Prezista 800mg film-coated tablets

  • Name:

    Prezista 800mg film-coated tablets

  • Company:
    info
  • Active Ingredients:

    darunavir ethanolate

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 20/05/20

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Summary of Product Characteristics last updated on medicines.ie: 15/5/2020

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Janssen Sciences Ireland

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 20 May 2020 PIL

Reasons for updating

  • Change to section 3 - how to take/use
  • Change to section 6 - what the product looks like and pack contents
  • Change to section 6 - date of revision

Free text change information supplied by the pharmaceutical company

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.

Updated on 15 May 2020 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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 Cmin. 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.
     

DIONE

Outcomes at week 48

PREZISTA/ritonavir

N=12

HIV‑1 RNA < 50 copies/mla

83.3% (10)

CD4+ percent change from baselineb

14

CD4+ cell count mean change from baselineb

221

≥ 1.0 log10 decrease from baseline in plasma viral load

100%

a    Imputations according to the TLOVR algorithm.

b    Non‑completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0.

 

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.

Updated on 12 March 2020 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 2 March 2020 PIL

Reasons for updating

  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - date of revision

Free text change information supplied by the pharmaceutical company

  • zolpidem zoldipem (sedative agents)

Updated on 2 March 2020 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

 

SEDATIVES/HYPNOTICS

Buspirone

Clorazepate

Diazepam

Estazolam

Flurazepam

Midazolam (parenteral)

ZolpidemZoldipem

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Midazolam (oral)

Triazolam

Not studied. Sedative/hypnotics are extensively metabolised by CYP3A. Co‑administration with boosted PREZISTA may cause a large increase in the concentration of these medicines.

 

 

 

If parenteral midazolam is co‑administered with boosted PREZISTA it may cause a large increase in the concentration of this benzodiazepine. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3‑4 fold increase in midazolam plasma levels.

Clinical monitoring is recommended when co‑administering boosted PREZISTA with these sedatives/hypnotics and a lower dose of the sedatives/hypnotics should be considered.

 

If parenteral midazolam is co‑administered with boosted PREZISTA, it should be done in an intensive care unit (ICU) or similar setting, which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.

 

Boosted PREZISTA with triazolam or oral midazolam is contraindicated (see section 4.3)

 

6.3     Shelf life

 

PREZISTA 400 mg film‑coated tablets

3 years

 

PREZISTA 800 mg film‑coated tablets

years

Updated on 10 May 2019 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 9 May 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - what the product contains
  • Change to section 6 - date of revision

Updated on 27 November 2018 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - date of revision

Updated on 27 November 2018 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.3     Contraindications

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

ANTICOAGULANTS/PLATELET AGGREGATION INHIBITOR

Apixaban

Edoxaban

Dabigatran etexilate

Rivaroxaban

Not studied. Co‑administration of boosted PREZISTA with these anticoagulants may increase concentrations of the anticoagulant, which may lead to an increased bleeding risk.

(CYP3A and/or P‑gp inhibition)

The use of boosted PREZISTA and these anticoagulants is not recommended.

Dabigatran

Ticagrelor

Not studied. Coadministration with boosted PREZISTA may lead to a substantial increase in exposure to dabigatran or ticagrelor.

Concomitant administration of boosted PREZISTA with dabigatran or ticagrelor is contraindicated (see section 4.3).

 

Use of other antiplatelets not affected by CYP inhibition or induction (e.g. prasugrel) is recommended.

 

 

 

 

HEPATITIS C VIRUS (HCV) DIRECT‑ACTING ANTIVIRALS

 

NS3‑4A protease inhibitors

Glecaprevir/pibrentasvir

Based on theoretical considerations boosted PREZISTA may increase the exposure to glecaprevir and pibrentasvir.

(Pgp, BCRP and/or OATP1B1/3 inhibition)

It is not recommended to coadminister boosted PREZISTA with glecaprevir/pibrentasvir.

 

 

  •  

Updated on 30 October 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Removal/change of distributor

Updated on 29 October 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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).

Updated on 29 October 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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).

 

Updated on 17 July 2018 PIL

Reasons for updating

  • Change to section 2 - pregnancy, breast feeding and fertility
  • Change to section 6 - date of revision

Updated on 17 July 2018 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 26 March 2018 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.9 - Overdose
  • Change to section 10 - Date of revision of the text
  • Change from individual to joint SPC

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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 Cmin. 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).

 

Elvitegravir

elvitegravir AUC ↔

elvitegravir Cmin

elvitegravir Cmax

darunavir AUC ↔

darunavir Cmin ↓ 17%

darunavir Cmax

When PREZISTA co‑administered with low dose ritonavir (600/100 mg twice daily) is used in combination with elvitegravir, the dose of elvitegravir should be 150 mg once daily.

 

PREZISTA co‑administered with cobicistat should not be used in combination with another antiretroviral that requires pharmacoenhancement since dosing recommendations for such combination have not been established.

 

The pharmacokinetics and dosing recommendations for other doses of darunavir or with elvitegravir/cobicistat have not been established. Therefore, co‑administration of PREZISTA with low dose ritonavir in doses other than 600/100 mg twice daily and elvitegravir is not recommended. Co‑administration of PREZISTA with low dose ritonavir and elvitegravir in the presence of cobicistat is not recommended.

 

 

Tenofovir disoproxil fumarate

245300 mg once daily

tenofovir AUC ↑ 22%

tenofovir Cmin ↑ 37%

tenofovir Cmax ↑ 24%

#darunavir AUC ↑ 21%

#darunavir Cmin ↑ 24%

#darunavir Cmax ↑ 16%

(↑ tenofovir from effect on MDR‑1 transport in the renal tubules)

Monitoring of renal function may be indicated when boosted PREZISTA is given in combination with tenofovir disoproxil, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.

 

PREZISTA co‑administered with cobicistat lowers the creatinine clearance. Refer to section 4.4 if creatinine clearance is used for dose adjustment of tenofovir disoproxil.

Emtricitabine/tenofovir alafenamide

Tenofovir alafenamide  

Tenofovir ↑

The recommended dose of emtricitabine/tenofovir alafenamide is 200/10 mg once daily when used with boosted PREZISTA.

 

 

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide

Flecainide

Lidocaine (systemic)

Mexiletine

Propafenone

 

 

 

 

Amiodarone

Bepridil

Dronedarone

Lidocaine (systemic)

Quinidine

Ranolazine

Not studied. Boosted PREZISTA is expected to increase these antiarrhythmic plasma concentrations.

(CYP3A and/or CYP2D6 inhibition)

Caution is warranted and therapeutic concentration monitoring, if available, is recommended for these antiarrhythmics when co‑administered with boosted PREZISTA.

 

Boosted PREZISTA and amiodarone, bepridil, dronedarone, systemic lidocaine, quinidine, or ranolazine is contraindicated (see section 4.3).

 

 

Clonazepam

Not studied. Co‑administration of boosted PREZISTA with clonazepam may increase concentrations of clonazepam. (CYP3A inhibition)

Clinical monitoring is recommended when co‑administering boosted PREZISTA and clonazepam.

 

 

Ketoconazole

200 mg twice daily

ketoconazole AUC ↑ 212%

ketoconazole Cmin ↑ 868%

ketoconazole Cmax ↑ 111%

#darunavir AUC ↑ 42%

#darunavir Cmin ↑ 73%

#darunavir Cmax ↑ 21%

(CYP3A inhibition)

Caution is warranted and clinical monitoring is recommended when combined with boosted PREZISTA. When co‑administration is required the daily dose of ketoconazole should not exceed 200 mg.

Fluconazole

Isavuconazole

Itraconazole

Posaconazole

 

 

 

 

Clotrimazole

Not studied. Boosted PREZISTA may increase antifungal plasma concentrations (P‑gp inhibition) and posaconazole, isavuconazole, itraconazole  or fluconazole may increase darunavir concentrations.

(CYP3A and/or P‑gp inhibition)

 

Not studied. Concomitant systemic use of clotrimazole and boosted PREZISTA may increase plasma concentrations of darunavir and/or clotrimazole.

darunavir AUC24h ↑ 33% (based on population pharmacokinetic model)

 

Caution is warranted and clinical monitoring is recommended.

 When co‑administration is required the daily dose of itraconazole should not exceed 200 mg.

Itraconazole

Not studied. Concomitant systemic use of itraconazole and boosted PREZISTA may increase plasma concentrations of darunavir and itraconazole.

(CYP3A and/or P‑gp inhibition)

Caution is warranted and clinical monitoring is recommended when combined with boosted PREZISTA. When co‑administration is required the daily dose of itraconazole should not exceed 200 mg.

Clotrimazole

Not studied. Concomitant systemic use of clotrimazole and boosted PREZISTA may increase plasma concentrations of darunavir and/or clotrimazole.

darunavir AUC24h ↑ 33% (based on population pharmacokinetic model)

Caution is warranted and clinical monitoring is recommended, when co‑administration of clotrimazole is required.

 

 

Telaprevir

750 mg every 8 hours

telaprevir AUC ↓ 35%

telaprevir Cmin ↓ 32%

telaprevir Cmax ↓ 36%

darunavir AUC12 ↓ 40%

darunavir Cmin ↓ 42%

darunavir Cmax ↓ 40%

It is not recommended to co‑administer boosted PREZISTA and telaprevir.

 

 

Atorvastatin

10 mg once daily

atorvastatin AUC ↑ 3‑4 fold

atorvastatin Cmin5.5‑10 fold

atorvastatin Cmax ↑ ≈2 fold

#darunavir/ritonavir

 

atorvastatin AUC ↑ 290% Ω

atorvastatin Cmax ↑ 319% Ω

atorvastatin Cmin ND Ω

Ω with darunavir/cobicistat 800/150 mg

 

When administration of atorvastatin and boosted PREZISTA is desired, it is recommended to start with an atorvastatin dose of 10 mg once daily. A gradual dose increase of atorvastatin may be tailored to the clinical response.

 

 

OTHER LIPID MODIFYING AGENTS

Lomitapide

Based on theoretical considerations boosted PREZISTA is expected to increase the exposure of lomitapide when co-administered.

(CYP3A inhibition)

Co-administration is contraindicated (see section 4.3)

 

 

Fentanyl

Oxycodone

Tramadol

Based on theoretical considerations boosted PREZISTA may increase plasma concentrations of these analgesics.

(CYP2D6 and/or CYP3A inhibition)

Clinical monitoring is recommended when co‑administering boosted PREZISTA with these analgesics.

OESTROGEN‑BASED CONTRACEPTIVES

Drospirenone Ethinylestradiol (3 mg/0.02 mg once daily)

 

 

 

 

Ethinylestradiol

Norethindrone

35 mg/1 mg once daily

drospirenone AUC ↑ 58%

drospirenone Cmin ND

drospirenone Cmax ↑ 15%

ethinylestradiol AUC ¯ 30%

ethinylestradiol Cmin ND

ethinylestradiol Cmax ¯ 14%

with darunavir/cobicistat

 

ethinylestradiol AUC ↓ 44%β

ethinylestradiol Cmin ↓ 62%β

ethinylestradiol Cmax ↓ 32%β

norethindrone AUC ↓ 14%β

norethindrone Cmin 30%β

norethindrone Cmaxβ

β with darunavir/ritonavir

When PREZISTA is coadministered with a drospirenone-containing product, clinical monitoring is recommended due to the potential for hyperkalaemia.

 

Alternative or additional contraceptive measures are recommended when oestrogen‑based contraceptives are co‑administered with boosted PREZISTA. Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.

 

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.

 

Updated on 26 March 2018 SmPC

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  • New SmPC for new product

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Updated on 23 March 2018 PIL

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  • New PIL for new product

Updated on 23 March 2018 PIL

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  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - date of revision

Updated on 10 July 2017 SmPC

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  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
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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

 

Updated on 5 July 2017 PIL

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  • Change to section 2 - use in children and adolescents
  • Change to section 6 - date of revision

Updated on 27 March 2017 SmPC

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  • Change to section 4.3 - Contraindications
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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

 

 

 

 

α1-ADRENORECEPTOR ANTAGONIST

Alfuzosin

Based on theoretical considerations PREZISTA is expected to increase alfuzosin plasma concentrations.

(CYP3A inhibition)

Co-administration of PREZISTA with low dose ritonavir and alfuzosin is contraindicated (see section 4.3).

 

Risperidone

Thioridazine

 

 

 

Lurasidone

Pimozide

Sertindole

Not studied. PREZISTA is expected to increase these antipsychotic plasma concentrations.

(CYP3A, CYP2D6 inhibition and/or P‑gp)

A dose decrease may be needed for these drugs when co‑administered with PREZISTA co‑administered with low dose ritonavir.

 

Concominant administration of PREZISTA with low dose ritonavir and lurasidone, pimozide or sertindole is contraindicated (see section 4.3).

 

CORTICOSTEROIDS

Corticosteroids primarily metabolised by CYP3A (including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone)Fluticasone

Budesonide

Fluticasone: Iin a clinical study where ritonavir 100 mg capsules twice daily were co‑administered with 50 mg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, fluticasone propionate plasma concentrations increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% CI 82‑89%). Greater effects may be expected when fluticasone is inhaled. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone; this could also occur with other corticosteroids metabolised via the P4503A pathway, e.g., budesonide. The effects of high fluticasone systemic exposure on ritonavir plasma levels are unknown.

 

Other corticosteroids: interaction not studied. Plasma concentrations of these medicinal products may be increased when co-administered with PREZISTA with low dose ritonavir, resulting in reduced serum cortisol concentrations.

Concomitant use of PREZISTA with low dose ritonavir and corticosteroids that are metabolised by CYP3A (e.g. fluticasone propionate or other inhaled or nasal corticosteroids) may increase the risk of development of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression.

Co-administration with CYP3A-metabolised corticosteroids is not recommended unless the potential benefit to the patient outweighs the risk, in which case patients should be monitored for systemic corticosteroid effects.

Alternative corticosteroids which are less dependent on CYP3A metabolism e.g. beclomethasone for intranasal or inhalational use should be considered, particularly for long term use.Concomitant administration of PREZISTA co‑administered with low dose ritonavir and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid which is not a substrate for CYP3A (e.g., beclomethasone). Moreover, in case of withdrawal of glucocorticoids, progressive dose reduction may have to be performed over a longer period.

 

Prednisone

Not studied. Darunavir may increase plasma concentrations of prednisone.

(CYP3A inhibition)

Concomitant use of PREZISTA with low dose ritonavir and prednisone may increase the risk for development of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression. Clinical monitoring is recommended when co‑administering PREZISTA with low dose ritonavir with corticosteroids.

 

Elbasvir/grazoprevir

PREZISTA with low dose ritonavir may increase the exposure to grazoprevir.

(CYP3A and OATP1B inhibition)

Concomitant use of PREZISTA with low dose ritonavir and elbasvir/grazoprevir is contraindicated (see section 4.3).

 

4.8     Undesirable effects

 

 

Adverse reactions with darunavir/cobicistat in adult patients

 

Musculoskeletal and connective tissue disorders

 

common

myalgia, osteonecrosis*

 

 

uncommon

osteonecrosis*

Updated on 27 March 2017 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - date of revision

Updated on 2 February 2016 SmPC

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  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
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$04.4     Special warnings and precautions for use$0$0 $0$0Diabetesmellitus/hyperglycaemia$0$0New onset diabetes mellitus, hyperglycaemia, orexacerbation of existing diabetes mellitus has been reported in patientsreceiving antiretroviral therapy, including PIs. In some of these patients thehyperglycaemia was severe and in some cases also associated with ketoacidosis.Many patients had confounding medical conditions some of which required therapywith agents that have been associated with the development of diabetes mellitusor hyperglycaemia.$0$0 $0$0Fatredistribution and metabolic disorders$0$0Combination antiretroviral therapy has beenassociated with redistribution of body fat (lipodystrophy) in HIV infectedpatients. The long‑term consequences of these events are currently unknown.Knowledge about the mechanism is incomplete. A connection between viscerallipomatosis and PIs and lipoatrophy and NRTIs has been hypothesised. A higherrisk of lipodystrophy has been associated with individual factors such as olderage and with drug related factors such as longer duration of antiretroviraltreatment and associated metabolic disturbances. Clinical examination shouldinclude evaluation for physical signs of fat redistribution. Considerationshould be given to measurement of fasting serum lipids and blood glucose. Lipiddisorders should be managed as clinically appropriate (see section 4.8).$0$0 $0$0Weight and metabolic parameters$0$0An increase in weight and in levels of blood lipidsand glucose may occur during antiretroviral therapy. Such changes may in partbe linked to disease control and life style. For lipids, there is in some casesevidence for a treatment effect, while for weight gain there is no strongevidence relating this to any particular treatment. For monitoring of bloodlipids and glucose reference is made to established HIV treatment guidelines.Lipid disorders should be managed as clinically appropriate.$0$0 $0$0 $0$0 $0$04.8     Undesirable effects$0$0 $0$0$0$0$0$0Metabolism andnutrition disorders$0$0$0$0$0$0common$0$0$0$0lipodystrophy (including lipohypertrophy,lipodystrophy, lipoatrophy), diabetes mellitus,hypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemia$0$0 $0$0$0$0$0$0uncommon$0$0$0$0gout, anorexia, decreased appetite, decreased weight,increased weight, hyperglycaemia, insulin resistance, decreased high densitylipoprotein, increased appetite, polydipsia, increased blood lactatedehydrogenase$0$0$0$0$0$0 $0$0 $0$0 $0$0Lipodystrophy$0$0Combination antiretroviral therapy has beenassociated with redistribution of body fat (lipodystrophy) in HIV patients,including loss of peripheral and facial subcutaneous fat, increased intra‑abdominaland visceral fat, breast hypertrophy and dorsocervical fat accumulation(buffalo hump) (see section 4.4).$0$0 $0$0Metabolicabnormalities$0$0Combination antiretroviral therapy has also beenassociated with metabolic abnormalities such as hypertriglyceridaemia,hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia(see section 4.4).$0$0 $0$0Metabolic parameters$0$0Weight and levels of blood lipids and glucose mayincrease during antiretroviral therapy (see section 4.4).$0$0 $0

Updated on 1 February 2016 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects

Updated on 27 October 2015 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

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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

 

uncommon

immune reconstitution inflammatory syndrome, (drug) hypersensitivity

 

 

 

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.

 

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

Pharmacokinetics of total darunavir

(mean ± SD)

Second trimester of pregnancy

(n=11)a

Third trimester of pregnancy

(n=11)

Postpartum (6‑12 weeks)

(n=11)

Cmax, ng/ml

4,601 ± 1,125

5,111 ± 1,517

6,499 ± 2,411

AUC12h, ng.h/ml

38,950 ± 10,010

43,700 ± 16,400

55,300 ± 27,020

Cmin, ng/mlb

1,980 ± 839.9

2,498 ± 1,193

2,711 ± 2,268

a    n=10 for AUC12h

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

 

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 800/100 mg once daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum

Pharmacokinetics of total darunavir

(mean ± SD)

Second trimester of pregnancy

(n=16)

Third Trimester of pregnancy

(n=14)

Postpartum (6‑12 weeks)

(n=15)

Cmax, ng/ml

4,988 ± 1,551

5,138 ± 1,243

7,445 ± 1,674

AUC12h, ng.h/ml

61,303 ± 16,232

60,439 ± 14,052

94,529 ± 28,572

Cmin, ng/mla

1,193 ± 509

1,098 ± 609

1,572 ± 1,108

a    n=12 for postpartum, n=15 for second trimester and n=14 for third trimester

 

In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of pregnancy, mean intra‑individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 24% and 17% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC12h and Cmin 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 Cmax, AUC12h and Cmin were 34%, 34% and 32% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC12h and Cmin values were 31%, 35% and 50% lower, respectively, as compared with postpartum.

 

Updated on 22 October 2015 PIL

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Updated on 12 November 2014 PIL

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Updated on 28 March 2014 PIL

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Updated on 20 December 2013 PIL

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Updated on 23 October 2013 PIL

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Updated on 27 September 2013 PIL

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  • Change to dosage and administration

Updated on 11 June 2013 PIL

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Updated on 24 January 2013 PIL

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Updated on 17 November 2009 SmPC

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  • Individual presentations superceeded by joint SPC
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4.5

Interaction with other medicinal products and other forms of interaction

Addition of buprenorphine/naloxone DDI

5.1

Pharmacodynamic properties

Addition of 96 week trial data (ARTEMIS & TITAN trials)

10.

DATE OF REVISION OF THE TEXT

 

 23.10.09

 

Updated on 20 February 2009 SmPC

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