PREZISTA 75 mg film-coated tablets

PREZISTA 150 mg film-coated tablets

PREZISTA 400 mg film-coated tablets

PREZISTA 600 mg film-coated tablets

75 mg film-coated tablet:

Each film-coated tablet contains 75 mg of darunavir (as ethanolate).

150 mg film-coated tablet:

Each film-coated tablet contains 150 mg of darunavir (as ethanolate).

400 mg film-coated tablet:

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

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

600 mg film-coated tablet:

Each film-coated tablet contains 600 mg of darunavir (as ethanolate).

Excipient: Each tablet contains 2.750 mg sunset yellow FCF (E110).

For a full list of excipients, see section 6.1.

Film-coated tablet.

Film-coated tablet.

White caplet shaped tablet of 9.2 mm, debossed with “75” on one side and “TMC” on the other side.

White oval shaped tablet of 13.7 mm, debossed with “150” on one side and “TMC” on the other side.

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

Orange oval shaped tablet of 21.1 mm, debossed with “600MG” on one side and “TMC” on the other side.

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

PREZISTA 75mg, 150mg, 600 mg tablets may be used to provide suitable dose regimens (see section 4.2):

• For the treatment of HIV-1 infection in antiretroviral treatment (ART) experienced adult patients, including those that have been highly pre-treated.

• For the treatment of HIV-1 infection in ART-experienced children and adolescents from the age of 6 years and at least 20 kg body weight.

In deciding to initiate treatment with PREZISTA co-administered with 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.

PREZISTA 400 mg tablets may be used to provide suitable dose regimens (see section 4.2):

• For the treatment of HIV-1 infection in antiretroviral therapy (ART) naïve adults.

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

Therapy should be initiated by a physician experienced in the management of HIV infection. After therapy with PREZISTA has been initiated, patients should be advised not to alter the dosage or discontinue therapy without instruction of their physician.

PREZISTA must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of ritonavir must therefore be consulted prior to initiation of therapy with PREZISTA.

Patients should be instructed to take PREZISTA with 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).

Adults

ART-experienced patients

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

• In all other ART-experienced patients or if HIV-1 genotype testing is not available, the recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food. The use of 75 mg tablets to achieve the recommended dose is appropriate when there is a possibility of hypersensitivity to specific colouring agents, or difficulty in swallowing the 300 mg or 600 mg tablets.

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

ART-naïve patients

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

Paediatric population

ART-experienced paediatric patients (6 to 17 years of age and weighing at least 20 kg)

The recommended dose of PREZISTA with low dose ritonavir should not exceed the recommended adult dose (600/100 mg twice daily).

The use of only 75 mg and 150 mg tablets to achieve the recommended dose of PREZISTA could be appropriate when there is a possibility of hypersensitivity to specific colouring agents.

ART-experienced children less than 6 years of age or less than 20 kg body weight, and ART-naïve paediatric patients

There are insufficient data on the use of PREZISTA with low dose ritonavir in children less than 6 years of age or less than 20 kg body weight. Hence, PREZISTA is not recommended for use in this group (see sections 4.4 and 5.3).

PREZISTA 400mg is not indicated for ART-naïve children and adolescents

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 in patients with renal impairment (see sections 4.4 and 5.2).

In case a dose of PREZISTA and/or ritonavir was 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 was noticed later than 6 hours of the time it is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.

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

If an 800/100 mg once daily dose of PREZISTA/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 ritonavir with food as soon as possible. If this is noticed later than 12 hours of the time it is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.

This guidance is based on the 15 hour half-life of darunavir in the presence of ritonavir and the recommended dosing interval of approximately 24 hours.

Hypersensitivity to the active substance or to any of the excipients.

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

Combination of rifampicin with PREZISTA with concomitant low dose ritonavir is contraindicated (see section 4.5).

The combination product lopinavir/ritonavir should not be used with PREZISTA because co-administration causes large decreases in darunavir concentrations, which may in turn significantly decrease the darunavir therapeutic effect (see section 4.5).

Herbal preparations containing St John's wort (Hypericum perforatum) must not be used while taking PREZISTA due to the risk of decreased plasma concentrations and reduced clinical effects of darunavir (see section 4.5).

Co-administration of PREZISTA with low dose ritonavir, with active substances that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. These active substances include e.g. antiarrhythmics (amiodarone, bepridil, quinidine, systemic lidocaine), alfuzosin, antihistamines (astemizole, terfenadine), ergot derivatives (e.g. dihydroergotamine, ergonovine, ergotamine, methylergonovine), gastrointestinal motility agents (cisapride), neuroleptics (pimozide, sertindole), sedatives/hypnotics [triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5)], sildenafil (when used for the treatment of pulmonary arterial hypertension) and HMG-CoA reductase inhibitors (simvastatin and lovastatin) (see section 4.5).

Patients should be advised that current antiretroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be employed.

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

PREZISTA should only be used in combination with low dose ritonavir as a pharmacokinetic enhancer (see section 5.2).

Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect darunavir concentrations and is not recommended.

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/rtv 800/100 mg 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). The efficacy and safety of PREZISTA/rtv 800/100 mg once daily in combination with optimised background regimen (OBR) for the treatment of HIV-1 infection in ART-experienced adults with no darunavir resistance associated mutations (DRV-RAMs) was evaluated in one trial with a duration of 48 weeks. Combinations with OBRs other than 2 NRTIs have not been studied in this population. Limited data is available in patients with HIV-1 clades other than B (see section 5.1).

Paediatric population

PREZISTA is not recommended for use in children below 6 years of age or less than 20 kg body weight (see sections 4.2 and 5.3).

Elderly

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

Severe skin reactions

During the 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. Stevens-Johnson Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermal necrolysis has been reported. Discontinue PREZISTA/rtv immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with 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 + raltegravir compared to patients receiving PREZISTA 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/rtv. During the clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving combination antiretroviral therapy with PREZISTA/rtv. 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 events. 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/rtv 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/rtv 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/rtv, 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 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).

Haemophiliac patients

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

Diabetes mellitus/Hyperglycaemia

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

Fat redistribution and metabolic disorders

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

Osteonecrosis

Although the etiology 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 reactivation syndrome

In HIV infected patients with severe immune deficiency at the time of institution 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.

Interactions with medicinal products

Several of the interaction studies have been performed at lower than recommended doses of darunavir. 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.

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

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and Pgp (see section 4.5).

PREZISTA tablets (400mg and 600mg) contain sunset yellow FCF (E110) which may cause an allergic reaction.

Darunavir and ritonavir are both inhibitors of the CYP3A isoform. Co-administration of darunavir and ritonavir and medicinal products primarily metabolised by CYP3A may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.

PREZISTA 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). These medicinal products include amiodarone, bepridil, quinidine, systemic lidocaine, astemizole, alfuzosin, terfenadine, sildenafil (when used for the treatment of pulmonary arterial hypertension), midazolam administered orally, triazolam, cisapride, pimozide, sertindole, simvastatin, lovastatin and the ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine and methylergonovine) (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, PREZISTA must only be used in combination with low dose ritonavir as a pharmacokinetic enhancer (see sections 4.4 and 5.2).

A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and inhibition of CYP2D6 activity in the presence of PREZISTA/rtv, which may be attributed to the presence of low dose ritonavir. Co-administration of darunavir and ritonavir and medicinal products which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result in increased plasma concentrations of these medicinal products, which could increase or prolong their therapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir and medicinal products primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.

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

Medicinal products that affect darunavir/ritonavir exposure

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 darunavir and ritonavir (e.g. rifampicin, St John's wort, lopinavir). Co-administration of darunavir and ritonavir and other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (e.g. indinavir, systemic azoles like ketoconazole and clotrimazole). These interactions are described in the interaction table below.

Interaction table

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

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

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

There are no adequate and well controlled studies 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.

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).

PREZISTA in combination with 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 low dose ritonavir and should be borne in mind when considering a patient's ability to drive or operate machinery (see section 4.8).

The overall safety profile of PREZISTA is based on all available clinical trial and post-marketing data, and is consistent with the data below.

a. Summary of the safety profile

During the clinical development program (N=1,968 treatment-experienced subjects who initiated therapy with PREZISTA/rtv 600/100 mg twice daily), 49.5% of subjects experienced at least one adverse reaction. The total mean treatment duration for subjects was 48.58 weeks. For treatment-naïve patients, see the information below the table. The most frequent adverse reactions reported in clinical trials and as spontaneous reports are diarrhoea, immune reconstitution syndrome, nausea, pyrexia and rash. The most frequent serious reactions are diarrhoea, hepatitis, immune reconstitution syndrome, pyrexia and rash.

b. Tabulated summary 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 in clinical trials and post-marketing in adult patients

¹ see section 4.4

² see section 4.8 c)

³ In clinical studies of treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing PREZISTA + raltegravir compared to those containing PREZISTA without raltegravir or raltegravir without PREZISTA. 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).

In the 96 week analysis, the safety profile of PREZISTA/rtv 800/100 mg once daily in treatment-naïve subjects was similar to that seen with PREZISTA/rtv 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-naive subjects in which the mean treatment duration of PREZISTA/rtv 800/100 mg once daily was 162.5 weeks.

c. 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.

Lipodystrophy

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see section 4.4).

Metabolic abnormalities

Combination antiretroviral therapy has also been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (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 syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (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).

d. Paediatric population

The safety assessment in children and adolescents is based on the safety data from the Phase II trial DELPHI in which 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at least 20 kg received PREZISTA with low dose ritonavir in combination with other antiretroviral agents (see section 5.1).

Overall, the safety profile in these 80 children and adolescents was similar to that observed in the adult population.

e. 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).

Human experience of acute overdose with PREZISTA co-administered with 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. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

Pharmacotherapeutic group: Antiviral for systemic use, ATC code: J05AE10.

Mechanism of action

Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease (K_D of 4.5 x 10^-12M). It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus infected cells, thereby preventing the formation of mature infectious virus particles.

Antiviral activity in vitro

Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages with median EC₅₀ values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/ml). Darunavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M (A, B, C, D, E, F, G) and group O primary isolates with EC₅₀ values ranging from < 0.1 to 4.3 nM.

These EC₅₀ values are well below the 50% cellular toxicity concentration range of 87 µM to > 100 µM.

Resistance

In vitro selection of darunavir-resistant virus from wild type HIV-1 was lengthy (> 3 years). The selected viruses were unable to grow in the presence of darunavir concentrations above 400 nM. Viruses selected in these conditions and showing decreased susceptibility to darunavir (range: 23-50-fold) harboured 2 to 4 amino acid substitutions in the protease gene. Identification of determinants of decreased susceptibility to darunavir in those viruses is under investigation.

The clinical trial data from ART-experienced patients (TITAN trial and the pooled analysis of the POWER 1, 2 and 3 and DUET 1 and 2 trials) showed that virologic response to PREZISTA co-administered with low dose ritonavir was decreased when 3 or more darunavir RAMs (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V and L89V) were present at baseline or when these mutations developed during treatment.

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

Viruses isolated from patients on PREZISTA/rtv 600/100 mg twice daily experiencing virologic failure by rebound that were susceptible to tipranavir at baseline remained susceptible to tipranavir after treatment in the vast majority of cases.

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

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

^a TLOVR non-VF censored algorithm based on HIV-1 RNA < 50 copies/ml, except for TITAN (HIV-1 RNA < 400 copies/ml)

^b IAS-USA lists

Cross-resistance

Darunavir FC was less than 10 for 90% of 3,309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to most PIs remain susceptible to darunavir.

In the virologic failures of the ARTEMIS trial no cross-resistance with other PIs was observed.

Clinical results

Adult patients

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

The evidence of efficacy of PREZISTA/ritonavir 800/100 mg once daily is based on the analyses of 192 week data from the randomised, controlled, open-label Phase III trial ARTEMIS in antiretroviral treatment-naïve HIV-1 infected patients comparing PREZISTA/ritonavir 800/100 mg once daily with lopinavir/ritonavir 800/200 mg per day (given as a twice-daily or as a once-daily regimen). Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily and emtricitabine 200 mg once daily.

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

^a Data based on analyses at week 48

^b Data based on analyses at week 96

^c Imputations according to the TLOVR algorithm

^d Based on normal approximation to the difference in % response

^e Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0

Non-inferiority in virologic response to the PREZISTA/ritonavir treatment, defined as the percentage of patients with plasma HIV-1 RNA level < 50 copies/ml, was demonstrated (at the pre-defined 12% non-inferiority margin) for both Intent-To-Treat (ITT) and On Protocol (OP) populations in the 48 week analysis. These results were confirmed in the analyses of data at 96 weeks of treatment in the ARTEMIS trial. These results were sustained up to 192 weeks of treatment in the ARTEMIS trial.

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

ODIN is a Phase III, randomised, open-label trial comparing PREZISTA/rtv 800/100 mg once daily versus PREZISTA/rtv 600/100 mg twice daily in ART-experienced HIV-1 infected patients with screening genotype resistance testing showing no darunavir RAMs (i.e. V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, L89V) and a screening HIV-1 RNA > 1,000 copies/ml. Efficacy analysis is based on 48 weeks of treatment (see table below). Both arms used an optimised background regimen (OBR) of 2 NRTIs.

^a Imputations according to the TLOVR algorithm

^b Based on a normal approximation of the difference in % response

^c Clades A1, D, F1, G, K, CRF02_AG, CRF12_BF, and CRF06_CPX

^d Difference in means

^e Last Observation Carried Forward imputation

At 48 weeks, virologic response, defined as the percentage of patients with plasma HIV-1 RNA level < 50 copies/ml, with PREZISTA/ritonavir 800/100 mg once daily treatment was demonstrated to be non-inferior (at the pre-defined 12% non-inferiority margin) compared to PREZISTA/ritonavir 600/100 mg twice daily for both ITT and OP populations.

PREZISTA/rtv 800/100 mg 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 and 4.4). Limited data is available in patients with HIV-1 clades other than B.

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

The evidence of efficacy of PREZISTA co-administered with ritonavir (600/100 mg twice daily) in ART-experienced patients is based on the 96 weeks analysis of the Phase III trial TITAN in ART-experienced lopinavir naïve patients, on the 48 week analysis of the Phase III trial ODIN in ART-experienced patients with no DRV-RAMs, and on the analyses of 96 weeks data from the Phase IIb trials POWER 1 and 2 in ART-experienced patients with high level of PI resistance.

TITAN is a randomised, controlled, open-label Phase III trial comparing PREZISTA co-administered with ritonavir (600/100 mg twice daily) versus lopinavir/ritonavir (400/100 mg twice daily) in ART-experienced, lopinavir naïve HIV-1 infected adult patients. Both arms used an Optimised Background Regimen (OBR) consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs).

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

^a Imputations according to the TLOVR algorithm

^b Based on a normal approximation of the difference in % response

^c NC=F

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

POWER 1 and POWER 2 are randomised, controlled trials comparing PREZISTA co-administered with ritonavir (600/100 mg twice daily) with a control group receiving an investigator-selected PI(s) regimen in HIV-1 infected patients who had previously failed more than 1 PI containing regimen. An OBR consisting of at least 2 NRTIs with or without enfuvirtide (ENF) was used in both trials.

The table below shows the efficacy data of the 48-week and 96-week analyses from the pooled POWER 1 and POWER 2 trials.

^a Imputations according to the TLOVR algorithm

^b Last Observation Carried Forward imputation

^c 95% confidence intervals.

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

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

Baseline genotype or phenotype and virologic outcome

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

Proportion (%) of patients with response (HIV-1 RNA < 50 copies/ml at week 24) to PREZISTA co-administered with ritonavir (600/100 mg twice daily) by baseline genotype^a, and baseline darunavir FC and by use of enfuvirtide (ENF): As treated analysis of the POWER and DUET trials.

^a Number of mutations from the list of mutations associated with a diminished response to PREZISTA/ritonavir (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V)

^b fold change in EC₅₀

^c “Patients with no/non-naïve use of ENF” are patients who did not use ENF or who used ENF but not for the first time

^d “Patients with naïve use of ENF” are patients who used ENF for the first time

Children from the age of 6 years and adolescents

DELPHI is an open-label, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of PREZISTA with low dose ritonavir in 80 ART-experienced HIV-1 infected paediatric patients aged 6 to 17 years and weighing at least 20 kg. These patients received PREZISTA/ritonavir in combination with other antiretroviral agents (see section 4.2 for dosage recommendations per body weight). Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1.0 log₁₀ versus baseline.

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

^a Imputations according to the TLOVR algorithm.

^b Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0.

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

The European Medicines Agency has deferred the obligation to submit the results of studies with PREZISTA in one or more subsets of the paediatric population in Human immunodeficiency virus infection, as per PIP decision in the granted indication. See section 4.2 for information on paediatric use.

The pharmacokinetic properties of darunavir, co-administered with 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 alpha-1-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. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir considerably.

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 low dose ritonavir is 30% lower as compared to intake with food. Therefore, PREZISTA tablets should be taken with 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 alpha-1-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.

Metabolism

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 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).

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 of 65 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).

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.

Tablet core

Microcrystalline cellulose

Colloidal anhydrous silica

Crospovidone

Magnesium stearate

Tablet film-coat

Poly(vinyl alcohol) – partially hydrolyzed

Macrogol 3350

Titanium dioxide (E171)

Talc

Sunset yellow FCF (E110) (400mg and 600mg tablets only)

Not applicable.

2 years

This medicinal product does not require any special storage conditions.

75mg tablets

Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 480 tablets, fitted with polypropylene (PP) child resistant closure.

One bottle

150mg tablets

Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 240 tablets, fitted with polypropylene (PP) child resistant closure.

One bottle

400mg tablets

Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 60 tablets, fitted with polypropylene (PP) child resistant closure.

One bottle

600mg tablets

Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 60 tablets, fitted with polypropylene (PP) child resistant closure.

One bottle

No special requirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/06/380/005

EU/1/06/380/004

EU/1/06/380/003

EU/1/06/380/002

Date of first authorisation: 12 February 2007

Date of latest renewal: 12 February 2009

April 2012

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.