PREZISTA^® 300 mg filmcoated tablets

Each filmcoated tablet contains 300 mg of darunavir (as ethanolate).

Excipient: Each tablet contains 1.375 mg sunset yellow FCF (E110). For a full list of excipients, see section 6.1.

Filmcoated tablet.

Orange oval shaped tablet, debossed with “300MG” on one side and “TMC114” on the other side.

PREZISTA, coadministered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV1) infection in antiretroviral treatment (ART) experienced adult patients, including those that have been highly pre-treated and for the treatment of HIV1 infection in ARTexperienced children and adolescents from the age of 6 years and at least 20 kg body weight.

In deciding to initiate treatment with PREZISTA coadministered 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.

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

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.

Adults

ARTexperienced patients

The recommended dose of PREZISTA is 600 mg twice daily (b.i.d.) taken with ritonavir 100 mg b.i.d. and with food. The type of food does not affect the exposure to darunavir (see sections 4.4, 4.5 and 5.2).

The use of only 75 mg and 150 mg tablets to achieve the recommended dose of PREZISTA in adults is appropriate when there is a possibility of hypersensitivity to specific colouring agents, or difficulty in swallowing the 300 mg or 600 mg tablets.

ARTnaïve patients

PREZISTA 300 mg tablets are not indicated for ARTnaïve patients. For dosage recommendations in ARTnaïve patients see the Summary of Product Characteristics for PREZISTA 400 mg tablets.

After therapy with PREZISTA has been initiated, patients should be advised not to alter the dosage or discontinue therapy without instruction of their physician.

Children and adolescents

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

The recommended dose of PREZISTA with low dose ritonavir for paediatric patients is based on body weight. +of 40 kg or more. For children weighing less than 40 kg, please also refer to the PREZISTA Summary of Product Characteristics of the 75 mg and 150 mg tablets.

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

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.

PREZISTA tablets should be taken with ritonavir twice daily and with food. The type of food does not affect the exposure to darunavir.

ARTexperienced children less than 6 years of age or less than 20 kg body weight, and ARTnaïve 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).

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 (ChildPugh Class A) or moderate (ChildPugh 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 (ChildPugh 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 halflife of darunavir in the presence of ritonavir and the recommended dosing interval of approximately 12 hours.

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

Patients with severe (ChildPugh 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 coadministration 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).

Coadministration 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 lifethreatening events is contraindicated. These active substances include e.g. antiarrhythmics (amiodarone, bepridil, quinidine, systemic lidocaine), 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)] and HMGCoA 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.

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.

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).

Darunavir binds predominantly to α1acid glycoprotein. This protein binding is concentration dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products highly bound to α1acid glycoprotein cannot be ruled out.

Severe skin rash, which may be accompanied with fever and/or elevations of transaminases, has occurred in 0.5% of patients treated with PREZISTA. Erythema multiforme and Stevens-Johnson Syndrome have been rarely (< 0.1%) observed. Treatment with PREZISTA should be discontinued if such a condition develops.

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

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).

Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for 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.

Patients with preexisting liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.

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 longterm 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 longterm 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 jiroveci (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 coadministered 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 coadministered 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.

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

Darunavir and ritonavir are both inhibitors of the CYP3A4 isoform. Coadministration of darunavir and ritonavir and medicinal products primarily metabolised by CYP3A4 may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.

PREZISTA coadministered with low dose ritonavir must not be combined with medicinal products that are highly dependent on CYP3A4 for clearance and for which increased systemic exposure is associated with serious and/or lifethreatening events (narrow therapeutic index). These medicinal products include amiodarone, bepridil, quinidine, systemic lidocaine, astemizole, terfenadine, 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 14fold 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 b.i.d. 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. Coadministration 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. Coadministration 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, coadministration 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). Coadministration 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 tables below.

Interaction table

Interactions between darunavir/ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors and other nonantiretroviral medicinal products are listed in the tables below (increase is indicated as “↑”, decrease as “”, no change as “↔”, not determined as “ND”, twice daily as “b.i.d.”, once daily as “q.d.” and once every other day as “q.o.d.”).

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.

Interactions – Darunavir/ritonavir with Protease Inhibitors

The efficacy and safety of the use of PREZISTA with low dose ritonavir and any other PI (e.g. (fos)amprenavir, nelfinavir and tipranavir) has not been established in HIV patients. Generally, dual therapy with protease inhibitors is not recommended.

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 coadministered 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 breastfeed 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).

No studies on the effects of PREZISTA in combination with ritonavir on the ability to drive and use machines have been performed. However, dizziness has been reported in some patients during treatment with regimens containing PREZISTA coadministered 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).

Adult patients

The adverse drug reactions are derived from Phase IIb and Phase III trials, in which a total of 1,968 treatmentexperienced patients initiated therapy with the recommended dose of PREZISTA 600 mg with ritonavir 100 mg twice daily. Median exposure to PREZISTA/ritonavir in this group was 37.3 weeks. Thirty percent of these patients experienced at least one adverse drug reaction of at least grade 2 severity. The most frequent ( 2%) of those were diarrhoea (3.9%), hypertriglyceridaemia (3.8%), rash (2.8%), nausea (2.6%), hypercholesterolaemia (2.5%) and headache (2.0%).

2.6% of the patients discontinued treatment due to adverse reactions.

Adverse reactions are listed by system organ class (SOC) and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as very common ( 1/10), common ( 1/100 to < 1/10) and uncommon ( 1/1,000 to < 1/100).

In clinical trials (n=1,968), rash (all grades, at least possibly related) occurred in 5.6% of patients treated with PREZISTA. Rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. Grade 24 rash was reported in 2.9% of patients. The discontinuation rate due to rash in patients using PREZISTA coadministered with 100 mg ritonavir was 0.5%.

Severe cases of skin rash, including erythema multiforme and StevensJohnson Syndrome (both rare) have been reported in ongoing clinical trials with PREZISTA coadministered with 100 mg ritonavir.

The safety assessment in antiretroviral treatmentnaïve adult patients (n=343) is based on all safety data from the Phase III trial ARTEMIS comparing PREZISTA/rtv 800/100 mg q.d. versus lopinavir/ritonavir 800/200 mg per day. Median exposure in the PREZISTA/ritonavir group was 56.3 weeks.

0.6% of the patients discontinued treatment due to adverse drug reactions.

In these treatment naïvepatients, the following adverse drug reactions were identified:

ADRs of at least moderate intensity and reported in more than one patient

Common: hypertriglyceridaemia, hypercholesterolaemia, headache, diarrhoea, nausea, increased alanine aminotransferase.

Uncommon: hyperlipidaemia, vomiting, abdominal pain, increased aspartate aminotransferase, rash (including maculopapular rash), allergic dermatitis, pruritus.

ADRs of all severity grades and reported in more than one patient

Very common: diarrhoea, nausea.

Common: hypertriglyceridaemia, hypercholesterolaemia, anorexia, insomnia, headache, dizziness, dysgeusia, vomiting, abdominal pain, abdominal discomfort, abdominal distension, flatulence, increased alanine aminotransferase, rash (including maculopapular, papular rash), alopecia, dry skin, pruritus, fatigue.

Uncommon: upper respiratory tract infection, diabetes mellitus, hyperlipidaemia, abnormal dreams, hypoaesthesia, disturbance in attention, somnolence, dyspepsia, eructation, increased aspartate aminotransferase, allergic dermatitis, urticaria, dermatitis, night sweats, myalgia, muscle spasms, asthenia.

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

Combination antiretroviral therapy has also been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).

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 longterm exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

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).

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

Children and adolescents

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.

Patients coinfected with hepatitis B and/or hepatitis C virus

Among 1,968 treatment-experienced patients receiving PREZISTA coadministered with ritonavir 600/100 mg b.i.d., 236 patients were coinfected with hepatitis B or C. Coinfected 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 coadministered 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 HIV1 protease (K_D of 4.5 x 10^-12M). It selectively inhibits the cleavage of HIV encoded GagPol 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 HIV1 and laboratory strains of HIV2 in acutely infected Tcell 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 HIV1 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.

The EC₅₀ value of darunavir increases by a median factor of 5.4 in the presence of human serum.

Darunavir showed synergistic antiviral activity when studied in combination with the protease inhibitors ritonavir, nelfinavir, or amprenavir and additive antiviral activity when studied in combination with the protease inhibitors indinavir, saquinavir, lopinavir, atazanavir, or tipranavir, the N(t)RTIs zidovudine, lamivudine, zalcitabine, didanosine, stavudine, abacavir, emtricitabine, or tenofovir, the NNRTIs nevirapine, delavirdine, or efavirenz and the fusion inhibitor enfuvirtide. No antagonism was observed between darunavir and any of those antiretrovirals.

Resistance

In vitro selection of darunavirresistant virus from wild type HIV1 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: 23-50fold) 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.

In vitro selection of darunavir resistant HIV1 (range: 53-641fold change in EC₅₀ values [FC]) from 9 HIV1 strains harbouring multiple PI ResistanceAssociated Mutations (RAMs) showed that a minimum of 8 darunavir in vitro selected mutations were required in the HIV1 protease to render a virus resistant (FC> 10) to darunavir.

In a pooled analysis of the POWER 1, 2 and 3 (see Clinical experience subsection) and DUET 1 and 2 (TMC125C206 and TMC125C216) trials the amino acid substitutions identified that developed on PREZISTA coadministered with ritonavir (600/100 mg b.i.d.) in 20% of the isolates from subjects who experienced virologic failure by rebound were V32I, I54L and L89V. Amino acid substitutions that developed in 10 to 20% of the isolates were V11I, I13V, L33F, I50V and F53L. Amino acid substitutions that developed in 5 to 10% of isolates were L10F, I15V, M36L, K43T, M46I, I47V, A71I, G73S, T74P, L76V, V82I and I84V.

Of the viruses isolated from patients experiencing virologic failure by rebound from the PREZISTA/rtv 600/100 mg b.i.d. group of the POWER and DUET trials, 85% of those susceptible to darunavir at baseline developed decreased susceptibility to darunavir during treatment.

In the same group of patients, 71% of viruses that were susceptible to tipranavir at baseline remained susceptible after treatment.

Crossresistance

Darunavir has a < 10fold decreased susceptibility against 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.

Clinical experience

Adult patients

Efficacy of PREZISTA coadministered with 100 mg ritonavir in treatmentnaïve patients

There are no data on the efficacy of darunavir coadministered with 100 mg ritonavir in treatmentnaïve HIV1 infected patients.

Efficacy of PREZISTA coadministered with 100 mg ritonavir in treatmentexperienced patients

The evidence of efficacy of PREZISTA coadministered with ritonavir (600/100 mg b.i.d.) in treatmentexperienced patients is based on the 48 weeks analysis of the Phase III trial TITAN in treatment-experienced lopinavir naïve patients and on the analyses of 96 weeks data from the Phase IIb trials POWER 1, 2 and 3 in patients with high level of PI resistance.

TITAN is an ongoing randomised, controlled, open-label Phase III trial comparing PREZISTA co-administered with ritonavir (600/100 mg b.i.d.) versus lopinavir/ritonavir (400/100 mg b.i.d) in treatment-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 mean baseline plasma HIV-1 RNA was 4.33 log₁₀ copies/ml and the median baseline CD4+ cell count was 235 x 10⁶ cells/l (range 3 – 831 x 10⁶ cells/l) in the PREZISTA/ritonavir arm.

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

Non-inferiority in virologic response, defined as the percentage of subjects with plasma HIV-1 RNA level < 400 copies/ml, was demonstrated (at the chosen 12% non-inferiority margin) for both Intent-To-Treat and On Protocol populations.

POWER 1 and POWER 2 are randomised, controlled trials consisting of an initial dosefinding part and a second longterm part in which all patients randomised to PREZISTA coadministered with 100 mg ritonavir received the recommended dose of 600/100 mg b.i.d.

HIV1 infected patients who were eligible for these trials had previously failed more than 1 PI containing regimen. PREZISTA coadministered with 100 mg ritonavir plus an optimised background regimen (OBR) was compared to a control group receiving an investigatorselected PI(s) regimen plus an OBR. The OBR consisted of at least 2 NRTIs with or without enfuvirtide (ENF).

POWER 3: additional data on the efficacy of PREZISTA coadministered with ritonavir 600/100 mg b.i.d. with OBR have been obtained in similar treatmentexperienced patients participating in the nonrandomised trial TMC114C215. Entry criteria were the same as and baseline characteristics were comparable to those of POWER 1 and POWER 2.

The table below shows the efficacy data of the 48week analyses on the recommended 600 mg dose of PREZISTA coadministered with 100 mg ritonavir b.i.d. from the pooled POWER 1 and POWER 2 trials as well as from the POWER 3 trial.

^a Noncompleter is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0

^b Last Observation Carried Forward imputation

^c Imputations according to the TLOVR algorithm

^d 95% confidence intervals.

Analyses of data through 96 weeks of treatment in the three POWER trials demonstrated sustained antiretroviral efficacy and immunological benefit. Treatment with PREZISTA coadministered with ritonavir (600/100 mg b.i.d.) resulted in 56.5% (POWER 1 and 2) and 52.2% (POWER 3) of responders with a decrease of at least 1 log10 in HIV RNA from baseline, 38.9% (POWER 1 and 2) and 42.1% (POWER 3) of subjects with an HIV RNA level < 50 copies/ml and 49.6% (POWER 1 and 2) and 50.0% (POWER 3) respectively of subjects with an HIV RNA level less than 400 copies/ml. The mean decrease in HIV RNA level compared to baseline was 1.58 (POWER 1 and 2) and 1.43 (POWER 3) log10 copies/ml and a mean increase in CD4+ cell count of 133 x 10⁶ cells/l (POWER 1 and 2) and 103 x 10⁶ cells/l (POWER 3) was observed.

Out of the 206 subjects who responded with complete viral suppression (< 50 copies/ml) at week 48, 177 subjects (86% of the responders at week 48) remained responders at week 96.

Baseline genotype or phenotype and virologic outcome

In a pooled analysis of the 600/100 mg b.i.d. groups of the POWER and DUET trials, the presence at baseline of 3 or more of mutations V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V was associated with a decreased virologic response to PREZISTA coadministered with 100 mg ritonavir. The presence of these individual mutations was associated with a median of 13 to 15 PI resistance associated mutations of the IASUSA list of mutations.

In early treatment-experienced patients (TITAN) three or more of these mutations were only found in 4% of the patients at baseline.

Response (HIV1 RNA < 50 copies/ml at week 24) to PREZISTA coadministered with ritonavir (600/100 mg b.i.d.) by baseline genotype* and by use of enfuvirtide (ENF): As treated analysis of the POWER and DUET trials.

* 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)

Baseline darunavir phenotype (shift in susceptibility relative to reference) was shown to be a predictive factor of virologic outcome.

Response (HIV1 RNA < 50 copies/ml at week 24) to PREZISTA coadministered with ritonavir (600/100 mg b.i.d.) by baseline darunavir phenotype and by use of enfuvirtide: As treated analysis of the POWER and DUET trials.

Children from the age of 6 years and adolescents

DELPHI is an openlabel, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of PREZISTA with low dose ritonavir in 80 ARTexperienced HIV1 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 HIV1 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 weightbased ritonavir dose without changes in observed safety.

According to the TLOVR nonvirologic failure censored algorithm 24 (30.0%) subjects experienced virological failure, of which 17 (21.3%) subjects were rebounders and 7 (8.8%) subjects were nonresponders.

The pharmacokinetic properties of darunavir, coadministered with ritonavir, have been evaluated in healthy adult volunteers and in HIV1 infected patients. Exposure to darunavir was higher in HIV1 infected patients than in healthy subjects. The increased exposure to darunavir in HIV1 infected patients compared to healthy subjects may be explained by the higher concentrations of alpha1acid glycoprotein (AAG) in HIV1 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 b.i.d. ritonavir. The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14fold 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 b.i.d. (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 alpha1acid 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 twicedaily 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 ¹⁴Cdarunavir 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 10fold less than the activity of darunavir against wild type HIV.

Elimination

After a 400/100 mg ¹⁴Cdarunavir with ritonavir dose, approximately 79.5% and 13.9% of the administered dose of ¹⁴Cdarunavir 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 halflife 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

Paediatrics

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 b.i.d. (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 ¹⁴Cdarunavir 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 coadministered with ritonavir (600/100 mg) twice daily, it was demonstrated that the total plasma concentrations of darunavir in subjects with mild (ChildPugh Class A, n=8) and moderate (ChildPugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects. However, unbound darunavir concentrations were approximately 55% (ChildPugh Class A) and 100% (ChildPugh 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 repeateddose 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 cellrelated 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 preweaning 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 drugmetabolising 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. Doserelated 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 0.7fold (mice) and 0.7 and 1fold (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 filmcoat

Poly (vinyl alcohol) – partially hydrolyzed

Macrogol 3350

Titanium dioxide (E171)

Talc

Sunset yellow FCF (E110)

Not applicable.

2 years

This medicinal product does not require any special storage conditions.

Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 120 tablets, fitted with polypropylene (PP) child resistant closure.

One bottle

No special requirements.

JanssenCilag International NV

Turnhoutseweg 30

B2340 Beerse

Belgium

EU/1/06/380/001

Date of first authorisation: 12 February 2007

Date of latest renewal: 12 February 2009

23^rd June 2009

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.