Prezista 100mg per ml suspension

Approval of variation type II - WS2342- crystal nephropathy + CHMP-requested text on HIV transmission and breastfeeding - day 27 - 7Dec2022

Approval of variation type II - WS2342- crystal nephropathy + CHMP-requested text on HIV transmission and breastfeeding - day 27 - 7Dec2022

EU Approval EMEA/H/C/707/WS/2250

EU Approval EMEA/H/C/707/WS/2250

Section 4.5          Interaction with other medicinal products and other forms of interaction

Interaction table

Table 1:                Interactions between the individual components of Prezista and other medicinal   products

Corticosteroids - updated to address co-administration of cutaneous administered corticosteroids sensitive to CYP3A inhibition in section 4.5 (interaction table)

Updates are in red

Deleted: “for intranasal or inhalation use”

               “e.g. fluticasone propionate or other inhaled or nasal corticosteroids ”

Section 2.            What you need to know before you take PREZISTA

The effects of other medicines might be influenced if you take PREZISTA. Tell your doctor if you take:

• Corticosteroids including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone. These medicines are used to treat allergies, asthma, inflammatory bowel diseases, inflammatory conditions of the skin, eyes, joints and muscles and other inflammatory conditions. These medicines are generally taken orally, inhaled, injected or applied to the skin. If alternatives cannot be used, its use should only take place after medical evaluation and under close monitoring by your doctor for corticosteroid side effects.
   
  Updates are in red
  Last revision date : 09/2021

4.1     Therapeutic indications

PREZISTA, co‑administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV‑1) infection in adult and paediatric patients from the age of 3 years and at least 15 kg body weight (see section 4.2).

PREZISTA, co‑administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV‑1) infection in adults and adolescents (aged 12 years and older, weighing at least 40 kg) patients (see section 4.2).

4.2     Posology and method of administration

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.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as pharmacokinetic enhancer. Darunavir may therefore have different contraindications and recommendations for concomitant medications depending on whether the compound is boosted with ritonavir or cobicistat (see sections 4.3, 4.4 and 4.5).

Posology

PREZISTA must always be given orally with cobicistat or low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of cobicistat or ritonavir as appropriate, must therefore be consulted prior to initiation of therapy with PREZISTA. Cobicistat is not indicated for use in twice daily regimens or for use in the paediatric population less than 12 years of age and weighing less than 40 kg.

ART‑naïve adult patients

The recommended dose regimen is 800 mg once daily with cobicistat 150 mg once daily or ritonavir 100 mg once daily taken with food.

ART‑experienced adult patients

The recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food.

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

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

If HIV‑1 genotype testing is not available, the recommended dose regimen is PREZISTA 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food.

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

The weight‑based dose of PREZISTA and taken with ritonavir or cobicistat taken with food in paediatric patients is provided in the table below. The dose of cobicistat to be used with PREZISTA in children less than 18 12 years of age has not been established.

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

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

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

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

The weight‑based dose of PREZISTA and taken with ritonavir or cobicistat in paediatric patients is provided in the table below. The recommended dose of PREZISTA with low dose ritonavir should not exceed the recommended adult dose (600/100 mg twice daily or 800/100 mg once daily). The dose of PREZISTA with cobicistat in adolescent patients 12 years of age and older weighing at least 40 kg is 800/150 mg once daily taken with food. The dose of cobicistat to be used with PREZISTA in children less than 18 12 years of age has not been established.

For ART‑experienced paediatric patients HIV genotypic testing is recommended. However, when HIV genotypic testing is not feasible, the PREZISTA/ (taken with ritonavir or cobicistat) once daily dosing regimen is recommended in HIV protease inhibitor‑naïve paediatric patients and the PREZISTA taken with ritonavir twice daily dosing regimen is recommended in HIV protease inhibitor‑experienced patients.

If a patient vomits within 4 hours of taking the medicine, another dose of PREZISTA with cobicistat or ritonavir should be taken with food as soon as possible. If a patient vomits more than 4 hours after taking the medicine, the patient does not need to take another dose of PREZISTA with cobicistat or ritonavir until the next regularly scheduled time.

Paediatric population

PREZISTA should not be used in children

-                 below 3 years of age, because of safety concerns (see sections 4.4 and 5.3), or,

-                 less than 15 kg body weight, as the dose for this population has not been established in a sufficient number of patients (see section 5.1).

PREZISTA taken with cobicistat should not be used in children aged 3 to 11 years of age weighing < 40 kg as the dose of cobicistat to be used in these children has not been established (see sections 4.4 and 5.3).

The weight-based dose regimen for PREZISTA and ritonavir is provided in the tables above. The dose of cobicistat to be used with PREZISTA has not been established in this patient population.

4.4     Special warnings and precautions for use

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 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).

4.5     Interaction with other medicinal products and other forms of interaction

Medicinal products that affect darunavir exposure (cobicistat as pharmacoenhancer)

Darunavir and cobicistat are metabolised by CYP3A, and co‑administration with CYP3A inducers may therefore result in subtherapeutic plasma exposure to darunavir. Darunavir boosted with cobicistat is more sensitive to CYP3A induction than ritonavir‑boosted darunavir: co‑administration of darunavir/cobicistat with medicinal products that are strong inducers of CYP3A (e.g. St John’s wort, rifampicin, carbamazepine, phenobarbital, and phenytoin) is contraindicated (see section 4.3). Co‑administration of darunavir/cobicistat with weak to moderate CYP3A inducers (e.g. efavirenz, etravirine, nevirapine, boceprevir, fluticasone, and bosentan) is not recommended (see interaction table below).

4.8     Undesirable effects

Paediatric population

The safety assessment of PREZISTA with ritonavir in paediatric patients is based on the 48‑week analysis of safety data from three Phase II trials. The following patient populations were evaluated (see section 5.1):

·                80 ART‑experienced HIV‑1 infected paediatric patients aged from 6 to 17 years and weighing at least 20 kg who received PREZISTA tablets with low dose ritonavir twice daily in combination with other antiretroviral agents.

·                21 ART‑experienced HIV‑1 infected paediatric patients aged from 3 to < 6 years and weighing 10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received PREZISTA oral suspension with low dose ritonavir twice daily in combination with other antiretroviral agents.

·                12 ART‑naïve HIV‑1 infected paediatric patients aged from 12 to 17 years and weighing at least 40 kg who received PREZISTA tablets with low dose ritonavir once daily in combination with other antiretroviral agents (see section 5.1).

Overall, the safety profile in these paediatric patients was similar to that observed in the adult population.

The safety assessment of PREZISTA with cobicistat in paediatric patients was evaluated in adolescents aged 12 to less than 18 years, weighing at least 40 kg through the clinical trial GS‑US‑216‑0128 (treatment‑experienced, virologically suppressed, N=7). Safety analyses of this study in adolescent subjects did not identify new safety concerns compared to the known safety profile of darunavir and cobicistat in adult subjects.

Other special populations

5.1     Pharmacodynamic properties

PREZISTA/ritonavir 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/lL (see section 4.2 and 4.4). Limited data is available in patients with HIV‑1 clades other than B.

6.       Contents of the pack and other information

What PREZISTA contains

• The active substance is darunavir. Each milliliter contains 100 milligram of darunavir (as ethanolate).
• The other ingredients are hydroxypropylcellulose, microcrystalline cellulose and carmellose sodium, citric acid monohydrate, sucralose, strawberry cream flavour, masking flavour, sodium methyl parahydroxybenzoate (E219), hydrocholoric acid (for pH adjustment), purified water.
• This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ‘sodium-free’.

What PREZISTA looks like and contents of the pack

White to off‑white opaque oral suspension. Provided in a 200 ml amber glass bottle with polypropylene child resistant closure and a 6 ml low density polyethylene (LDPE) oral dosing pipette with 0.2 ml gradations. The bottle neck is filled with a low density polyethylene (LDPE) insert that accommodates the dosing pipette. Do not use the oral dosing pipette for any other medicines.

PREZISTA is also available as 75 milligram, 150 milligram, 300 milligram, 400 milligram, 600 milligram and 800 milligram film‑coated tablets.

4.2          Posology and method of administration

PREZISTA oral suspension can be used in patients unable to swallow PREZISTA tablets. PREZISTA is also available as 75 mg, 150 mg, 300 mg, 400 mg, 600 mg and 800 mg film‑coated tablets.

4.4     Special warnings and precautions for use

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

zolpidem zoldipem

4.3     Contraindications   Added    dabigatran,
 
4.5     Interaction with other medicinal products and other forms of interaction

4.4     Special warnings and precautions for use

Immune reactivation syndrome

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

4.8     Undesirable effects

Immune reconstitution inflammatory syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

4.4     Special warnings and precautions for use 

Immune reactivation syndrome

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

Update to preganancy information. Warning that therapy with PREZISTA/cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with PREZISTA/cobicistat should be switched to an alternative regimen.

Insufficient space in document history to add all text update.

4.2     Posology and method of administration

Cobicistat inhibits the tubular secretion of creatinine and may cause modest increases in serum creatinine and modest declines in creatinine clearance. Hence, the use of creatinine clearance as an estimate of renal elimination capacity may be misleading. Cobicistat as a pharmacokinetic enhancer of darunavir should, therefore, not be initiated in patients with creatine clearance less than 70 ml/min if any co‑administered agent requires dose adjustment based on creatinine clearance: e.g. emtricitabine, lamivudine, tenofovir disoproxil (as fumarate, phosphate or succinate)fumarate or adefovir dipovoxil.

4.3     Contraindications

-                 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)

-                 elbasvir/grazoprevir (hepatitis C virus direct-acting antiviral)

-                 cisapride (gastrointestinal motility agents)

-                 lurasidone, 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, lomitapide (HMG‑CoA reductase inhibitors) (see section 4.5)

-                 ticagrelor (antiplatelets) (see section 4.5).

4.4     Special warnings and precautions for use

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 boosted 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, 300 mg andor 600 mg tablets (see section 4.5).

4.5     Interaction with other medicinal products and other forms of interaction

4.9     Overdose

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.

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.

10.     DATE OF REVISION OF THE TEXT

22 June 201715 February 2018

Section 4.5. Interaction with other medicinal products and other forms of interaction

Dolutegravir:

dolutegravir AUC ↓ 3222%

dolutegravir C24h ↓ 38%

dolutegravir Cmax ↓ 11%

darunavir ↔*

* Using cross_study comparisons to historical pharmacokinetic data

Elvitegravir:

elvitegravir AUC ↔

elvitegravir Cmin ↔

elvitegravir Cmax ↔

darunavir AUC ↔

darunavir Cmin ↓17%

darunavir Cmax ↔

Section 5.2: Pharmacokinetic properties

Table: Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 600/100 mg twice daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum

b     excluding Cmin value below LLOQ, n=10 for reference postpartum

4.2     Posology and method of administration

Pregnancy and postpartum

No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. Prezista should be used during pregnancy only if the potential benefit justifies the potential risk (see sections 4.4, 4.6 and 5.2).

4.4     Special warnings and precautions for use

Pregnancy

Prezista should be used during pregnancy only if the potential benefit justifies the potential risk. Caution should be used in pregnant women with concomitant medications which may further decrease darunavir exposure (see sections 4.5 and 5.2).

4.6     Fertility, pregnancy and lactation

Pregnancy

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account.

There are no adequate and well controlled studies on pregnancy outcome with darunavir in pregnant women. Studies in animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

PREZISTA co‑administered with cobicistat or low dose ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk.

4.8     Undesirable effects

5.1     Pharmacodynamic properties

Pregnancy and postpartum

Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a background regimen was evaluated in a clinical trial of 34 pregnant women (17 in each arm) during the second and third trimesters, and postpartum. Virologic response was preserved throughout the study period in both arms. No mother to child transmission occurred in the infants born to the 29 subjects who stayed on the antiretroviral treatment through delivery. There were no new clinically relevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV 1 infected adults (see sections 4.2, 4.4 and 5.2).

5.2     Pharmacokinetic properties

Pregnancy and postpartum

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

In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of pregnancy, mean intra‑individual values for total darunavir C_max, AUC_12h and C_min were 28%, 24% and 17% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir C_max, AUC_12h and C_min values were 19%, 17% lower and 2% higher, respectively, as compared with postpartum.

In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of pregnancy, mean intra‑individual values for total darunavir C_max, AUC_12h and C_min were 34%, 34% and 32% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir C_max, AUC_12h and C_min values were 31%, 35% and 50% lower, respectively, as compared with postpartum.

Major revision of SmPC,

Notable changes once daily dosing in Paediatrics.

Option to use cobicistat as a booster in patients  18 years and older.

Addition drug-drug interactions

Adverse effects experienced with cobicistat combination

4.4          Special warnings and precautions for use

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

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.

ART‑naïve paediatric patients (12 to 17 years of age and weighing at least 40 kilograms).

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

In paediatric patients 12 to 17 years of age and weighing at least 40 kg with prior exposure to antiretroviral medicinal products but without 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.

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

Administration of PREZISTA 800 mg once daily in treatment‑naïve adolescents 12 to 17 years weighing at least 40 kg leads to darunavir exposures within the therapeutic range as established in adults receiving the same dosing regimen. Since PREZISTA 800 mg 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 800 mg once daily applies to treatment‑experienced adolescents 12 to 17 years weighing at least 40 kg.

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

4.4          Special warnings and precautions for use

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.

 4.8 undesirable effects – change to frequency category for some ADRs

Addition of DRESS and reporting ADR statements