PREZISTA 100 MG / ML ORAL SUSPENSION - summary of medicine characteristics

PREZISTA 100 mg/ml oral suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of oral suspension contains 100 mg of darunavir (as ethanolate).

Excipient with known effect: sodium methyl parahydroxybenzoate (E219) 3.43 mg/ml.

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Oral suspension

White to off-white opaque suspension

4 CLINICAL PARTICULARS

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-naive 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-naive 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.

a

b

ritonavir oral solution: 80 mg/ml adolescents 12 years and older

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.

ritonavir oral solution: 80 mg/ml

adolescents 12 years and older

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-naive 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).

– 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

– 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) dabigatran, ticagrelor (see section 4.5).

4.4 Special warnings and precautions for use

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 a1-acid glycoprotein. This protein binding is concentration-dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products highly bound to a1-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 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 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. 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 (f) 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.

ANTIDEPRESSANTS

ENDOTHELIN RECEPTOR ANTAGONISTS

UROLOGICAL DRUGS

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

f __    …                                                                                          ,­,,,,,,,,

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.

i

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. Because of both the potential for HIV transmission and the potential for adverse reactions in breast-fed infants, mothers should be instructed not to breast-feed under any circumstances if they are receiving PREZISTA.

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

Adverse reactions observed with darunavir/cobi­cistat in adult patients

* 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.

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-naive 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: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

5.2 Pharmacokinetic properties

The pharmacokinetic properties of darunavir, co-administered with cobicistat or ritonavir, have been evaluated in healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1 infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1 infected patients compared to healthy subjects may be explained by the higher concentrations of a1-acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG and, therefore, higher plasma concentrations.

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

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

Absorption

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

The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% and increased to approximately 82% in the presence of 100 mg twice daily ritonavir. The 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 (see section 4.4).

When administered without food, the relative bioavailability of darunavir in the presence of cobicistat or low dose ritonavir is lower as compared to intake with food. Therefore, PREZISTA tablets should be taken with cobicistat or ritonavir and with food. The type of food does not affect exposure to darunavir.

Distribution

Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma <x1-acid glycoprotein.

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

Biotransformation

In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system and almost exclusively by isozyme CYP3A4. A 14C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a single 400/100 mg darunavir with ritonavir dose was due to the parent active substance. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild type HIV.

Elimination

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

The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was 32.8 l/h and 5.9 l/h, respectively.

Special populations

Paediatric population

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

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

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART-naive paediatric patients, aged 12 to < 18 years and weighing at least 40 kg, showed that PREZISTA/ritonavir 800/100 mg once daily results in darunavir exposure that was comparable to that achieved in adults receiving PREZISTA/ritonavir 800/100 mg once daily. Therefore the same once daily dosage may be used in treatment-experienced adolescents aged 12 to < 18 years and weighing at least 40 kg 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 (see section 4.2).

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

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 10 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 14 kg to < 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in adults receiving PREZISTA/ritonavir 800/100 mg once daily (see section 4.2). In addition, pharmacokinetic modeling and simulation of darunavir exposures in paediatric patients across the ages of 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and allowed the identification of weight-based PREZISTA/ritonavir once daily dosing regimens for paediatric patients weighing at least 15 kg that are either ART-naive or treatment-experienced paediatric patients without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count > 100 cells x 106/L (see section 4.2).

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

The pharmacokinetics of darunavir 800 mg co-administered with cobicistat 150 mg in paediatric patients have been studied in 7 adolescents aged 12 to less than 18 years, weighing at least 40 kg in Study GS-US-216–0128. The geometric mean adolescent exposure (AUCtau) was similar for darunavir and increased 19% for cobicistat compared to exposures achieved in adults who received darunavir 800 mg co-administered with cobicistat 150 mg in Study GS-US-216–0130. The difference observed for cobicistat was not considered clinically relevant.

a b c d

Week 24 intensive PK data from subjects who received DRV 800 mg + COBI 150 mg.

Day 10 intensive PK data from subjects who received DRV 800 mg + COBI 150 mg.

N=59 for AUCtau and Ctau.

Concentration at predose (0 hours) was used as surrogate for concentration at 24 hours for the purposes of estimating AUCtau and Ctau in Study GS-US-216–0128.

N=57 and N=5 for GLSM of Ctau in Study GS-US-216–0130 and Study GS-US-216–0128, respectively.

Elderly

Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients (n=12, age > 65) (see section 4.4). However, only limited data were available in patients above the age of65 year.

Gender

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

Renal impairment

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

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

Hepatic impairment

Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose study with PREZISTA co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the total plasma concentrations of darunavir in subjects with mild (Child-Pugh Class A, n=8) and moderate (Child-Pugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects. However, unbound darunavir concentrations were approximately 55% (Child-Pugh Class A) and 100% (Child-Pugh Class B) higher, respectively. The clinical relevance of this increase is unknown therefore, PREZISTA should be used with caution. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied (see sections 4.2, 4.3 and 4.4).

Pregnancy and postpartum

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

n=11 for AUC12h

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

In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 33%, 31% and 30% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were 29%, 32% and 50% lower, respectively, as compared with postpartum.

Treatment with darunavir/cobi­cistat 800/150 mg once daily during pregnancy results in low darunavir exposure. In women receiving darunavir/cobi­cistat during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 49%, 56% and 92% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were 37%, 50% and 89% lower, respectively, as compared with postpartum. The unbound fraction was also substantially reduced, including around 90% reductions of Cmin levels. The main cause of these low exposures is a marked reduction in cobicistat exposure as a consequence of pregnancy-associated enzyme induction (see below).

The exposure to cobicistat was lower during pregnancy, potentially leading to suboptimal boosting of darunavir. During the second trimester of pregnancy, cobicistat Cmax, AUC24h, and Cmin were 50%, 63%, and 83% lower, respectively, as compared with postpartum. During the third trimester of pregnancy, cobicistat Cmax, AUC24h, and Cmin, were 27%, 49%, and 83% lower, respectively, as compared with postpartum.

5.3 Preclinical safety data

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

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

Changes were observed in liver (hepatocyte hypertrophy, vacuolation, increased liver enzymes) and thyroid (follicular hypertrophy). In the rat, the combination of darunavir with ritonavir lead to a small increase in effect on RBC parameters, liver and thyroid and increased incidence of islet fibrosis in the pancreas (in male rats only) compared to treatment with darunavir alone. In the dog, no major toxicity findings or target organs were identified up to exposures equivalent to clinical exposure at the recommended dose.

In a study conducted in rats, the number of corpora lutea and implantations were decreased in the presence of maternal toxicity. Otherwise, there were no effects on mating or fertility with darunavir treatment up to 1,000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at the clinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir in rats and rabbits when treated alone nor in mice when treated in combination with ritonavir. The exposure levels were lower than those with the recommended clinical dose in humans. In a pre- and postnatal development assessment in rats, darunavir with and without ritonavir, caused a transient reduction in body weight gain of the offspring pre-weaning and there was a slight delay in the opening of eyes and ears. Darunavir in combination with ritonavir caused a reduction in the number of pups that exhibited the startle response on day 15 of lactation and a reduced pup survival during lactation. These effects may be secondary to pup exposure to the active substance via the milk and/or maternal toxicity. No post weaning functions were affected with darunavir alone or in combination with ritonavir. In juvenile rats receiving darunavir up to days 23–26, increased mortality was observed with convulsions in some animals. Exposure in plasma, liver and brain was considerably higher than in adult rats after comparable doses in mg/kg between days 5 and 11 of age. After day 23 of life, the exposure was comparable to that in adult rats. The increased exposure was likely at least partly due to immaturity of the drug-metabolising enzymes in juvenile animals. No treatment related mortalities were noted in juvenile rats dosed at 1,000 mg/kg darunavir (single dose) on day 26 of age or at 500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were comparable to those observed in adult rats.

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

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

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

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

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Hydroxypropyl cellulose

Microcrystalline cellulose

Carmellose sodium

Citric acid monohydrate

Sucralose

Strawberry cream flavour

Masking flavour

Sodium methyl parahydroxybenzoate (E219)

Hydrochloric acid (for pH adjustment)

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 30°C.

Do not refrigerate or freeze. Avoid exposure to excessive heat.

Store in the original container.

6.5 Nature and contents of container

Amber-coloured multiple-dose glass bottle for 200 ml suspension with a polypropylene closure with LDPE liner packaged with a 6 ml oral dosing pipette with 0.2 ml gradations. The bottle neck is filled with a low density polyethylene (LDPE) insert that accommodates the dosing pipette.

PREZISTA oral suspension is available in packs of one bottle.

6.6 Special precautions for disposal

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

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Janssen-Cilag Limited

50–100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 00242/0692

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

01/01/2021