Prezista 800mg film-coated tablets

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 patients with human immunodeficiency virus (HIV‑1) infection.

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).

PREZISTA 400 mg and 800 mg tablets may be used to provide suitable dose regimens for the treatment of HIV‑1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are:

• antiretroviral therapy (ART)‑naïve (see section 4.2).
• ART‑experienced 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/lL. In deciding to initiate treatment with PREZISTA in such ART‑experienced patients, genotypic testing should guide the use of PREZISTA (see sections 4.2, 4.3, 4.4 and 5.1).
   
  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 weighing less than 40 kg.
  ART‑naïve adult patients
  The recommended dose regimen is 800 mg once daily taken with cobicistat 150 mg once daily or ritonavir 100 mg once daily taken with food. PREZISTA 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.
   
  ART‑experienced adult patients
  The recommended dose regimens are as follows:
• In ART‑experienced patients with no darunavir resistance associated mutations (DRV‑RAMs)* and who have plasma HIV‑1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/l L (see section 4.1) a regimen of 800 mg once daily with cobicistat 150 mg once daily or ritonavir 100 mg once daily taken with food may be used. PREZISTA 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.
• In all other ART‑experienced patients or if HIV‑1 genotype testing is not available, the recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food. See the Summary of Product Characteristics for PREZISTA 100 mg/ml oral suspension, 75 mg, 150 mg or 600 mg tablets.
  *   DRV‑RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
   
  ART‑naïve paediatric patients (3 to 17 years of age and weighing at least 40 kg)
  The recommended dose regimen is 800 mg once daily with ritonavir 100 mg once daily taken with food or 800 mg once daily with cobicistat 150 mg once daily taken with food (in adolescent patients 12 years of age or older). PREZISTA 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen. 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 40 kg)
  The dose of cobicistat to be used with PREZISTA in children less than 18 12 years of age has not been established.
   
  The recommended dose regimens are as follows:
  In ART‑experienced patients without DRV‑RAMs* and who have plasma HIV‑1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/l L (see section 4.1) a regimen of 800 mg once daily with ritonavir 100 mg once daily taken with food or 800 mg once daily with cobicistat 150 mg once daily taken with food (in adolescent patients 12 years of age or older) may be used. PREZISTA 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen The dose of cobicistat to be used with PREZISTA in children less than 12 years of age has not been established.
  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 paediatric patients below 3 years of age or less than 15 kg body weight (see sections 4.4 and 5.3).

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).
   
  ART‑naïve paediatric patients (3 to 17 years of age and weighing at least 40 kg)
  The recommended dose regimen is 800 mg once daily with ritonavir 100 mg once daily taken with food.
   
  ART‑experienced paediatric patients (3 to 17 years of age and weighing at least 40 kg)
  In ART‑experienced patients without DRV‑RAMs* and who have plasma HIV‑1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/l, a 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
   
  Paediatric patients (3 to 17 years of age and weighing less than 40 kg)
  ThePREZISTA 400 and 800 mg tablets are not suitable for this patient population. Other formulations are available, see the Summary of Product Characteristics for PREZISTA 75 mg, 150 mg, 600 mg tablets and 100 mg/ml oral suspension.
   
  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).
  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 and 600 mg tablets (see section 4.5).
   
  Life‑threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and P‑glycoprotein (P‑gp; see sections 4.3 and 4.5).
   
  PREZISTA 400 mg tablets contain sunset yellow FCF (E110) which may cause an allergic reaction.
   
  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).
  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 darunavir/ritonavir, which may be attributed to the presence of low dose ritonavir. Co‑administration of darunavir and ritonavir with 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 with 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.

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.
   
  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/l L (see section 4.2 and 4.4). Limited data is available in patients with HIV‑1 clades other than B.
  In the open‑label, Phase II/III trial GS‑US‑216‑0128, the efficacy, safety, and pharmacokinetics of darunavir 800 mg and cobicistat 150 mg (administered as separate tablets) and at least 2 NRTIs were evaluated in 7 HIV‑1 infected, treatment‑experienced, virologically suppressed adolescents weighing at least 40 kg. Patients were on a stable antiretroviral regimen (for at least 3 months), consisting of darunavir administered with ritonavir, combined with 2 NRTIs. They were switched from ritonavir to cobicistat 150 mg once daily and continued darunavir (N=7) and 2 NRTIs.
   

5.2     Pharmacokinetic properties

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART‑naïve paediatric patients, aged 12 to < 18 years and weighing at least 40 kg, showed that PREZISTA/ritonavir 800/100 mg once daily results in darunavir exposure that was comparable to that achieved in adults receiving PREZISTA/ritonavir 800/100 mg once daily. Therefore the same once daily dosage may be used in treatment‑experienced adolescents aged 12 to < 18 years and weighing at least 40 kg 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 L (see section 4.2).

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 10 treatment‑experienced paediatric patients, aged 3 to < 6 years and weighing at least 14 kg to < 20 kg, showed that weight‑based dosages resulted in darunavir exposure that was comparable to that achieved in adults receiving PREZISTA/ritonavir 800/100 mg once daily (see section 4.2). In addition, pharmacokinetic modeling and simulation of darunavir exposures in paediatric patients across the ages of 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and allowed the identification of weight‑based PREZISTA/ritonavir once daily dosing regimens for paediatric patients weighing at least 15 kg that are either ART‑naïve or treatment‑experienced paediatric patients without DRV‑RAMs* and who have plasma HIV‑1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/lL (see section 4.2).

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

The pharmacokinetics of darunavir 800 mg co‑administered with cobicistat 150 mg in paediatric patients have been studied in 7 adolescents aged 12 to less than 18 years, weighing at least 40 kg in Study GS‑US‑216‑0128. The geometric mean adolescent exposure (AUC_tau) was similar for darunavir and increased 19% for cobicistat compared to exposures achieved in adults who received darunavir 800 mg co‑administered with cobicistat 150 mg in Study GS‑US‑216‑0130. The difference observed for cobicistat was not considered clinically relevant.

6.6     Special precautions for disposal

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

3.       How to take PREZISTA

Always use this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has told you. Check with your doctor, pharmacist or nurse if you are not sure.

Even if you feel better, do not stop taking PREZISTA and cobicistat or ritonavir without talking to your doctor.

After therapy has been initiated, the dose or dosage form must not be changed or therapy must not be stopped without instruction of the doctor.

PREZISTA 800 milligram tablets are intended for once daily use only.

Dose for adults who have not taken antiretroviral medicines before (your doctor will determine this)

The usual dose of PREZISTA is 800 milligram (2 tablets containing 400 milligram of PREZISTA or 1 tablet containing 800 milligram of PREZISTA) once daily.

You must take PREZISTA every day and always in combination with 150 milligram of cobicistat or 100 milligram of ritonavir and with food. PREZISTA cannot work properly without cobicistat or ritonavir and food. You must eat a meal or a snack within 30 minutes prior to taking your PREZISTA and cobicistat or ritonavir. The type of food is not important. Even if you feel better, do not stop taking PREZISTA and cobicistat or ritonavir without talking to your doctor.

Instructions for adults

• Take one 800 milligram tablet at the same time, once a day, every day.
• Take PREZISTA always together with 150 milligram of cobicistat or 100 milligram of ritonavir.
• Take PREZISTA with food.
• Swallow the tablet with a drink such as water or milk.
• Take your other HIV medicines used in combination with PREZISTA and cobicistat or ritonavir as recommended by your doctor.
• PREZISTA 100 milligram per milliliter oral suspension has been developed for use in children, but can also be used in adults in some cases.
   
  Dose for adults who have taken antiretroviral medicines before (your doctor will determine this)
  The dose is either:
• 800 milligram PREZISTA (2 tablets containing 400 milligram of PREZISTA or 1 tablet containing 800 milligram of PREZISTA) together with 150 milligram cobicistat or 100 milligram ritonavir once daily.
  OR
• 600 milligram PREZISTA (2 tablets containing 300 milligram of PREZISTA or 1 tablet containing 600 milligram of PREZISTA) together with 100 milligram ritonavir twice daily.
   
  Please discuss with your doctor which dose is right for you.
   
  Dose for children 3 years of age and above, weighing more than 40 kilograms who have not taken antiretroviral medicines before (your child’s doctor will determine this)
• The usual dose of PREZISTA is 800 milligram (2 tablets containing 400 milligram of PREZISTA or 1 tablet containing 800 milligram of PREZISTA) together with 100 milligram ritonavir once daily.
   
  Dose for children 3 years of age and above, weighing more than 40 kilograms who have taken antiretroviral medicines before (your child’s doctor will determine this)
  The dose is either:
• 800 milligram PREZISTA (2 tablets containing 400 milligram of PREZISTA or 1 tablet containing 800 milligram of PREZISTA) together with 100 milligram ritonavir once daily.
  OR
• 600 milligram PREZISTA (2 tablets containing 300 milligram of PREZISTA or 1 tablet containing 600 milligram of PREZISTA) together with 100 milligram ritonavir twice daily.
   
  Please discuss with your doctor which dose is right for you.

What PREZISTA looks like and contents of the pack

Film‑coated, dark red, oval shaped tablet, mentioning T on one side, 800 on the other side. 30 tablets in a plastic bottle. The PREZISTA 800 milligram tablets are available in packs containing one bottle or three bottles per carton.

Not all pack sizes may be marketed.

PREZISTA is also available as 75 milligram, 150 milligram, 300 milligram, 400 milligram and 600 milligram film‑coated tablets and 100 milligram per milliliter oral suspension.

4.2     Posology and method of administration

ART‑experienced adult patients

The recommended dose regimens are as follows:

• In ART‑experienced patients with no darunavir resistance associated mutations (DRV‑RAMs)* and who have plasma HIV‑1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/l (see section 4.1) a regimen of 800 mg once daily with cobicistat 150 mg once daily or ritonavir 100 mg once daily taken with food may be used. PREZISTA 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.
• In all other ART‑experienced patients or if HIV‑1 genotype testing is not available, the recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food. See the Summary of Product Characteristics for PREZISTA 100 mg/ml oral suspension, 75 mg, 150 mg, 300 mg or 600 mg tablets.
   
  The recommended dose regimens are as follows:
• In ART‑experienced patients without DRV‑RAMs* and who have plasma HIV‑1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/l (see section 4.1) a regimen of 800 mg once daily with ritonavir 100 mg once daily taken with food may be used. PREZISTA 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.
• In all other ART‑experienced patients or if HIV‑1 genotype testing is not available, the recommended dose regimen is described in the Summary of Product Characteristics for PREZISTA 100 mg/ml oral suspension,75 mg, 150 mg, 300 mg and 600 mg tablets.
   
  Paediatric patients (3 to 17 years of age and weighing less than 40 kg)
  The 400 and 800 mg tablets are not suitable for this patient population. Other formulations are available, see the Summary of Product Characteristics for PREZISTA 75 mg, 150 mg, 300 mg, 600 mg tablets and 100 mg/ml oral suspension.
   
  4.4     Special warnings and precautions for use
   
  Efavirenz in combination with 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).
   
  5.1     Pharmacodynamic properties
   
  Paediatric patients
   
  ART‑naïve paediatric patients from the age of 12 years to < 18 years, and weighing at least 40 kg
  DIONE is an open‑label, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of PREZISTA with low dose ritonavir in 12 ART‑naïve HIV‑1 infected paediatric patients aged 12 to less than 18 years and weighing at least 40 kg. These patients received PREZISTA/ritonavir 800/100 mg once daily in combination with other antiretroviral agents. Virologic response was defined as a decrease in plasma HIV‑1 RNA viral load of at least 1.0 log₁₀ versus baseline.
   

For additional clinical study results in ART‑experienced adults and paediatric patients, refer to the Summary of Product Characteristics for PREZISTA 75 mg, 150 mg, 300 mg or 600 mg tablets and 100 mg/ml oral suspension.

• zolpidem zoldipem (sedative agents)

4.2       Posology and method of administration

Paediatric population

PREZISTA should not be used in paediatric patients below 3 years of age or less than 15 kg body weight (see sections 4.4 and 5.3).

ART‑naïve paediatric patients (3 to 17 years of age and weighing at least 40 kg)

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

ART‑experienced paediatric patients (3 to 17 years of age and weighing at least 40 kg)

In ART‑experienced patients without DRV‑RAMs* and who have plasma HIV‑1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/l, a 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

Paediatric patients (3 to 17 years of age and weighing less than 40 kg)

The 400 and 800 mg tablets are not suitable for this patient population. Other formulations are availableFor dosage recommendations in children, see the Summary of Product Characteristics for PREZISTA 75 mg, 150 mg, 300 mg, 600 mg tablets and 100 mg/ml oral suspension.

The dose of cobicistat to be used with PREZISTA has not been established in this patient population.

4.5     Interaction with other medicinal products and other forms of interaction

6.3     Shelf life

PREZISTA 400 mg film‑coated tablets

3 years

PREZISTA 800 mg film‑coated tablets

2 3 years

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).

Pregnancy update: 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

Changes due to combining 400mg and 800mg strengths plus

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 and 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 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

Medicinal products that affect darunavir exposure (ritonavir as pharmacoenhancer)

….

Co‑administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir, which may result in increased plasma concentrations of darunavir and ritonavir. Co‑administration with strong CYP3A4 inhibitors is not recommended and caution is warranted, these interactions are described in the interaction table below (e.g. indinavir, systemic azole antifungalss like ketoconazole and clotrimazole).

Medicinal products that may be affected by darunavir boosted with ritonavir

…

The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14‑fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily. Cobicistat 150 mg given with darunavir 800 mg once daily enhances darunavir pharmacokinetic parameters in a comparable way to ritonavir (see section 5.2).Therefore, darunavir must only be used in combination with a pharmacokinetic enhancer (see sections 4.4 and 5.2).

4.9          Overdose

Human experience of acute overdose with PREZISTA co‑administered with cobicistat or 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.

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.

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

indications

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

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

4.5     Interaction with other medicinal products and other forms of interaction

4.8     Undesirable effects

Adverse reactions with darunavir/cobicistat in adult patients

4.1     Therapeutic indications

PREZISTA 400 mg tablets may be used to provide suitable dose regimens for the treatment of HIV‑1 infection in adult and paediatric patients from the age of 312 years and at least 40 kg body weight who are:

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.