. When co-administration is required the daily dose of itraconazole should not exceed 200 mg.

ANTIGOUT MEDICINES

Colchicine

Not studied. Concomitant use of colchicine and boosted PREZISTA may increase the exposure to colchicine.

(CYP3A and/ or P-gp inhibition)

A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with boosted PREZISTA is required. For patients with renal or hepatic impairment colchicine with boosted PREZISTA is contraindicated (see sections 4.3 and 4.4).

ANTIMALARIALS

Artemether/Lumefantrine

80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours

artemether AUC ↓ 16%

artemether Cmin ↔

artemether Cmax ↓ 18%

dihydroartemisinin AUC ↓ 18%

dihydroartemisinin Cmin ↔

dihydroartemisinin Cmax ↓ 18%

lumefantrine AUC ↑ 175%

lumefantrine Cmin ↑ 126%

lumefantrine Cmax ↑ 65%

darunavir AUC ↔

darunavir Cmin ↓ 13%

darunavir Cmax ↔

The combination of boosted PREZISTA and artemether/lumefantrine can be used without dose adjustments; however, due to the increase in lumefantrine exposure, the combination should be used with caution.

ANTIMYCOBACTERIALS

Rifampicin

Rifapentine

Not studied. Rifapentine and rifampicin are strong CYP3A inducers and have been shown to cause profound decreases in concentrations of other protease inhibitors, which can result in virological failure and resistance development (CYP450 enzyme induction). During attempts to overcome the decreased exposure by increasing the dose of other protease inhibitors with low dose ritonavir, a high frequency of liver reactions was seen with rifampicin.

The combination of rifapentine and boosted PREZISTA is not recommended.

The combination of rifampicin and boosted PREZISTA is contraindicated (see section 4.3).

Rifabutin

150 mg once every other day

rifabutin AUC** ↑ 55%

rifabutin Cmin** ↑ ND

rifabutin Cmax** ↔

darunavir AUC ↑ 53%

darunavir Cmin ↑ 68%

darunavir Cmax ↑ 39%

** sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite)

The interaction trial showed a comparable daily systemic exposure for rifabutin between treatment at 300 mg once daily alone and 150 mg once every other day in combination with PREZISTA/ritonavir (600/100 mg twice daily) with an about 10-fold increase in the daily exposure to the active metabolite 25-O-desacetylrifabutin. Furthermore, AUC of the sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite) was increased 1.6-fold, while Cmax remained comparable.

Data on comparison with a 150 mg once daily reference dose is lacking.

(Rifabutin is an inducer and substrate of CYP3A.) An increase of systemic exposure to darunavir was observed when PREZISTA co-administered with 100 mg ritonavir was co-administered with rifabutin (150 mg once every other day).

A dosage reduction of rifabutin by 75% of the usual dose of 300 mg/day (i.e. rifabutin 150 mg once every other day) and increased monitoring for rifabutin related adverse events is warranted in patients receiving the combination with PREZISTA co-administered with ritonavir. In case of safety issues, a further increase of the dosing interval for rifabutin and/or monitoring of rifabutin levels should be considered.

Consideration should be given to official guidance on the appropriate treatment of tuberculosis in HIV infected patients.

Based upon the safety profile of PREZISTA/ritonavir, the increase in darunavir exposure in the presence of rifabutin does not warrant a dose adjustment for PREZISTA/ritonavir.

Based on pharmacokinetic modeling, this dosage reduction of 75% is also applicable if patients receive rifabutin at doses other than 300 mg/day.

Co-administration of PREZISTA co-administered with cobicistat and rifabutin is not recommended.

ANTINEOPLASTICS

Dasatinib

Nilotinib

Vinblastine

Vincristine

Everolimus

Irinotecan

Not studied. Boosted PREZISTA is expected to increase these antineoplastic plasma concentrations.

(CYP3A inhibition)

Concentrations of these medicinal products may be increased when co-administered with boosted PREZISTA resulting in the potential for increased adverse events usually associated with these agents.

Caution should be exercised when combining one of these antineoplastic agents with boosted PREZISTA.

Concomitant use of everolimus or irinotecan and boosted PREZISTA is not recommended.

ANTIPSYCHOTICS/NEUROLEPTICS

Quetiapine

Not studied. Boosted PREZISTA is expected to increase these antipsychotic plasma concentrations.

(CYP3A inhibition)

Concomitant administration of boosted PREZISTA and quetiapine is contraindicated as it may increase quetiapine-related toxicity. Increased concentrations of quetiapine may lead to coma (see section 4.3).

Perphenazine

Risperidone

Thioridazine

Lurasidone

Pimozide

Sertindole

Not studied. Boosted PREZISTA is expected to increase these antipsychotic plasma concentrations.

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

A dose decrease may be needed for these drugs when co-administered with boosted PREZISTA.

Concomitant administration of boosted PREZISTA and lurasidone, pimozide or sertindole is contraindicated (see section 4.3).

β-BLOCKERS

Carvedilol

Metoprolol

Timolol

Not studied. Boosted PREZISTA is expected to increase these β-blocker plasma concentrations.

(CYP2D6 inhibition)

Clinical monitoring is recommended when co-administering boosted PREZISTA with β-blockers. A lower dose of the β-blocker should be considered.

CALCIUM CHANNEL BLOCKERS

Amlodipine

Diltiazem

Felodipine

Nicardipine

Nifedipine

Verapamil

Not studied. Boosted PREZISTA can be expected to increase the plasma concentrations of calcium channel blockers.

(CYP3A and/or CYP2D6 inhibition)

Clinical monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with boosted PREZISTA.

CORTICOSTEROIDS

Corticosteroids primarily metabolised by CYP3A (including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone)

Fluticasone: in a clinical study where ritonavir 100 mg capsules twice daily were co-administered with 50 µg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, fluticasone propionate plasma concentrations increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% CI 82-89%). Greater effects may be expected when fluticasone is inhaled. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone. The effects of high fluticasone systemic exposure on ritonavir plasma levels are unknown.

Other corticosteroids: interaction not studied. Plasma concentrations of these medicinal products may be increased when co-administered with boosted PREZISTA, resulting in reduced serum cortisol concentrations.

Concomitant use of boosted PREZISTA and corticosteroids (all routes of administration) that are metabolised by CYP3A may increase the risk of development of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.

Co-administration with CYP3A-metabolised corticosteroids is not recommended unless the potential benefit to the patient outweighs the risk, in which case patients should be monitored for systemic corticosteroid effects.

Alternative corticosteroids which are less dependent on CYP3A metabolism e.g. beclomethasone should be considered, particularly for long term use.

Dexamethasone (systemic)

Not studied. Dexamethasone may decrease plasma concentrations of darunavir.

(CYP3A induction)

Systemic dexamethasone should be used with caution when combined with boosted PREZISTA.

ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan

Not studied. Concomitant use of bosentan and boosted PREZISTA may increase plasma concentrations of bosentan.

Bosentan is expected to decrease plasma concentrations of darunavir and/or its pharmacoenhancer.

(CYP3A induction)

When administered concomitantly with PREZISTA and low dose ritonavir, the patient's tolerability of bosentan should be monitored.

Co-administration of PREZISTA co-administered with cobicistat and bosentan is not recommended.

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS

NS3-4A protease inhibitors

Elbasvir/grazoprevir

Boosted PREZISTA may increase the exposure to grazoprevir.

(CYP3A and OATP1B inhibition)

Concomitant use of boosted PREZISTA and elbasvir/grazoprevir is contraindicated (see section 4.3).

Glecaprevir/pibrentasvir

Based on theoretical considerations boosted PREZISTA may increase the exposure to glecaprevir and pibrentasvir.

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

It is not recommended to co-administer boosted PREZISTA with glecaprevir/pibrentasvir.

HERBAL PRODUCTS

St John's Wort (Hypericum perforatum)

Not studied. St John's Wort is expected to decrease the plasma concentrations of darunavir or its pharmacoenhancers.

(CYP450 induction)

Boosted PREZISTA must not be used concomitantly with products containing St John's Wort (Hypericum perforatum) (see section 4.3). If a patient is already taking St John's Wort , stop St John's Wort and if possible check viral levels. Darunavir exposure (and also ritonavir exposure) may increase on stopping St John's Wort . The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's Wort .

HMG CO-A REDUCTASE INHIBITORS

Lovastatin

Simvastatin

Not studied. Lovastatin and simvastatin are expected to have markedly increased plasma concentrations when co-administered with boosted PREZISTA.

(CYP3A inhibition)

Increased plasma concentrations of lovastatin or simvastatin may cause myopathy, including rhabdomyolysis. Concomitant use of boosted PREZISTA with lovastatin and simvastatin is therefore contraindicated (see section 4.3).

Atorvastatin

10 mg once daily

atorvastatin AUC ↑ 3-4 fold

atorvastatin Cmin ↑ ≈5.5-10 fold

atorvastatin Cmax ↑ ≈2 fold

# darunavir/ritonavir

atorvastatin AUC ↑ 290% Ω

atorvastatin Cmax ↑ 319% Ω

atorvastatin Cmin ND Ω

Ω with darunavir/cobicistat 800/150 mg

When administration of atorvastatin and boosted PREZISTA is desired, it is recommended to start with an atorvastatin dose of 10 mg once daily. A gradual dose increase of atorvastatin may be tailored to the clinical response.

Pravastatin

40 mg single dose

pravastatin AUC ↑ 81%¶

pravastatin Cmin ND

pravastatin Cmax ↑ 63%

¶ an up to five-fold increase was seen in a limited subset of subjects

When administration of pravastatin and boosted PREZISTA is required, it is recommended to start with the lowest possible dose of pravastatin and titrate up to the desired clinical effect while monitoring for safety.

Rosuvastatin

10 mg once daily

rosuvastatin AUC ↑ 48%‖

rosuvastatin Cmax ↑ 144%‖

‖ based on published data with darunavir/ritonavir

rosuvastatin AUC ↑ 93%§

rosuvastatin Cmax ↑ 277%§

rosuvastatin Cmin ND§

§ with darunavir/cobicistat 800/150 mg

When administration of rosuvastatin and boosted PREZISTA is required, it is recommended to start with the lowest possible dose of rosuvastatin and titrate up to the desired clinical effect while monitoring for safety.

OTHER LIPID MODIFYING AGENTS

Lomitapide

Based on theoretical considerations boosted PREZISTA is expected to increase the exposure of lomitapide when co-administered.

(CYP3A inhibition)

Co-administration is contraindicated (see section 4.3).

H2-RECEPTOR ANTAGONISTS

Ranitidine

150 mg twice daily

#darunavir AUC ↔

#darunavir Cmin ↔

#darunavir Cmax ↔

Boosted PREZISTA can be co-administered with H2-receptor antagonists without dose adjustments.

IMMUNOSUPPRESSANTS

Ciclosporin

Sirolimus

Tacrolimus

Everolimus

Not studied. Exposure to these immunosuppressants will be increased when co-administered with boosted PREZISTA.

(CYP3A inhibition)

Therapeutic drug monitoring of the immunosuppressive agent must be done when co-administration occurs.

Concomitant use of everolimus and boosted PREZISTA is not recommended.

INHALED BETA AGONISTS

Salmeterol

Not studied. Concomitant use of salmeterol and boosted darunavir may increase plasma concentrations of salmeterol.

Concomitant use of salmeterol and boosted PREZISTA is not recommended. The combination may result in increased risk of cardiovascular adverse event with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

NARCOTIC ANALGESICS / TREATMENT OF OPIOID DEPENDENCE

Methadone individual dose ranging from 55 mg to 150 mg once daily

R(-) methadone AUC ↓ 16%

R(-) methadone Cmin ↓ 15%

R(-) methadone Cmax ↓ 24%

PREZISTA/cobicistat may, in contrast, increase methadone plasma concentrations (see cobicistat SmPC).

No adjustment of methadone dosage is required when initiating co-administration with boosted PREZISTA. However, adjustment of the methadone dose may be necessary when concomitantly administered for a longer period of time. Therefore, clinical monitoring is recommended, as maintenance therapy may need to be adjusted in some patients.

Buprenorphine/naloxone

8/2 mg–16/4 mg once daily

buprenorphine AUC ↓ 11%

buprenorphine Cmin ↔

buprenorphine Cmax ↓ 8%

norbuprenorphine AUC ↑ 46%

norbuprenorphine Cmin ↑ 71%

norbuprenorphine Cmax ↑ 36%

naloxone AUC ↔

naloxone Cmin ND

naloxone Cmax ↔

The clinical relevance of the increase in norbuprenorphine pharmacokinetic parameters has not been established. Dose adjustment for buprenorphine may not be necessary when co-administered with boosted PREZISTA but a careful clinical monitoring for signs of opiate toxicity is recommended.

Fentanyl

Oxycodone

Tramadol

Based on theoretical considerations boosted PREZISTA may increase plasma concentrations of these analgesics.

(CYP2D6 and/or CYP3A inhibition)

Clinical monitoring is recommended when co-administering boosted PREZISTA with these analgesics.

OESTROGEN-BASED CONTRACEPTIVES

Drospirenone Ethinylestradiol (3 mg/0.02 mg once daily)

Ethinylestradiol

Norethindrone

35 µg/1 mg once daily

drospirenone AUC ↑ 58%€

drospirenone Cmin ND€

drospirenone Cmax ↑ 15%€

ethinylestradiol AUC ↓ 30%€

ethinylestradiol Cmin ND€

ethinylestradiol Cmax ↓ 14%€

€ with darunavir/cobicistat

ethinylestradiol AUC ↓ 44%β

ethinylestradiol Cmin ↓ 62%β

ethinylestradiol Cmax ↓ 32%β

norethindrone AUC ↓ 14%β

norethindrone Cmin ↓ 30%β

norethindrone Cmax ↔β

β with darunavir/ritonavir

When PREZISTA is co-administered with a drospirenone-containing product, clinical monitoring is recommended due to the potential for hyperkalaemia.

Alternative or additional contraceptive measures are recommended when oestrogen-based contraceptives are co-administered with boosted PREZISTA. Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.

OPIOID ANTAGONIST

Naloxegol

Not studied.

Co-administration of boosted PREZISTA and naloxegol is contraindicated.

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS

For the treatment of erectile dysfunction

Avanafil

Sildenafil

Tadalafil

Vardenafil

In an interaction study #, a comparable systemic exposure to sildenafil was observed for a single intake of 100 mg sildenafil alone and a single intake of 25 mg sildenafil co-administered with PREZISTA and low dose ritonavir.

The combination of avanafil and boosted PREZISTA is contraindicated (see section 4.3).

Concomitant use of other PDE-5 inhibitors for the treatment of erectile dysfunction with boosted PREZISTA should be done with caution. If concomitant use of boosted PREZISTA with sildenafil, vardenafil or tadalafil is indicated, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours or tadalafil at a single dose not exceeding 10 mg in 72 hours is recommended.

For the treatment of pulmonary arterial hypertension

Sildenafil

Tadalafil

Not studied. Concomitant use of sildenafil or tadalafil for the treatment of pulmonary arterial hypertension and boosted PREZISTA may increase plasma concentrations of sildenafil or tadalafil.

(CYP3A inhibition)

A safe and effective dose of sildenafil for the treatment of pulmonary arterial hypertension co-administered with boosted PREZISTA has not been established. There is an increased potential for sildenafil-associated adverse events (including visual disturbances, hypotension, prolonged erection and syncope). Therefore, co-administration of boosted PREZISTA and sildenafil when used for the treatment of pulmonary arterial hypertension is contraindicated (see section 4.3).

Co-administration of tadalafil for the treatment of pulmonary arterial hypertension with boosted PREZISTA is not recommended.

PROTON PUMP INHIBITORS

Omeprazole

20 mg once daily

#darunavir AUC ↔

#darunavir Cmin ↔

#darunavir Cmax ↔

Boosted PREZISTA can be co-administered with proton pump inhibitors without dose adjustments.

SEDATIVES/HYPNOTICS

Buspirone

Clorazepate

Diazepam

Estazolam

Flurazepam

Midazolam (parenteral)

Zolpidem

Midazolam (oral)

Triazolam

Not studied. Sedative/hypnotics are extensively metabolised by CYP3A. Co-administration with boosted PREZISTA may cause a large increase in the concentration of these medicines.

If parenteral midazolam is co-administered with boosted PREZISTA it may cause a large increase in the concentration of this benzodiazepine. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels.

Clinical monitoring is recommended when co-administering boosted PREZISTA with these sedatives/hypnotics and a lower dose of the sedatives/hypnotics should be considered.

If parenteral midazolam is co-administered with boosted PREZISTA, it should be done in an intensive care unit (ICU) or similar setting, which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.

Boosted PREZISTA with triazolam or oral midazolam is contraindicated (see section 4.3).

TREATMENT FOR PREMATURE EJACULATION

Dapoxetine

Not studied.

Co-administration of boosted PREZISTA with dapoxetine is contraindicated.

UROLOGICAL DRUGS

Fesoterodine

Solifenacin

Not studied.

Use with caution. Monitor for fesoterodine or solifenacin adverse reactions, dose reduction of fesoterodine or solifenacin may be necessary.

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

† The efficacy and safety of the use of PREZISTA with 100 mg ritonavir and any other HIV PI (e.g. (fos)amprenavir and tipranavir) has not been established in HIV patients. According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.

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

4.6. Fertility, pregnancy and lactation

Pregnancy

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant 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 pregnant women. Studies in animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

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

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

Breast-feeding

It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that darunavir 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 to breast feed if they are receiving PREZISTA.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast feed.

Fertility

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

4.7. Effects on ability to drive and use machines

PREZISTA in combination with cobicistat or ritonavir has no or negligible influence on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing PREZISTA co-administered with cobicistat or low dose ritonavir and should be borne in mind when considering a patient's ability to drive or operate machinery (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

During the clinical development program (N=2,613 treatment-experienced subjects who initiated therapy with PREZISTA/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one adverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequent adverse 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, myocardial infarction, immune reconstitution inflammatory syndrome, thrombocytopenia, osteonecrosis, diarrhoea, hepatitis and pyrexia.

In the 96 week analysis, the safety profile of PREZISTA/ritonavir 800/100 mg once daily in treatment-naïve subjects was similar to that seen with PREZISTA/ritonavir 600/100 mg twice daily in treatment-experienced subjects except for nausea which was observed more frequently in treatment-naïve subjects. This was driven by mild intensity nausea. No new safety findings were identified in the 192 week analysis of the treatment-naïve subjects in which the mean treatment duration of PREZISTA/ritonavir 800/100 mg once daily was 162.5 weeks.

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

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

Tabulated list of adverse reactions

Adverse reactions are listed by system organ class (SOC) and frequency category. Within each frequency category, adverse reactions are presented in order of decreasing seriousness. Frequency categories 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 estimated from the available data).

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

MedDRA system organ class

Frequency category

Adverse reaction

Infections and infestations

uncommon

herpes simplex

Blood and lymphatic system disorders

uncommon

thrombocytopenia, neutropenia, anaemia, leukopenia

rare

increased eosinophil count

Immune system disorders

uncommon

immune reconstitution inflammatory syndrome, (drug) hypersensitivity

Endocrine disorders

uncommon

hypothyroidism, increased blood thyroid stimulating hormone

Metabolism and nutrition disorders

common

diabetes mellitus, hypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemia

uncommon

gout, anorexia, decreased appetite, decreased weight, increased weight, hyperglycaemia, insulin resistance, decreased high density lipoprotein, increased appetite, polydipsia, increased blood lactate dehydrogenase

Psychiatric disorders

common

insomnia

uncommon

depression, disorientation, anxiety, sleep disorder, abnormal dreams, nightmare, decreased libido

rare

confusional state, altered mood, restlessness

Nervous system disorders

common

headache, peripheral neuropathy, dizziness

uncommon

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

rare

syncope, convulsion, ageusia, sleep phase rhythm disturbance

Eye disorders

uncommon

conjunctival hyperaemia, dry eye

rare

visual disturbance

Ear and labyrinth disorders

uncommon

vertigo

Cardiac disorders

uncommon

myocardial infarction, angina pectoris, prolonged electrocardiogram QT, tachycardia

rare

acute myocardial infarction, sinus bradycardia, palpitations

Vascular disorders

uncommon

hypertension, flushing

Respiratory, thoracic and mediastinal disorders

uncommon

dyspnoea, cough, epistaxis, throat irritation

rare

rhinorrhoea

Gastrointestinal disorders

very common

diarrhoea

common

vomiting, nausea, abdominal pain, increased blood amylase, dyspepsia, abdominal distension, flatulence

uncommon

pancreatitis, gastritis, gastrooesophageal reflux disease, aphthous stomatitis, retching, dry mouth, abdominal discomfort, constipation, increased lipase, eructation, oral dysaesthesia

rare

stomatitis, haematemesis, cheilitis, dry lip, coated tongue

Hepatobiliary disorders

common

increased alanine aminotransferase

uncommon

hepatitis, cytolytic hepatitis, hepatic steatosis, hepatomegaly, increased transaminase, increased aspartate aminotransferase, increased blood bilirubin, increased blood alkaline phosphatase, increased gamma-glutamyltransferase

Skin and subcutaneous tissue disorders

common

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

uncommon

angioedema, generalised rash, allergic dermatitis, urticaria, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, dry skin, nail pigmentation

rare

DRESS, Stevens-Johnson syndrome, erythema multiforme, dermatitis, seborrhoeic dermatitis, skin lesion, xeroderma

not known

toxic epidermal necrolysis, acute generalised exanthematous pustulosis

Musculoskeletal and connective tissue disorders

uncommon

myalgia, osteonecrosis, muscle spasms, muscular weakness, arthralgia, pain in extremity, osteoporosis, increased blood creatine phosphokinase

rare

musculoskeletal stiffness, arthritis, joint stiffness

Renal and urinary disorders

uncommon

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

rare

decreased creatinine renal clearance

rare

crystal nephropathy§

Reproductive system and breast disorders

uncommon

erectile dysfunction, gynaecomastia

General disorders and administration site conditions

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 using the "Rule of 3".

Adverse reactions observed with darunavir/cobicistat in adult patients

MedDRA system organ class

Frequency category

Adverse reaction

Immune system disorders

common

(drug) hypersensitivity

uncommon

immune reconstitution inflammatory syndrome

Metabolism and nutrition disorders

common

anorexia, diabetes mellitus, hypercholesterolaemia, hypertriglyceridaemia, hyperlipidaemia

Psychiatric disorders

common

abnormal dreams

Nervous system disorders

very common

headache

Gastrointestinal disorders

very common

diarrhoea, nausea

common

vomiting, abdominal pain, abdominal distension, dyspepsia, flatulence, pancreatic enzymes increased

uncommon

pancreatitis acute

Hepatobiliary disorders

common

hepatic enzyme increased

uncommon

hepatitis*, cytolytic hepatitis*

Skin and subcutaneous tissue disorders

very common

rash (including macular, maculopapular, papular, erythematous, pruritic rash, generalised rash, and allergic dermatitis)

common

angioedema, pruritus, urticaria

rare

drug reaction with eosinophilia and systemic symptoms*, Stevens-Johnson syndrome*

not known

toxic epidermal necrolysis*, acute generalised exanthematous pustulosis*

Musculoskeletal and connective tissue disorders

common

Myalgia

uncommon

osteonecrosis*

Renal and urinary disorders

rare

crystal nephropathy*§

Reproductive system and breast disorders

uncommon

gynaecomastia*

General disorders and administration site conditions

common

Fatigue

uncommon

Asthenia

Investigations

common

increased blood creatinine

* these adverse drug reactions have not been reported in clinical trial experience with darunavir/cobicistat but have been noted with darunavir/ritonavir treatment and could be expected with darunavir/cobicistat too.

§ adverse reaction identified in the post marketing setting. Per the guideline on Summary of Product Characteristics (Revision 2, September 2009), the frequency of this adverse reaction in the post marketing setting was determined using the "Rule of 3".

Description of selected adverse reactions

Rash

In clinical trials, rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. In cases of severe skin reaction see the warning in section 4.4. In a single arm trial investigating darunavir 800 mg once daily in combination with cobicistat 150 mg once daily and other antiretrovirals 2.2% of patients discontinued treatment due to rash.

During the clinical development program of raltegravir in treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing PREZISTA/ritonavir + raltegravir compared to those containing PREZISTA/ritonavir without raltegravir or raltegravir without PREZISTA/ritonavir. Rash considered by the investigator to be drug-related occurred at similar rates. 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. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section 4.4).

Metabolic parameters

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

Musculoskeletal abnormalities

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

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, 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 combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Bleeding in haemophiliac patients

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

Paediatric population

The safety assessment of PREZISTA with ritonavir 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 at least 20 kg who received PREZISTA tablets with low dose ritonavir twice daily in combination with other antiretroviral agents.

• 21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing 10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received PREZISTA oral suspension with 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 least 40 kg who received PREZISTA tablets with low dose ritonavir once daily in combination with other antiretroviral agents (see section 5.1).

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

The safety assessment of PREZISTA with cobicistat in paediatric patients was evaluated in adolescents aged 12 to less than 18 years, weighing at least 40 kg through the clinical trial GS-US-216-0128 (treatment-experienced, virologically suppressed, N=7). Safety analyses of this study in adolescent subjects did not identify new safety concerns compared to the known safety profile of darunavir and cobicistat in adult subjects.

Other special populations

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

Among 1,968 treatment-experienced patients receiving PREZISTA co-administered with ritonavir 600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients were more likely to have baseline and treatment emergent hepatic transaminase elevations than those without chronic viral hepatitis (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: https://yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Human experience of acute overdose with PREZISTA co-administered with cobicistat or low dose ritonavir is limited. Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.

There is no specific antidote for overdose with PREZISTA. Treatment of overdose with PREZISTA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.