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.

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 75 mg, 150 mg and 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

• For 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, a dose regimen of 800 mg once daily with ritonavir 100 mg once daily taken with food may be used.

• In all other ART-experienced adults 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. PREZISTA 75 mg and 150 mg tablets can be used to construct the twice daily 600 mg regimen. The use of 75 mg or 150 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 is based on body weight and 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).

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 eva luated 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 eva luation for physical signs of fat redistribution. Consideration should be given to measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

Osteonecrosis

Although the 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 eva luated and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical studies with PREZISTA co-administered with low dose ritonavir.

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 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 400 mg and 600 mg tablets 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.