REZOLSTA 800 mg/150 mg film coated tablets

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

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

EU Approval EMEA/H/C/2819/WS/2250

EU Approval EMEA/H/C/2819/WS/2250

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

Interaction table

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

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

Updates are in red

Deleted: “Interaction not studied with any of the components of REZOLSTA.”

                “for intranasal or inhalation use”

-last revision date 2 September 2021

Other medicines and REZOLSTA

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

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

• Corticosteroids including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone. These medicines are used to treat allergies, asthma, inflammatory bowel diseases, inflammatory conditions of the skin, eyes, joints and muscles and other inflammatory conditions. These medicines are generally taken orally, inhaled, injected or applied to the skin. If alternatives cannot be used, its use should only take place after medical evaluation and under close monitoring by your doctor for corticosteroid side effects.
   
  Updates are in red
  Last revision date : 09/2021
  Section 4 IE and UK(NI) details added and at the end local repr. For IE and UK(NI) listed

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 tablet‑cutter. 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.

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 tablet‑cutter, 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

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.

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 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.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

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 GS‑US‑216‑0128 in HIV‑1 infected adolescents evaluating components of REZOLSTA. For additional supportive information, refer to the Summary of Product Characteristics of darunavir and cobicistat.

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 (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.

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 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 who received darunavir 800 mg co‑administered with cobicistat 150 mg in Study GS‑US‑216‑0128. The geometric mean adolescent exposure (AUC_tau) was similar for darunavir and increased 19% for cobicistat compared to exposures achieved in adults who received darunavir 800 mg co‑administered with cobicistat 150 mg in Study GS‑US‑216‑0130. The difference observed for cobicistat was not considered clinically relevant.

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

^b     N = 59 for AUC_tau and C_tau.

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

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

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

   

4.4     Special warnings and precautions for use 

Immune reactivation syndrome 

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

4.8     Undesirable effects 

Immune reconstitution inflammatory syndrome

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

4.4     Special warnings and precautions for use 

Immune reactivation syndrome

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

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

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.

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

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

4.8     Undesirable effects

4.5     Interaction with other medicinal products and other forms of interaction