Prezista 100mg per ml suspension

  • Name:

    Prezista 100mg per ml suspension

  • Company:
    info
  • Active Ingredients:

    darunavir ethanolate

  • Legal Category:

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

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Summary of Product Characteristics last updated on medicines.ie: 20/10/2020

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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 October 2020 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • 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)

Updated on 20 October 2020 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 6 - date of revision

Updated on 7 September 2020 PIL

Reasons for updating

  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 3 - use in children/adolescents
  • Change to section 3 - how to take/use
  • Change to section 6 - date of revision

Updated on 2 September 2020 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 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • 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

4.1     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.

 

Recommended dose for treatment‑naïve paediatric patients (3 to 17years) with PREZISTA and ritonavira or cobicistatb

Body weight (kg)

Dose (once daily with food)

≥15kg to <30kg

600mg (6ml) PREZISTA/100mg (1.2ml) ritonavir once daily

≥30kg to <40kg

675mg (6.8ml)b c PREZISTA/100mg (1.2ml) ritonavir once daily

≥40kg

800mg (8ml) PREZISTA/100mg (1.2ml) ritonavir once daily or

800mg (8ml) PREZISTA/150mg (tablet) cobicistatb once daily

a ritonavir oral solution: 80mg/ml

b adolescents 12years and older

bc rounded up for suspension dosing convenience

 

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.

 

Recommended dose for treatment‑experienced paediatric patients (3 to 17years) with PREZISTA and ritonavira or cobicistatb

Body weight (kg)

Dose (once daily with food)

Dose (twice daily with food)

≥15kg to <30kg

600mg (6ml) PREZISTA/100mg (1.2ml) ritonavir once daily

380mg (3.8ml) PREZISTA/50mg (0.6ml) ritonavir twice daily

≥30kg to <40kg

675mg (6.8ml)bc PREZISTA/100mg (1.2ml) ritonavir once daily

460mg (4.6ml) PREZISTA/60mg (0.8ml) ritonavir twice daily

≥40kg

800mg (8ml) PREZISTA/100mg (1.2ml) ritonavir once daily or

800mg (8ml) PREZISTA/150mg (tablet) cobicistatb once daily

600mg (6ml) PREZISTA/100mg (1.2ml) ritonavir twice daily

a ritonavir oral solution: 80mg/ml

b adolescents 12 years and older

bc rounded up for suspension dosing convenience

 

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).

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 with clonazepam.

 

ANTINEOPLASTICS

Dasatinib

Nilotinib

Vinblastine

Vincristine

 

 

 

 

 

 

 

 

Everolimus

Irinotecan

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

(CYP3A inhibition)

Concentrations of these medicinal products may be increased when co‑administered with boosted PREZISTA resulting in the potential for increased adverse events usually associated with these agents.

Caution should be exercised when combining one of these antineoplastic agents with boosted PREZISTA.

 

Concominant Concomitant use of everolimus or irinotecan and boosted PREZISTA is not recommended.

ANTIPSYCHOTICS/NEUROLEPTICS

Quetiapine

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

(CYP3A inhibition)

Concomitant administration of boosted PREZISTA and quetiapine is contraindicated as it may increase quetiapine‑related toxicity. Increased concentrations of quetiapine may lead to coma (see section4.3).

Perphenazine

Risperidone

Thioridazine

 

Lurasidone

Pimozide

Sertindole

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

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

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

 

Concominant Concomitant administration of boosted PREZISTA and lurasidone, pimozide or sertindole is contraindicated (see section4.3).

 

Boceprevir

800mg three times daily

boceprevir AUC ↓ 32%

boceprevir Cmin ↓ 35%

boceprevir Cmax ↓ 25%

darunavir AUC ↓ 44%

darunavir Cmin ↓ 59%

darunavir Cmax ↓ 36%

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

Glecaprevir/pibrentasvir

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

(P‑gp, BCRP and/or OATP1B1/3 inhibition)

It is not recommended to co‑administer boosted PREZISTA with glecaprevir/pibrentasvir.

Simeprevir

simeprevir AUC ↑ 159%

simeprevir Cmin ↑ 358%

simeprevir Cmax ↑ 79%

darunavir AUC ↑ 18%

darunavir Cmin ↑ 31%

darunavir Cmax «

The dose of simeprevir in this interaction study was 50mg when co‑administered in combination with darunavir/ritonavir, compared to 150mg in the simeprevir alone treatment group.

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

 

OESTROGEN‑BASED CONTRACEPTIVES

Drospirenone Ethinylestradiol (3mg/0.02mg once daily)

 

 

 

 

 

Ethinylestradiol

Norethindrone

35mg/1mg 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 co‑administered 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.

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

 

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

 

ODIN

Outcomes

PREZISTA/ritonavir 800/100 mg once daily + OBR

N=294

PREZISTA/ritonavir 600/100 mg twice daily + OBR

N=296

Treatment difference

(95% CI of difference)

HIV‑1 RNA < 50 copies/mla

72.1% (212)

70.9% (210)

1.2% (‑6.1; 8.5)b

With Baseline HIV‑1 RNA (copies/ml)

 < 100,000

≥ 100,000

 

 

77.6% (198/255)

35.9% (14/39)

 

 

73.2% (194/265)

51.6% (16/31)

 

 

4.4% (‑3.0; 11.9)

‑15.7% (‑39.2; 7.7)

With Baseline CD4+ cell count (x 106/lL)

≥ 100

< 100

 

 

75.1% (184/245)

57.1% (28/49)

 

 

72.5% (187/258)

60.5% (23/38)

 

 

2.6% (‑5.1; 10.3)

‑3.4% (‑24.5; 17.8)

With HIV‑1 clade

Type B

Type AE

Type C

Otherc

 

70.4% (126/179)

90.5% (38/42)

72.7% (32/44)

55.2% (16/29)

 

64.3% (128/199)

91.2% (31/34)

78.8% (26/33)

83.3% (25/30)

 

6.1% (‑3.4; 15.6)

‑0.7% (‑14.0; 12.6)

‑6.1% (‑2.6; 13.7)

‑28.2% (‑51.0; ‑5.3)

mean CD4+ cell count change from baseline

(x 106/lL)e

108

112

‑5d (‑25; 16)

a     Imputations according to the TLOVR algorithm

b     Based on a normal approximation of the difference in % response

c     Clades A1, D, F1, G, K, CRF02_AG, CRF12_BF, and CRF06_CPX

d     Difference in means

e     Last Observation Carried Forward imputation

 

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.

 

 

POWER1 and POWER2 pooled data

 

Week 48

Week 96

Outcomes

PREZISTA/ ritonavir 600/100mg twice daily n=131

Control n=124

Treatment difference

PREZISTA/ ritonavir 600/100mg twice daily n=131

Control n=124

Treatment difference

HIVRNA <50copies/mla

45.0%

(59)

11.3%

(14)

33.7%

(23.4%; 44.1%)c

38.9%

(51)

8.9%

(11)

30.1%

(20.1; 40.0)c

CD4+cell count

mean change from baseline (x 106/lL)b

103

17

86

(57; 114)c

133

15

118

(83.9; 153.4)c

a Imputations according to the TLOVR algorithm

b Last Observation Carried Forward imputation

c 95% confidence intervals.

 

 

 

 

Paediatric patients

 

Efficacy of PREZISTA with ritonavir in paediatric patients

 

ART‑experienced paediatric patients from the age of 6 to < 18 years, and weighing at least 20 kg

DELPHI is an open‑label, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of PREZISTA with low dose ritonavir in 80 ART‑experienced HIV‑1 infected paediatric patients aged 6 to 17 years and weighing at least 20 kg. These patients received PREZISTA/ritonavir twice daily in combination with other antiretroviral agents (see section 4.2 for dosage recommendations per body weight). Virologic response was defined as a decrease in plasma HIV‑1 RNA viral load of at least 1.0 log10 versus baseline.

 

 

Efficacy of PREZISTA with cobicistat in paediatric patients

 

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.

 

Virologic outcome in ART‑experienced, virologically suppressed adolescents at week48

GS‑US‑216‑0128

Outcomes at Week48

Darunavir/cobicistat + at least 2NRTIs

(N=7)

HIV‑1 RNA <50copies/mL per FDA Snapshot Approach

85.7% (6)

CD4+ percent median change from baselinea

‑6.1%

CD4+ cell count median change from baselinea

‑342cells/mm³

a No imputation (observed data).

 

 

 

 

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).

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

 

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/l L (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 (AUCtau) 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.

 

 

Adults in Study GS‑US‑216‑0130, week24

(Reference)a

Mean (%CV)

GLSM

Adolescents in Study GS‑US‑216‑0128, day10

(Test)b

Mean (%CV)

GLSM

GLSM Ratio

(90% CI)

(Test/Reference)

N

60c

7

 

DRV PK Parameter

     

AUCtau (h.ng/mL)d

81,646 (32.2)

77,534

80,877 (29.5)

77,217

1.00 (0.79‑1.26)

Cmax (ng/mL)

7,663 (25.1)

7,422

7,506 (21.7)

7,319

0.99 (0.83‑1.17)

Ctau (ng/mL)d

1,311 (74.0)

947

1,087 (91.6)

676

0.71 (0.34‑1.48)

COBI PK Parameter

     

AUCtau (h.ng/mL)d

7,596 (48.1)

7,022

8,741 (34.9)

8,330

1.19 (0.95‑1.48)

Cmax (ng/mL)

991 (33.4)

945

1,116 (20.0)

1,095

1.16 (1.00‑1.35)

Ctau (ng/mL)d

32.8 (289.4)

17.2e

28.3 (157.2)

22.0e

1.28 (0.51‑3.22)

a Week24 intensive PK data from subjects who received DRV 800mg + COBI 150mg.

b Day10 intensive PK data from subjects who received DRV 800mg + COBI 150mg.

c N=59 for AUCtau and Ctau.

d Concentration at predose (0hours) was used as surrogate for concentration at 24hours for the purposes of estimating AUCtau and Ctau in Study GS-US-216-0128.

e N=57 and N=5 for GLSM of Ctau in Study GS-US-216-0130 and Study GS-US-216-0128, respectively.

 

 

6.6     Special precautions for disposal and other handling

 

No special requirements for disposal.

 

Shake the bottle vigorously prior to each dose. The supplied oral dosing pipette should not be used for any other medicinal products.

 

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

Updated on 20 May 2020 PIL

Reasons for updating

  • 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

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.

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 10 - Date of revision of the text

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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 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).

Updated on 11 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

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

Updated on 8 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 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)

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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 5 November 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

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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 30 October 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Change in co-marketing arrangement

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)

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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

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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.

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

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

 

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 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

 

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

300245 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.

Pravastatin

40 mg single dose

pravastatin AUC ↑ 81%

pravastatin Cmin ND

pravastatin Cmax ↑ 63%

an up to five-fold increase was seen in a limited subset of subjects

When administration of pravastatin and boosted PREZISTA is required, it is recommended to start with the lowest possible dose of pravastatin and titrate up to the desired clinical effect while monitoring for safety.

Rosuvastatin

10 mg once daily

rosuvastatin AUC ↑ 48%

rosuvastatin Cmax ↑ 144%

based on published data with darunavir/ritonavir

 

rosuvastatin AUC ↑ 93%§

rosuvastatin Cmax ↑ 277%§

rosuvastatin Cmin ND§

§ with darunavir/cobicistat 800/150 mg

 

When administration of rosuvastatin and boosted PREZISTA is required, it is recommended to start with the lowest possible dose of rosuvastatin and titrate up to the desired clinical effect while monitoring for safety.

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)

H2‑RECEPTOR ANTAGONISTS

Ranitidine

150 mg twice daily

#darunavir AUC ↔

#darunavir Cmin

#darunavir Cmax

Boosted PREZISTA can be co‑administered with H2‑receptor antagonists without dose adjustments.

 

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

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.

 

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

 

 

 

 

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

Updated on 26 March 2018 SmPC

Reasons for updating

  • New SmPC for new product

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

Updated on 23 March 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 23 March 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 10 July 2017 SmPC

Reasons for updating

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

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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 27 March 2017 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 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text

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

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$04.3     Contraindications$0$0 $0$0-                 elbasvir/grazoprevir (hepatitis C virus direct-acting antiviral)$0$0-                 lurasidone, pimozide, quetiapine, sertindole (antipsychotics/neuroleptics) (see section 4.5)$0$0 $0$0 $0$04.5     Interaction with other medicinal products and other forms of interaction$0$0 $0$0 $0$0 $0$0 $0$0$0$0$0$0$0α1-ADRENORECEPTOR ANTAGONIST$0$0$0$0$0$0Alfuzosin$0$0$0$0Based on theoretical considerations PREZISTA is expected to increase alfuzosin plasma concentrations.$0$0(CYP3A inhibition)$0$0$0$0$0$0Co-administration of PREZISTA with low dose ritonavir and alfuzosin is contraindicated (see section 4.3).$0$0$0$0$0$0$0 $0$0$0$0$0$0$0Risperidone$0$0Thioridazine$0$0 $0$0 $0$0 $0$0Lurasidone$0$0Pimozide$0$0Sertindole $0$0$0$0$0$0Not studied. PREZISTA is expected to increase these antipsychotic plasma concentrations.$0$0(CYP3A, CYP2D6 inhibition and/or P‑gp)$0$0$0$0A dose decrease may be needed for these drugs when co‑administered with PREZISTA co‑administered with low dose ritonavir.$0$0 $0$0Concominant administration of PREZISTA with low dose ritonavir and lurasidone, pimozide or sertindole is contraindicated (see section 4.3).$0$0$0$0$0$0$0 $0$0 $0$0$0$0$0$0CORTICOSTEROIDS $0$0$0$0$0$0Corticosteroids primarily metabolised by CYP3A (including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone)Fluticasone$0$0Budesonide$0$0$0$0$0$0Fluticasone: 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.$0$0 $0$0Other 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. $0$0$0$0$0$0$0$0Concomitant 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. $0$0Co-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.$0$0Alternative 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.$0$0$0$0$0$0$0$0$0$0 $0$0$0$0$0$0$0Prednisone $0$0$0$0Not studied. Darunavir may increase plasma concentrations of prednisone.$0$0(CYP3A inhibition) $0$0$0$0$0$0Concomitant 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. $0$0$0$0$0$0$0 $0$0$0$0$0$0$0Elbasvir/grazoprevir$0$0$0$0PREZISTA with low dose ritonavir may increase the exposure to grazoprevir.$0$0(CYP3A and OATP1B inhibition)$0$0$0$0$0$0Concomitant use of PREZISTA with low dose ritonavir and elbasvir/grazoprevir is contraindicated (see section 4.3).$0$0$0$0$0$0$0 $0$04.8     Undesirable effects$0$0 $0$0 $0$0Adverse reactions with darunavir/cobicistat in adult patients$0$0 $0$0$0$0$0$0$0Musculoskeletal and connective tissue disorders$0$0$0$0 $0$0$0$0$0$0common$0$0$0$0myalgia, osteonecrosis*$0$0 $0$0$0$0 $0$0$0$0$0$0uncommon$0$0$0$0osteonecrosis*$0$0$0$0$0$0$0$0$0$0$0$0

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 3 February 2016 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

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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 4.2 - 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

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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

Reasons for updating

  • Change to date of revision
  • Change of distributor details

Updated on 14 November 2014 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - 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 4.8 - 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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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

Updated on 12 November 2014 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to side-effects
  • Change to drug interactions
  • Change to date of revision
  • Changes to therapeutic indications

Updated on 28 March 2014 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to date of revision

Updated on 27 March 2014 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

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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.

Updated on 20 December 2013 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 24 October 2013 PIL

Reasons for updating

  • Change of contraindications
  • Change to date of revision

Updated on 23 October 2013 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 10 - Date of revision of the text

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uodate to section 4.3 and 4.5 quetiapine contraindication

Updated on 26 September 2013 PIL

Reasons for updating

  • Change to side-effects
  • Change to drug interactions
  • Change to date of revision
  • Change to dosage and administration

Updated on 26 September 2013 SmPC

Reasons for updating

  • New individual SPC (was previously included in combined SPC)

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Approval of changes to Prezista suspension and Tablets SPC does not make a full combination SPC suitable.

Section 4.2 posology

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

Updated on 11 June 2013 PIL

Reasons for updating

  • Change to warnings or special precautions for use

Updated on 24 January 2013 PIL

Reasons for updating

  • Introduction of new strength

Updated on 7 November 2012 PIL

Reasons for updating

  • New PIL for new product