REZOLSTA 800 mg/150 mg film coated tablets

  • Name:

    REZOLSTA 800 mg/150 mg film coated tablets

  • Company:
    info
  • Active Ingredients:

    Cobicistat, 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: 20/10/20

files-icon(Click to Download)
Summary of Product Characteristics last updated on medicines.ie: 20/10/2020

Click on this link to Download PDF directly

Janssen Sciences Ireland

Company Products

Medicine NameActive Ingredients
Medicine Name Caelyx pegylated liposomal 2mg/ml concentrate for solution for infusion Active Ingredients Doxorubicin hydrochloride
Medicine Name CONCERTA XL 18 mg prolonged-release tablets Active Ingredients Methylphenidate Hydrochloride
Medicine Name Concerta XL 27mg Active Ingredients Methylphenidate Hydrochloride
Medicine Name Concerta XL 36 mg prolonged-release tablets Active Ingredients Methylphenidate Hydrochloride
Medicine Name Dacogen 50 mg powder for concentrate for solution for infusion. Active Ingredients Decitabine
Medicine Name Daktacort 2% 1% Cream Active Ingredients Hydrocortisone, Miconazole nitrate
Medicine Name DARZALEX 1,800 mg solution for injection Active Ingredients Daratumumab
Medicine Name DARZALEX 20 mg/mL concentrate for solution for infusion. Active Ingredients Daratumumab
Medicine Name Durogesic DTrans 100 micrograms/hour Transdermal Patch Active Ingredients Fentanyl
Medicine Name Durogesic DTrans 12 micrograms/hour Transdermal Patch Active Ingredients Fentanyl
Medicine Name Durogesic DTrans 25 micrograms/hour Transdermal Patch Active Ingredients Fentanyl
Medicine Name Durogesic DTrans 50 micrograms/hour Transdermal Patch Active Ingredients Fentanyl
Medicine Name Durogesic DTrans 75 micrograms/hour Transdermal Patch Active Ingredients Fentanyl
Medicine Name Edurant 25mg film-coated tablets Active Ingredients Rilpivirine Hydrochloride
Medicine Name Erleada 60 mg film coated tablets Active Ingredients Apalutamide
Medicine Name Evra transdermal patch Active Ingredients Ethinylestradiol, Norelgestromin
Medicine Name Gyno-Daktarin 20 mg/g vaginal cream Active Ingredients Miconazole nitrate
Medicine Name Gyno-Pevaryl Once 150mg vaginal pessary Active Ingredients Econazole Nitrate
Medicine Name Haldol Decanoate Active Ingredients Haloperidol decanoate
Medicine Name IMBRUVICA 140 mg, 280 mg, 420 mg and 560 mg film-coated tablets Active Ingredients Ibrutinib
Medicine Name Intelence 200 mg tablets Active Ingredients Etravirine
Medicine Name Invega 3 mg, 6mg, 9mg, 12mg prolonged-release tablets Active Ingredients Paliperidone
Medicine Name Lyrinel XL 5mg & 10mg prolonged release tablets Active Ingredients Oxybutynin Hydrochloride
Medicine Name PARIET 10 mg gastro-resistant tablets Active Ingredients Rabeprazole Sodium
Medicine Name PARIET 20 mg gastro-resistant tablets Active Ingredients Rabeprazole Sodium
1 - 0 of 59 items.Total: Infinity pages

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 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 20 October 2020 SmPC

Reasons for updating

  • 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 10 - Date of revision of the text

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

Updated on 17 March 2020 PIL

Reasons for updating

  • Change to section 1 - what the product is used for
  • Change to section 2 - use in children and adolescents
  • Change to section 3 - how to take/use
  • Change to section 3 - overdose, missed or forgotten doses
  • Change to section 6 - date of revision

Free text change information supplied by the pharmaceutical company

1.       What REZOLSTA is and what it is used for

What it is used for?

REZOLSTA is used to treat adults and adolescents aged 12 years and older who weigh at least 40 kilograms and 18 years or older who are infected by HIV (see How to take REZOLSTA).

2.       What you need to know before you take REZOLSTA

Children and adolescents

REZOLSTA is not for use in children younger than 12 years, or weighing less than 40 kilogramsand adolescents, as it has not been studied in patients under 18 years.

3.       How to take REZOLSTA

 

  • Swallow the tablet whole with a drink such as water or milk. If you have difficulty swallowing REZOLSTA, tell your doctor. The tablet may be split using a tabletcutter. After splitting the tablet, the entire dose (both halves) should then be taken right away with a drink such as water or milk.

If you vomit after taking REZOLSTA

If you vomit within 4 hours of taking the medicine, another dose of REZOLSTA should be taken with food as soon as possible. If you vomit more than 4 hours after taking the medicine, then you do not need to take another dose of REZOLSTA until the next regularly scheduled time.

 

Contact your doctor if you are uncertain about what to do if you miss a dose or vomit.

Updated on 17 March 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 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

 

REZOLSTA is indicated, in combination with other antiretroviral medicinal products, for the treatment of human immunodeficiency virus‑1 (HIV‑1) infection in adults and adolescents (aged 128 years or and older, weighing at least 40 kg).

 

Genotypic testing should guide the use of REZOLSTA (see sections 4.2, 4.4 and 5.1).

 

4.2     Posology and method of administration

 

Therapy should be initiated by a healthcare provider experienced in the management of HIV infection.

 

Posology

 

The recommended dose regimen in adults and adolescents aged 12 years and older, weighing at least 40 kg, is one tablet taken once daily with food.

 

Advice on missed doses

If REZOLSTA is missed within 12 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of REZOLSTA with food as soon as possible. If this is noticed later than 12 hours of the time it is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.

 

If a patient vomits within 4 hours of taking the medicine, another dose of REZOLSTA 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 REZOLSTA until the next regularly scheduled time.

 

Paediatric population

The safety and efficacy of REZOLSTA in paediatric patients aged 3 to 117 years, or weighing < 40 kg, have not been established (see sections 4.4 and 5.3). No data are available. REZOLSTA should not be used in paediatric patients below 3 years of age because of safety concerns (see sections 4.4 and 5.3).

 

Method of administration

 

Oral use

To ensure administration of the entire dose of both darunavir and cobicistat, the tablet should be swallowed whole. For patients unable to swallow the whole tablet, REZOLSTA may be split into two pieces using a tabletcutter, and the entire dose should be consumed immediately after splitting.

Patients should be instructed to take REZOLSTA within 30 minutes after completion of a meal (see sections 4.4, 4.5 and 5.2).

4.4     Special warnings and precautions for use

 

ART‑experienced patients

 

REZOLSTA should not be used in treatment‑experienced patients with one or more 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 regimens (OBRs) other than ≥ 2 NRTIs have not been studied in this population. Limited data is available in patients with HIV‑1 clades other than B (see section 5.1).

Paediatric population

 

REZOLSTA is not recommended for use in paediatric patients (3 to 117 years of age). REZOLSTA should not be used in paediatric patients below 3 years of age (see sections 4.2 and 5.3).

 

4.5     Interaction with other medicinal products and other forms of interaction

 

ANTIFUNGALS

Clotrimazole

Fluconazole

Itraconazole

Isavuconazole

Posaconazole

 

 

 

 

 

Voriconazole

Based on theoretical considerations REZOLSTA is expected to increase these antifungal plasma concentrations, and darunavir and/or cobicistat plasma concentrations may be increased by the antifungals.

(CYP3A inhibition and/or P‑gp inhibition)

 

Concentrations of voriconazole may increase or decrease when co‑administered with REZOLSTA.

Caution is warranted and clinical monitoring is recommended.

 

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

 

 

 

Voriconazole should not be combined with REZOLSTA unless an assessment of the benefit/risk ratio justifies the use of voriconazole.

 

4.8     Undesirable effects

 

Summary of the safety profile

 

The overall safety profile of REZOLSTA is based on available clinical trial data from darunavir boosted with either cobicistat or ritonavir, from cobicistat and from post‑marketing data from darunavir/ritonavir.

 

As REZOLSTA contains darunavir and cobicistat, the adverse reactions associated with each of the individual compounds may be expected.

 

The most frequent adverse reactions reported in the pooled data of the Phase 3 III study GS-US-216-130 and the REZOLSTA arm of Phase 3 III study TMC114FD2HTX3001 were diarrhoea (23%), nausea (17%), rash (13%), and headache (10%). Serious adverse reactions were diabetes mellitus, (drug) hypersensitivity, immune reconstitution inflammatory syndrome, rash, Stevens-Johnson syndrome, and vomiting. All of these serious ADRs occurred in one (0.1%) subject except for rash in 4 (0.6%) subjects.

 

Musculoskeletal and connective tissue disorders

Common

mMyalgia

 

 

When also taking into account the clinical trial data of DRV/COBI/emtricitabine/tenofovir alafenamide, Stevens-Johnson syndrome occurred rarely (in 1 out of 2,551 subjects) consistent with the DRV/rtv clinical trial program (see Severe skin reactions in sSection 4.4).

Decrease estimated creatinine clearance

Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of renal tubular secretion of creatinine. An increase in serum creatinine due to the inhibitory effect of cobicistat generally does not exceed 0.4 mg/dldL.

Paediatric population

 

The safety of components of REZOLSTA was evaluated in adolescents aged 12 to less than 18 years, weighing at least 40 kg through the clinical trial GSUS2160128 (treatmentexperienced, 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.The safety and efficacy of REZOLSTA in paediatric patients aged 3 to 17 years has not been established (see sections 4.4 and 5.3).

 

5.1     Pharmacodynamic properties

 

median CD4+ cell count change from baseline (x 106/lL)e

+137

+141

 

+171

+188

 

 

ODIN

 

Week 48

Outcomes

darunvir/ritonavir 800/100 mg once daily + OBR

N = 294

darunvir/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)

 

REZOLSTA 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 sections 4.2 and 4.4). Limited data is available in patients with HIV‑1 clades other than B.

 

Paediatric population

 

The use of REZOLSTA in adolescent patients from the age of 12 years to less than 18 years, and weighing at least 40 kg is supported by adult trials and by trial GSUS2160128 in HIV1 infected adolescents evaluating components of REZOLSTA. For additional supportive information, refer to the Summary of Product Characteristics of darunavir and cobicistat.

 

In the openlabel, Phase II/III trial GSUS2160128, 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, treatmentexperienced, virologically suppressed adolescents (see section 5.2). Patients were on a stable antiretroviral regimen (for at least 3 months), consisting of darunavir adminstered 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 week 48

GSUS2160128

Outcomes at week 48

Darunavir/cobicistat + at least 2 NRTIs

(N = 7)

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

85.7% (6)

CD4+ percent median change from baseline

6.1%

CD4+ cell count median change from baseline

342 cells/mm³

 

The European Medicines Agency has deferred the obligation to submit the results of studies with REZOLSTA in all one or more subsets of the paediatric population in the condition of treatment of HIV‑1 infection.

 

5.2     Pharmacokinetic properties

 

Distribution

 

Darunavir

Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma α1‑acid glycoprotein.

Following intravenous administration, the volume of distribution of darunavir alone was 88.1 ± 59.0 l L (Mean ± SD) and increased to 131 ± 49.9 l L (Mean ± SD) in the presence of 100 mg twice‑daily ritonavir.

 

Elimination

 

Darunavir

After a 400/100 mg 14C‑darunavir with ritonavir dose, approximately 79.5% and 13.9% of the administered dose of 14C‑darunavir could be retrieved in faeces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine, respectively. The terminal elimination half‑life of darunavir was approximately 15 hours when combined with ritonavir.

The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was 32.8 lL/h and 5.9 lL/h, respectively.

Special populations

 

Paediatric population

The pharmacokinetics of REZOLSTA in paediatric patients have not been investigated.Available pharmacokinetic data for the different components of REZOLSTA indicate there were no clinically relevant differences in exposure between adults and adolescents. In addition, the pharmacokinetics of darunavir 800 mg coadministered 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 who received darunavir 800 mg coadministered with cobicistat 150 mg in Study GSUS2160128. 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 coadministered with cobicistat 150 mg in Study GSUS2160130. The difference observed for cobicistat was not considered clinically relevant.

 

DRV PK Parameter

Adults in Study GSUS2160130, week 24

(Reference)

Mean (%CV)

GLSM

Adolescents in Study GSUS2160128, day 10

(Test)a

Mean (%CV)

GLSM

% GLSM Ratio

(90% CI)

(Test/Reference)

N

60b

7

 

AUCtau (h.ng/mL)c

81,646 (32.2)

77,534

80,877 (29.5)

77,217

1.00 (0.791.26)

Cmax (ng/mL)

7,663 (25.1)

7,422

7,506 (21.7)

7,319

0.99 (0.831.17)

Ctau (ng/mL)c

1,311 (74.0)

947

1,087 (91.6)

676

0.71 (0.341.48)

COBI PK Parameter

 

 

 

AUCtau (h.ng/mL)c

7,596 (48.1)

7,022

8,741 (34.9)

8,330

1.19 (0.951.48)

Cmax (ng/mL)

991 (33.4)

945

1,116 (20.0)

1,095

1.16 (1.001.35)

Ctau (ng/mL)c

32.8 (289.4)

17.2

28.3 (157.2)

22.0

1.28 (0.513.22)

a     PK parameters for the test group were from day 10 intensive PK assessment when DRV was boosted by COBI.

b     N = 59 for AUCtau and Ctau.

c     Concentration at predose (0 hours) was used as surrogate for concentration at 24 hours for the purposes of estimating AUCtau and Ctau.

Updated on 18 December 2019 PIL

Reasons for updating

  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 18 December 2019 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 4.5 - Interaction with other medicinal products and other forms of interaction
  • 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

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

Updated on 9 August 2019 PIL

Reasons for updating

  • Change to Section 1 - what the product is
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision
  • Removal of Black Inverted Triangle

Updated on 8 August 2019 SmPC

Reasons for updating

  • Change to section 3 - Pharmaceutical form
  • 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 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text
  • Removal of Black Inverted Triangle

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

Updated on 9 May 2019 SmPC

Reasons for updating

  • 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 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 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)

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
  • ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR

    Apixaban

    Edoxaban

    Dabigatran etexilate

    Rivaroxaban

    Based on theoretical considerations co‑administration of REZOLSTA with these anticoagulants may increase concentrations of the anticoagulant, which may lead to an increased bleeding risk.

    (CYP3A and/or P‑glycoprotein inhibition)

    Co‑administration of REZOLSTA and these anticoagulants is not recommended.

    Dabigatran

    Ticagrelor

    Based on theoretical considerations co‑administration of REZOLSTA with dabigatran or ticagrelor may increase concentrations of the anticoagulant.

    (CYP3A and/or P‑glycoprotein inhibition).

    Concomitant administration of REZOLSTA with dabigatran or ticagrelor is contraindicated.

     

    Use of other antiplatelets not affected by CYP inhibition or induction (e.g. prasugrel) is recommended (see section 4.3).

     

    HEPATITIS C VIRUS (HCV) DIRECT‑ACTING ANTIVIRALS

    NS3‑4A inhibitors

     

    Glecaprevir/pibrentasvir

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

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

    It is not recommended to coadminister REZOLSTA with glecaprevir/pibrentasvir.

     

 

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 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 4 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 5.2 - 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

Section 4.2 – Addition of pregnancy and postpartum section to inform about low darunavir exposure and consideration for alternative regimen.

Section 4.4 – Addition of pregnancy data (low darunavir exposure, cobicistat levels decrease and may not provide sufficient boosting); advice not to initiate during pregnancy or switch to alternative regimen.

Section 4.6 -  addition of pregnancy data: low darunavir exposure which may be associated with an increased risk of treatment failure and an increased risk of HIV transmission to the child; advice not to initiate during pregnancy or switch to alternative regimen.

Section 5.2 – addition of pregnancy and postpartum data

Section 10 – revision date of 29 June 2018

Updated on 4 July 2018 PIL

Reasons for updating

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

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 26 March 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 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

 

 

4.3     Contraindications

 

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

 

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

 

Co‑administration with the following medicinal products is contraindicated due to the potential for loss of therapeutic effect (see section 4.5):

-                 carbamazepine, phenobarbital, phenytoin (anticonvulsants)

-                 rifampicin (antimycobacterial)

-                 lopinavir/ritonavir

-                 St John’s wort, (Hypericum perforatum) (herbal product).

 

Co‑administration with the following medicinal products is contraindicated due to the potential for serious and/or life‑threatening adverse reactions (see section 4.5):

-                 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)

-                 rifampicin (antimycobacterial)

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

-                 cisapride (gastrointestinal motility agent)

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

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

-                 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 (platelet aggregation inhibitor).

 

 

4.4     Special warnings and precautions for use

 

REZOLSTA should not be initiated in patients with creatinine clearance less than 70 ml/min when co‑administered with one or more agent requiring dose adjustment based on creatinine clearance (e.g. emtricitabine, lamivudine, tenofovir disoproxil (as fumarate, phosphate or succinate)fumarate or adefovir dipivoxil) (see sections 4.2, 4.8 and 5.2).

 

  4.5   Interaction with other medicinal products and other forms of interaction

 

No drug interaction trials have been performed using REZOLSTA. As REZOLSTA contains darunavir and cobicistat, interactions that have been identified with darunavir (in combination with cobicistat or with low dose ritonavir) orand with cobicistat determine the interactions that may occur with REZOLSTA. Interaction trials with darunavir/cobicistat, darunavir/ritonavir and with cobicistat have only been performed in adults.

 

….

 

Co‑administration of REZOLSTA and other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and cobicistat and may result in increased plasma concentrations of darunavir and cobicistat (e.g. systemic azoles antifungals such as  like ketoconazole and clotrimazole). These interactions are described in the interaction table below.

 

 

Tenofovir disoproxil fumarate*

 

*study was done with tenofovir disoproxil fumarate

Based on theoretical considerations REZOLSTA is expected to increase tenofovir plasma concentrations.

(P‑glycoprotein inhibition)

REZOLSTA and tenofovir disoproxil fumarate can be used without dose adjustments.

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

Emtricitabine/tenofovir alafenamide

 

 

Tenofovir alafenamide

Tenofovir ↑

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

 

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide

Flecainide

Lidocaine (systemic)

Mexiletine

Propafenone

 

 

 

Amiodarone

Bepridil

Dronedarone

Lidocaine (systemic)

Quinidine

Ranolazine

Based on theoretical considerations REZOLSTA 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 REZOLSTA.

 

Co‑administration of amiodarone, bepridil, dronedarone, lidocaine (systemic), quinidine, or ranolazine and REZOLSTA is contraindicated (see section 4.3).

 

 

ANTICONVULSANTS

Clonazepam

Based on theoretical considerations REZOLSTA is expected to  increase concentrations of clonazepam

(inhibition of CYP3A)

Clinical monitoring is recommended when co‑administering REZOLSTA with clonazepam.

 

 

ANTIFUNGALS

Clotrimazole

Fluconazole

Itraconazole

Isavuconazole

Ketoconazole

Posaconazole

 

 

 

 

Voriconazole

Based on theoretical considerations REZOLSTA is expected to increase these antifungal plasma concentrations, and darunavir and/or cobicistat plasma concentrations may be increased by the antifungals.

(CYP3A inhibition and/or P‑gp inhibition)

 

Concentrations of voriconazole may increase or decrease when co‑administered with REZOLSTA.

Caution is warranted and clinical monitoring is recommended.

 

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

 

 

Voriconazole should not be combined with REZOLSTA unless an assessment of the benefit/risk ratio justifies the use of voriconazole.

 

ANTIPSYCHOTICS/NEUROLEPTICS

Perphenazine

Risperidone

Thioridazine

 

 

 

 

 

 

 

Lurasidone

Pimozide

Sertindole

Quetiapine

Based on theoretical considerations REZOLSTA is expected to increase these neuroleptic plasma concentrations.

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

Clinical monitoring is recommended when co‑administering REZOLSTA perphenazine, risperidone or thioridazine. For these neuroleptics, consider reducing the dose of the neuroleptic upon co‑administration with REZOLSTA.

 

The combination of lurasidone, pimozide, quetiapine or sertindole and REZOLSTA is contraindicated (see section 4.3).

 

 

 

HEPATITIS C VIRUS (HCV) DIRECT‑ACTING ANTIVIRALS

Boceprevir

Telaprevir

Based on theoretical considerations these antiviralsboceprevir may decrease darunavir and/or cobicistat plasma concentrations. REZOLSTA may decrease these antiviralboceprevir plasma concentrations.

It is not recommended to co‑administer REZOLSTA with boceprevir or telaprevir.

 

 

HMG CO‑A REDUCTASE INHIBITORS

Atorvastatin

Fluvastatin

Pitavastatin

Pravastatin

Rosuvastatin

 

 

 

 

 

 

 

 

 

 

 

 

 

Lovastatin

Simvastatin

Atorvastatin (10 mg once daily):

atorvastatin AUC ↑ 290%

atorvastatin Cmax ↑ 319%

atorvastatin Cmin ND

 

Rosuvastatin (10 mg once daily):

rosuvastatin AUC ↑ 93%

rosuvastatin Cmax 277%

rosuvastatin Cmin ND

 

Based on theoretical considerations REZOLSTA is expected to increase these HMG Co‑A reductase inhibitor plasma concentrations of fluvastatin, pitavastatin, pravastatin, lovastatin and simvastatin.

(CYP3A inhibition and/or transport)

Concomitant use of a HMG CoA reductase inhibitor and REZOLSTA may increase plasma concentrations of the lipid lowering agent, which may lead to adverse events such as myopathy.

 

When administration of HMG CoA reductase inhibitors and REZOLSTA is desired, it is recommended to start with the lowest dose and titrate up to the desired clinical effect while monitoring for safety.

 

 

 

Concomitant use of REZOLSTA with lovastatin and simvastatin is contraindicated (see section 4.3).

OTHER LIPID MODIFYING AGENTS

Lomitapide

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

(CYP3A inhibition)

Co-administration is contraindicated (see section 4.3)

 

 

OESTROGEN‑BASED CONTRACEPTIVES

Drospirenone (3 mg once daily)

 

 

 

Ethinyl estradiol (0.02 mg once daily)

 

 

Norethindrone

drospirenone AUC ↑ 58%

drospirenone Cmax ↑ 15%

drospirenone Cmin ND

 

ethinylestradiol AUC ¯ 30%

ethinylestradiol Cmax ¯ 14%

ethinylestradiol Cmin ND

 

Based on theoretical considerations REZOLSTA may alter ethinyl estradiol and/or norethindrone plasma concentrations.

(CYP3A inhibition, UGT/SULT induction)

 

 

Plasma concentrations of drospirenone are increased when administered with darunavir/cobicistat. Alternative or additional contraceptive measures are recommended when oestrogen based contraceptives are co administered with REZOLSTA. Patients using oestrogens as

hormone replacement therapy

 should be clinically monitored for signs of oestrogen deficiency.

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

 

 

No dosing recommendations can be made on the use of

REZOLSTA with other oral contraceptives. Alternative forms of contraception should be considered.

 

 

 

 

4.9     Overdose

 

Human experience of acute overdose with REZOLSTA or darunavir in combination with cobicistat 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 REZOLSTA. Treatment of overdose with REZOLSTA 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 and cobicistat are highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substances.

 

 

10.     DATE OF REVISION OF THE TEXT

 

2315 February 20187

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 23 March 2018 PIL

Reasons for updating

  • New PIL for new product

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
  • 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

 

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

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

 

 

 

 

4.5     Interaction with other medicinal products and other forms of interaction

 

 

α1-ADRENORECEPTOR ANTAGONIST

Alfuzosin

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

(CYP3A inhibition)

Coadministration of REZOLSTA with alfuzosin is contraindicated (see section 4.3).

 

 

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide

Flecainide

Mexiletine

Propafenone

 

 

 

Amiodarone

Bepridil

Dronedarone

Lidocaine (systemic)

Quinidine

Ranolazine

Based on theoretical considerations REZOLSTA 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 REZOLSTA.

 

Co‑administration of amiodarone, bepridil, dronedarone, lidocaine (systemic), quinidine, or ranolazine and REZOLSTA is contraindicated (see section 4.3).

 

 

ANTIPSYCHOTICS/NEUROLEPTICS

Perphenazine

Risperidone

Thioridazine

 

 

 

 

 

 

 

Lurasidone

Pimozide

Sertindole

Quetiapine

Based on theoretical considerations REZOLSTA is expected to increase these neuroleptic plasma concentrations.

(CYP2D6 inhibition)

Clinical monitoring is recommended when co‑administering REZOLSTA perphenazine, risperidone or thioridazine. For these neuroleptics, consider reducing the dose of the neuroleptic upon co‑administration with REZOLSTA.

 

The combination of lurasidone, pimozide, quetiapine or sertindole and REZOLSTA is contraindicated (see section 4.3).

 

 

HEPATITIS C VIRUS (HCV) DIRECT‑ACTING ANTIVIRALS

NS3‑4A inhibitors

Elbasvir/grazoprevir

Based on theoretical considerations REZOLSTA may increase the exposure to grazoprevir.

(OATP1B and CYP3A inhibition)

Concomitant use of REZOLSTA with elbasvir/grazoprevir is contraindicated (see section 4.3).

 

 

4.8     Undesirable effects

 

 

Musculoskeletal and connective tissue disorders

common

myalgia, osteonecrosis*

 

uncommon

osteonecrosis*

Updated on 23 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 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 15 November 2016 SmPC

Reasons for updating

  • 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

4.5     Interaction with other medicinal products and other forms of interaction

CORTICOSTEROIDS

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

Fluticasone

 

 

 

 

 

 

Prednisone

Interaction not studied with any of the components of REZOLSTA.

 

Plasma concentrations of these medicinal products may be increased when co-administered with REZOLSTA, resulting in reduced serum cortisol concentrations. Based on theoretical considerations REZOLSTA is expected to increase these corticosteroid plasma concentrations.

(CYP3A inhibition)

Concomitant use of REZOLSTA 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.Co‑administration of REZOLSTA and budesonide or fluticasone is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid side effects.

 

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

Updated on 11 November 2016 PIL

Reasons for updating

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

Updated on 2 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

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

Free text change information supplied by the pharmaceutical company

$04.4     Special warnings and precautions for use$0$0 $0$0 $0$0Diabetesmellitus/hyperglycaemia$0$0New onset diabetes mellitus, hyperglycaemia, orexacerbation of existing diabetes mellitus has been reported in patientsreceiving antiretroviral therapy, including HIV PIs. In some of these patientsthe hyperglycaemia was severe and in some cases also associated withketoacidosis. Many patients had confounding medical conditions some of whichrequired therapy with agents that have been associated with the development ofdiabetes mellitus or 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 HIV PIs and lipoatrophy and NRTIs has been hypothesised. Ahigher risk of lipodystrophy has been associated with individual factors suchas older age and with drug related factors such as longer duration ofantiretroviral treatment and associated metabolic disturbances. Clinicalexamination should include evaluation for physical signs of fat redistribution.Consideration should be given to measurement of fasting serum lipids and bloodglucose. Lipid disorders should be managed as clinically appropriate (seesection 4.8).$0$0 $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$0$0$0$0Metabolism and nutritiondisorders$0$0$0$0$0$0common$0$0$0$0lipodystrophy(including lipohypertrophy, lipodystrophy, lipoatrophy)*, anorexia,diabetes mellitus, hypercholesterolaemia, hypertriglyceridaemia,hyperlipidaemia$0$0$0$0$0$0$0 $0$0 $0$0 $0$0 $0$0 $0$0 $0$0Description of selectedadverse reactions$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 (buffalohump) (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$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 2 March 2015 SmPC

Reasons for updating

  • New SPC for new product

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

Free text change information supplied by the pharmaceutical company

None provided

Updated on 2 March 2015 PIL

Reasons for updating

  • New PIL for new product