PREZISTA 75 mg film-coated tablets

PREZISTA 150 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).

600 mg film-coated tablet:

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

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

For the full list of excipients, see section 6.1.

Film-coated tablets.

75 mg tablets:

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

150 mg tablets:

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

600 mg tablets:

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 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 paediatric patients from the age of 3 years and at least 15 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.

Therapy should be initiated by a health care provider experienced in the management of HIV infection. After therapy with PREZISTA has been initiated, patients should be advised not to alter the dosage, dose form or discontinue therapy without discussing with their health care provider.

Posology

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.

PREZISTA is also available as an oral suspension for use in patients who are unable to swallow PREZISTA tablets (please refer to the Summary of Product Characteristics for PREZISTA oral suspension).

ART-experienced adult patients

The recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food. PREZISTA 75 mg, 150mg and 600 mg tablets can be used to construct the twice daily 600 mg regimen.

The use of 75 and 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 600 mg tablets.

A dose regimen of 800 mg once daily with cobicistat 150 mg once daily or ritonavir 100 mg once daily taken with food may be used in patients with prior exposure to antiretroviral medicinal products but without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/l (see the Summary of Product Characteristics for PREZISTA 400 mg and 800 mg tablets).

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

ART-naïve adult patients

For dosage recommendations in ART-naïve patients see the Summary of Product Characteristics for PREZISTA 400 mg and 800 mg tablets.

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

The weight-based dose of PREZISTA and ritonavir in paediatric patients is provided in the table below.

^a ritonavir oral solution: 80 mg/ml

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

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

A once daily dose regimen of PREZISTA taken with ritonavir taken with food may be used in patients with prior exposure to antiretroviral medicinal products but without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/l.

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

The recommended dose of PREZISTA with low dose ritonavir for paediatric patients is based on body weight and should not exceed the recommended adult dose (600/100 mg twice daily or 800/100 mg once daily).

^a with ritonavir oral solution: 80 mg/ml

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

The use of only 75 mg and 150 mg tablets or the 100 mg/ml oral suspension to achieve the recommended dose of PREZISTA could be appropriate when there is a possibility of hypersensitivity to specific colouring agents.

Advice on missed doses

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 after 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.

Special populations

Elderly

Limited information is available in this population, and therefore, PREZISTA should be used with caution in this age group (see sections 4.4 and 5.2).

Hepatic impairment

Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, however, PREZISTA should be used with caution in these patients. No pharmacokinetic data are available in patients with severe hepatic impairment. Severe hepatic impairment could result in an increase of darunavir exposure and a worsening of its safety profile. Therefore, PREZISTA must not be used in patients with severe hepatic impairment (Child-Pugh Class C) (see sections 4.3, 4.4 and 5.2).

Renal impairment

No dose adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).

Paediatric patients

PREZISTA/ritonavir should not be used in children with a body weight of less than 15 kg as the dose for this population has not been established in a sufficient number of patients (see section 5.1). PREZISTA/ritonavir should not be used in children below 3 years of age because of safety concerns (see sections 4.4 and 5.3).

Darunavir exposures in treatment-naïve adolescents 12 to 17 years weighing at least 40 kg receiving PREZISTA 800 mg once daily have been determined and were found to be within the therapeutic range as has been established in adults receiving PREZISTA 800 mg once daily. As a consequence, since PREZISTA once daily has also been registered for use in treatment-experienced adults without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/l, the same indication of PREZISTA once daily applies to treatment-experienced children 3 to 17 years weighing at least 15 kg.

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

Method of administration

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).

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

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

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

Co-administration with the combination product lopinavir/ritonavir (see section 4.5).

Co-administration with herbal preparations containing St John's wort (Hypericum perforatum) (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. These active substances include e.g.:

- alfuzosin (alpha 1-adrenoreceptor antagonist)

- amiodarone, bepridil, dronedarone, quinidine, ranolazine, systemic lidocaine (antiarrhythmics/antianginals)

- astemizole, terfenadine (antihistamines)

- colchicine when used in patients with renal and/or hepatic impairment (antigout) (see section 4.5)

- ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)

- cisapride (gastrointestinal motility agent)

- pimozide, quetiapine, sertindole (antipsychotics/neuroleptics) (see section 4.5)

- triazolam, midazolam administered orally (sedatives/hypnotics) (for caution on parenterally administered midazolam, see section 4.5)

- sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil (PDE-5 inhibitors)

- simvastatin and lovastatin (HMG-CoA reductase inhibitors) (see section 4.5)

- ticagrelor (antiplatelets) (see section 4.5).

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

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

PREZISTA 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 used in combination with cobicistat or low dose ritonavir once daily in ART-experienced patients should not be used in patients with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA ≥ 100,000 copies/ml or CD4+ cell count < 100 cells x 10⁶/l (see section 4.2). Combinations with optimised background regimen (OBRs) other than ≥ 2 NRTIs have not been studied in this population. Limited data are available in patients with HIV-1 clades other than B (see section 5.1).

Paediatric population

PREZISTA is not recommended for use in paediatric patients below 3 years of age or less than 15 kg body weight (see sections 4.2 and 5.3).

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. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermal necrolysis and acute generalised exanthematous pustulosis have been reported. PREZISTA/ritonavir should be discontinued immediately if signs or symptoms of severe skin reactions develop. These can include, but are not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.

Rash occurred more commonly in treatment-experienced patients receiving regimens containing PREZISTA + 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. During the clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving combination antiretroviral therapy with PREZISTA/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.

Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of PREZISTA/ritonavir treatment.

If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients using PREZISTA/ritonavir, interruption or discontinuation of treatment should be considered promptly.

Patients with coexisting conditions

Hepatic impairment

The safety and efficacy of PREZISTA have not been established in patients with severe underlying liver disorders and PREZISTA is therefore contraindicated in patients with severe hepatic impairment. Due to an increase in the unbound darunavir plasma concentrations, PREZISTA should be used with caution in patients with mild or moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).

Renal impairment

No special precautions or dose adjustments 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 aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Immune reconstitution inflammatory syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be 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.

Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.8).

Interactions with medicinal products

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

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

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

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and P-glycoprotein (P-gp; see sections 4.3 and 4.5).

Interaction studies have only been performed in adults.

Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of darunavir and ritonavir and medicinal products primarily metabolised by CYP3A and/or CYP2D6 or transported by P-gp may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.

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) (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/ritonavir, 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 PREZISTA /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.

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