Important new concerns or changes to the current ones will be included in updates of Symtuza's RMP.

Transcription

1 Summary of Risk Management Plan for Symtuza (D/C/F/TAF) This is a summary of the risk management plan (RMP) for Symtuza. The RMP details important risks of Symtuza, how these risks can be minimised, and how more information will be obtained about Symtuza's risks and uncertainties (missing information). Symtuza's summary of product characteristics (SmPC) and its package leaflet (PL) provide essential information to healthcare professionals and patients on how Symtuza should be used. This summary of the RMP for Symtuza should be read in the context of all this information including the assessment report of the evaluation and its plain-language summary, all which is part of the European Public Assessment Report (EPAR). Important new concerns or changes to the current ones will be included in updates of Symtuza's RMP. I. The Medicine and What it is Used For Symtuza is authorised for the treatment of human immunodeficiency virus (HIV) type-1 (HIV-1) infection in adults and adolescents (aged 12 years and older with body weight at least 40 kg) (see SmPC for the full indication). It contains darunavir (DRV) (as ethanolate), cobicistat (COBI), emtricitabine (FTC), and tenofovir alafenamide (TAF) (as fumarate) as the active substances and it is given as an oral fixed dose combination (FDC) tablet (DRV 800 mg, COBI 150 mg, FTC 200 mg, and TAF 10 mg). Further information about the evaluation of Symtuza s benefits can be found in Symtuza s EPAR, including in its plain-language summary, available on the European Medicine s Agency (EMA) website, under s webpage: II. Risks Associated with the Medicine and Activities to Minimise or Further Characterise the Risks Important risks of Symtuza, together with measures to minimise such risks and the proposed studies for learning more about Symtuza's risks, are outlined below. Measures to minimise the risks identified for medicinal products can be: Specific information, such as warnings, precautions, and advice on correct use, in the PL and SmPC addressed to patients and healthcare professionals; Important advice on s packaging; The authorised pack size the amount of medicine in a pack is chosen so to ensure that the medicine is used correctly; The medicine s legal status the way a medicine is supplied to the patient (eg, with or without prescription) can help to minimise its risks. Together, these measures constitute routine risk minimisation measures.

2 In addition to these measures, information about adverse reactions is collected continuously and regularly analysed, including Periodic Benefit-Risk Evaluation Report (PBRER)/Periodic Safety Update Report (PSUR) assessment so that immediate action can be taken as necessary. These measures constitute routine pharmacovigilance activities. If important information that may affect the safe use of Symtuza is not yet available, it is listed under missing information below. II.A. List of Important Risks and Missing Information Important risks of Symtuza are risks that need special risk management activities to further investigate or minimise the risk, so that the medicinal product can be safely taken. Important risks can be regarded as identified or potential. Identified risks are concerns for which there is sufficient proof of a link with the use of Symtuza. Potential risks are concerns for which an association with the use of this medicine is possible based on available data, but this association has not been established yet and needs further evaluation. Missing information refers to information on the safety of the medicinal product that is currently missing and needs to be collected (eg, on the long-term use of ); List of Important Risks and Missing Information Important identified risks Important potential risks Severe skin reactions Hepatotoxicity Hyperglycaemia Lipid abnormalities Immune reconstitution inflammatory syndrome Drug-drug interactions Post-treatment hepatic flares in HIV/hepatitis B virus (HBV) coinfected patients Development of drug resistance Coronary artery events Renal toxicity Bone events due to potential proximal renal tubulopathy/loss of bone mineral density (BMD) Ocular effects (posterior uveitis)

3 Missing information Use in elderly (65 years and above) Use in pregnant and breast-feeding women Use in children <12 years of age Long-term safety of Symtuza Use in patients with severe hepatic impairment (Child-Pugh C) Use in patients with moderate or severe renal impairment Use in patients coinfected with HIV and HBV and/or hepatitis C virus (HCV) Safety in patients with cardiac conduction disorders II.B. Summary of Important Risks Important Identified Risk: Severe skin reactions Severe skin reactions is an important identified risk for DRV. Severe skin reactions and rash in association with Symtuza were reported in the Phase 3 trials TMC114FD2HTX3001 and TMC114IFD3013, and in clinical trials of its components. During the DRV/ritonavir (rtv) clinical development programme, severe skin reactions, drug rash with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome (SJS) were reported, and during postmarketing experience, toxic epidermal necrolysis (TEN) and acute generalised exanthematous pustulosis (AGEP) were reported. These events were identified as adverse drug reactions (ADRs) and are described in the current prescribing information for Symtuza. Rash occurred more commonly in treatment-experienced patients receiving regimens containing DRV/rtv + raltegravir compared to patients receiving DRV/rtv without raltegravir or raltegravir without DRV/rtv. Darunavir contains a sulphonamide moiety. There may be an increased incidence of rash in patients with prior sulphonamide allergy. Trial GS-US showed no apparent relationship between the DRV exposure and the occurrence of rash-related adverse events (AEs). SmPC Section 4.4 SmPC section 4.8 PL Section 2 PL Section 4 Advice on the use of Symtuza in patients developing severe skin reactions is provided in SmPC Section 4.4 Warning on the use of Symtuza in patients with a known

4 sulphonamide allergy is provided in SmPC Section 4.4 and PL Section 2 Advice for patients who develop rash is provided in PL Sections 2 and 4 Important Identified Risk: Hepatotoxicity Hepatotoxicity is an important identified risk for DRV. Liver-related AEs such as abnormal liver tests and hepatitis in association with Symtuza have been reported in the Phase 3 trials TMC114FD2HTX3001 and TMC114IFD3013, and in clinical trials of its components, and were identified as ADRs. These events occurred more often in patients with both HIV-1 infection and HBV or HCV than in patients with only HIV-1 infection. These ADRs are described in the current prescribing information for Symtuza. Liver toxicity has been associated with antiretroviral therapy (ART), including the protease inhibitor (PI) class and has been seen to be more common in subjects coinfected with HBV or HCV. Didanosine, stavudine, nevirapine, efavirenz, and tenofovir (TFV) have been described to be hepatotoxic. SmPC Section 4.2 SmPC Section 4.3 SmPC Section 4.4 SmPC section 4.8 SmPC Section 5.2 PL Section 2 PL Section 4 Recommendation for liver function monitoring is provided in SmPC Section 4.4 Advice on the use of Symtuza in patients with evidence of new or worsening of liver dysfunction is provided in SmPC Section 4.4 Warning for patients with liver problems is provided in PL Section 2 Instructions on how to detect signs and symptoms of liver problems are provided in PL Section 4

5 Important Identified Risk: Hyperglycaemia Hyperglycaemia is an important identified risk for DRV. Hyperglycaemia has been reported in patients receiving ART, including PIs such as DRV. Hyperglycaemia in association with Symtuza has also been reported in the Phase 3 trials TMC114FD2HTX3001 and TMC114IFD3013 and in clinical trials of its components. This risk is described in the current prescribing information for Symtuza. Hyperglycaemia has been reported in patients receiving ART, including PIs. SmPC Section 4.4 SmPC Section 4.8 PL Section 2 PL Section 4 Recommendation for glucose monitoring is provided in SmPC Section 4.4 Warning for patients with diabetes is provided in PL Section 2 Important Identified Risk: Lipid abnormalities Lipid abnormalities is an important identified risk for DRV. Blood lipid-related adverse reactions including hypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemia, and decreased high density lipoprotein (HDL) in association with DRV have been reported in randomized, double-blind, controlled clinical trials with DRV boosted with rtv or COBI, and are described in the current prescribing information for DRV. Blood lipid-related AEs including hypertriglyceridaemia, hypercholesterolaemia, and hyperlipidaemia in association with Symtuza have been reported in the Phase 3 trials TMC114FD2HTX3001 and TMC114IFD3013, and in clinical trials of its components, and were identified as ADRs. These ADRs are described in the current prescribing information for Symtuza.

6 None have been specifically studied in the clinical trial population. SmPC Section 4.4 SmPC section 4.8 PL Section 4 Recommendation for blood lipid monitoring is provided in SmPC Section 4.4 Important Identified Risk: Immune reconstitution inflammatory syndrome Immune reconstitution inflammatory syndrome (IRIS) is an important identified risk for DRV. Immune reconstitution inflammatory syndrome in association with Symtuza has been reported in the Phase 3 trial TMC114FD2HTX3001 and in clinical trials of its components, and was identified as ADR. This ADR is described in the current prescribing information for Symtuza. None have been specifically studied in the clinical trial population. According to a review, the most common causes of IRIS are mostly mycobacterial, including tuberculosis (TB), atypical mycobacteria and bacillus Calmette-Guérin related. Very low CD4+ T-cell counts have also been cited as a risk factor for IRIS. SmPC Section 4.4 SmPC section 4.8 PL Section 2 PL Section 4 Recommendation on evaluation and treatment in case of inflammatory symptoms is provided in SmPC Section 4.4 Warning for patients with symptoms of infection or other symptoms of autoimmune disorders is provided in PL Section 2

7 Important Identified Risk: Drug-drug interactions Interactions between Symtuza and other drugs may occur. Current evidence is based on (Phase 1) clinical trials with individual components of Symtuza investigating drug-drug interactions and on theoretical considerations. Coadministration of Symtuza, together with medicines which are broken down by the same mechanisms (enzymes), may result in increased blood levels of such medicines. This could increase or prolong their therapeutic effect and side effects, which may be serious and potentially life-threatening. Some products may increase the breakdown of Symtuza, resulting in loss of efficacy. Clear recommendations on drugs that are contraindicated or that may interact, and the actions to be taken such as dose adjustment based upon drug monitoring trials are described in the current prescribing information for Symtuza. HIV patients often receive multiple medications, increasing the risk for drug interactions. SmPC Section 4.3 SmPC Section 4.4 SmPC section 4.5 PL Section 2 Recommendation regarding the use of Symtuza and other medicinal products is provided in SmPC Sections 4.4 and 4.5, and in PL Section 2 Important Identified Risk: Post-treatment hepatic flares in HIV/HBV coinfected patients Post-treatment hepatic flares is an important risk associated with stopping any agent with anti-hbv activity, including FTC and TAF. As FTC and TAF are active against HBV, discontinuation of Symtuza therapy in patients coinfected with HIV and HBV may be associated with severe acute exacerbations of hepatitis (posttreatment hepatic flares), as described in the current prescribing information for Symtuza. No such events have been described in clinical trials with Symtuza. HBV-infected patients with diminished hepatic function are at a greater risk of more severe outcomes following post-treatment hepatic flares.

8 SmPC Section 4.4 SmPC Section 4.8 PL Section 2 PL Section 4 Recommendation on monitoring and initiation of hepatitis B therapy in HIV/HBV coinfected patients who discontinue Symtuza therapy is provided in SmPC Section 4.4 Warning for HIV/HBV coinfected patients who discontinue Symtuza therapy is provided in PL Section 2 Important Identified Risk: Development of drug resistance Development of drug resistance is an important identified risk for DRV. Development of DRV drug resistance has been reported in clinical trials investigating DRV/rtv 600/100 mg twice daily in highly ART-experienced patients. Based on these data, development of drug resistance was classified as an important identified risk for DRV. Therefore, development of drug resistance was also included as an important identified risk for Symtuza. Overall, very low rates of resistance development were observed in subjects treated with Symtuza in the Phase 3 trials TMC114FD2HTX3001, in treatment-naïve patients, and TMC114IFD3013, in treatment-experienced, virologically suppressed patients. Patients with DRV or FTC/TFV (delivered as tenofovir disoproxil fumarate [TDF] or TAF) phenotypic/genotypic resistance are probably less likely to respond to a therapy with Symtuza. SmPC Section 4.1 SmPC Section 4.2 SmPC Section 4.4 SmPC Section 5.1 Recommendation to use genotypic testing to guide the use of Symtuza in treatment-experienced patients without DRV resistance-associated mutations is provided in SmPC Sections 4.1, 4.2, 4.4, and 5.1

9 Important Potential Risk: Coronary artery events Coronary artery events is an important potential risk for DRV. Hyperglycaemia and lipid abnormalities, which are considered identified risks, are risk factors for developing coronary artery events. Coronary artery events in association with Symtuza have been reported in the Phase 3 trials TMC114FD2HTX3001 and TMC114IFD3013, and in clinical trials of its components. Hyperglycaemia and lipid abnormalities are known risk factors for coronary artery disease. Additional factors that could contribute to developing coronary artery disease in patients with HIV include inflammatory and immunologic factors. The impact of HIV on cardiovascular disease risk is comparable to the traditional risk factors that include hypertension, diabetes, and hyperlipidaemia. Important Potential Risk: Renal toxicity Renal toxicity was identified as a potential risk for TAF, as TDF has been associated with renal toxicity. Circulating TFV levels are more than 90% lower with F/TAF-containing products compared to F/TDF-containing products. Potential risk factors for renal events include advanced HIV disease, older age, renal impairment, use of nephrotoxic medicines, hypertension, and also being infected with HCV. SmPC Section 4.4 SmPC Section 5.1 PL Section 2 Warning for patients with kidney problems is provided in PL Section 2

10 Important Potential Risk: Bone events due to potential proximal renal tubulopathy/loss of BMD Bone events due to potential proximal renal tubulopathy/loss of BMD is a potential risk for TAF as it is a known risk for TDF. Circulating TFV levels are more than 90% lower with F/TAFcontaining products compared to F/TDF-containing products. Changes in BMD for F/TAF-containing regimens are consistent with those for other ARV regimens that are not associated with a bone safety concern. HIV infection is known to be associated with bone disease. Many possible factors have been implicated in the pathogenesis of decreased BMD, including older age, female gender, white race, family history, alcohol, liver disease, low body weight, malnutrition, decreased physical activity, decreased bone acquisition, hypogonadism, amenorrhea, premature menopause, fat deposit in bone marrow, decreased muscle and fat mass, and medications. Important Potential Risk: Ocular effects (posterior uveitis) Posterior uveitis was identified as a nonclinical safety concern based upon nonclinical TAF data. Posterior uveitis in association with Symtuza has not been reported in the Phase 3 trials TMC114FD2HTX3001 and TMC114IFD3013. Not known for Symtuza as there have been no reports of posterior uveitis in the Week-48 analysis of trials TMC114FD2HTX3001 and TMC114IFD3013.

11 Missing Information: Use in elderly (65 years and above) SmPC Section 4.2 SmPC Section 4.4 SmPC Section 5.2 PL Section 2 Recommendation regarding the use of Symtuza in elderly patients is provided in SmPC Sections 4.2, 4.4, and PL Section 2 Missing Information: Use in pregnant and breast-feeding women Additional pharmacovigilance activities SmPC Section 4.6 PL Section 2 Recommendation regarding the use of Symtuza during pregnancy is provided in SmPC Section 4.6 and PL Section 2 Recommendation regarding the use of Symtuza during breastfeeding is provided in SmPC Section 4.6 and PL Section 2 Additional pharmacovigilance activities: Two trials in HIV-infected pregnant women: TMC114HIV3015, PANNA See section II.C of this summary for an overview of the postauthorisation development plan.

12 Missing Information: Use in children <12 years of age Additional pharmacovigilance activities SmPC Section 4.1 SmPC Section 4.2 SmPC Section 4.4 SmPC Section 4.8 SmPC Section 5.1 SmPC Section 5.2 PL Section 1 PL Section 2 PL Section 3 PL Section 5 Warning to keep the product out of the sight and reach of children Additional pharmacovigilance activities: Three clinical trials in HIV-1-infected children: GS-US (for DRV/COBI FDC), GS-US and GS-US (for F/TAF) See section II.C of this summary for an overview of the postauthorisation development plan. Missing Information: Long-term safety of Symtuza Additional pharmacovigilance activities SmPC Section 4.8 PL Section 2 Additional pharmacovigilance activities: Five long-term follow-up studies: TMC114IFD3013 and TMC114FD2HTX3001 (for D/C/F/TAF), GS-US , GS-US , and GS-US (for F/TAF) See section II.C of this summary for an overview of the postauthorisation development plan.

13 Missing Information: Use in patients with severe hepatic impairment (Child-Pugh C) SmPC Section 4.2 SmPC Section 4.3 SmPC Section 4.4 SmPC Section 5.2 PL Section 2 PL Section 4 Warning for patients with liver problems is provided in PL Section 2 Instructions on how to detect signs and symptoms of liver problems are provided in PL Section 4 None Missing Information: Use in patients with moderate or severe renal impairment SmPC Section 4.2 SmPC Section 4.4 SmPC Section 4.8 SmPC Section 5.2 PL Section 2 Recommendation on dose adjustments or discontinuation of Symtuza in patients with renal impairment is provided in SmPC Section 4.2 Advice on the use of Symtuza in patients taking coadministered medicinal products with effect on the estimated creatinine clearance (CrCl) is provided in SmPC Section 4.4 Warning for patients with kidney problems is provided in PL Section 2

14 Missing Information: Use in patients coinfected with HIV and HBV and/or HCV SmPC Section 4.4 SmPC Section 4.5 SmPC Section 4.8 SmPC Section 5.2 PL Section 2 PL Section 4 Recommendation for liver function monitoring is provided in SmPC Section 4.4 Recommendation regarding the use of Symtuza in patients taking coadministered medicinal products for the treatment of HBV or HCV infection is provided in SmPC Section 4.4 Warning for patients with liver problems is provided in PL Section 2 Instructions on how to detect signs and symptoms of liver problems are provided in PL Section 4 None Missing Information: Safety in patients with cardiac conduction disorders II.C. Post-authorisation Development Plan II.C.1. Studies Which are Conditions of the Marketing Authorisation There are no studies which are conditions of the marketing authorisation or specific obligation of Symtuza.

15 II.C.2. Other Studies in Post-authorisation Development Plan TMC114HIV A single-arm, open-label trial to assess the pharmacokinetics of DRV/rtv, DRV/COBI, etravirine, and rilpivirine in HIV-1-infected pregnant women. Purpose of the study: Rationale for inclusion in pharmacovigilance plan: Study the PK of the DRV/COBI component to address the use of Symtuza in pregnant women, which is considered missing information. Study objective: To assess the PK of DRV/COBI in HIV-1-infected pregnant women. PANNA (Investigator Initiated Study) - Study of Pharmacokinetics of newly developed ANtiretroviral agents in HIV-infected pregnant women. Purpose of the study: Rationale for inclusion in pharmacovigilance plan: Study the pharmacokinetics (PK) of the DRV/COBI component to address the use of Symtuza in pregnant women, which is considered missing information. Study objective: To assess the PK of DRV/COBI in HIV-infected pregnant women. GS-US A Phase 2/3, multicenter, open-label, multicohort, two-part study evaluating pharmacokinetics, safety, and efficacy of cobicistat-boosted atazanavir or cobicistat-boosted darunavir, administered with an optimized background regimen in HIV-1-infected, treatmentexperienced, virologically suppressed pediatric subjects. Purpose of the study: Rationale for inclusion in pharmacovigilance plan: Study the efficacy and safety of the DRV/COBI component to address the use of Symtuza in children, which is considered missing information. Study objectives: To evaluate the steady-state PK and confirm the dose of cobicistat-boosted atazanavir (ATV/COBI) or cobicistat-boosted DRV (DRV/COBI). To evaluate the safety, tolerability, and efficacy of ATV/COBI and DRV/COBI. GS-US A Phase 2/3, Open-Label, Multi-Cohort Switch Study to Evaluate Emtricitabine/Tenofovir Alafenamide (F/TAF) in HIV-1 Infected Children and Adolescents Virologically Suppressed on a 2-NRTI-Containing Regimen. Purpose of the study: Rationale for inclusion in pharmacovigilance plan: Study the PK, efficacy and safety of the F/TAF component to address the use of Symtuza in children, which is considered missing information.

16 Study objectives: To evaluate the PK and confirm the dose of TAF. To evaluate the safety, tolerability, and efficacy of F/TAF. TMC114IFD A Phase 3, randomized, active-controlled, open-label study to evaluate switching to a D/C/F/TAF once-daily single-tablet regimen versus continuing the current regimen consisting of a boosted protease inhibitor combined with FTC/TDF in virologicallysuppressed, HIV-1 infected subjects. Purpose of the study: Rationale for inclusion in pharmacovigilance plan: Study the long-term efficacy, resistance and safety of the D/C/F/TAF FDC to address the long-term safety of Symtuza, which is considered missing information. Study objectives: To demonstrate non-inferiority in efficacy of switching to a D/C/F/TAF once-daily singletablet regimen relative to continuing the current boosted protease inhibitor (bpi) combined with FTC/TDF in virologically-suppressed (HIV-1 RNA <50 copies/ml) HIV-1-infected subjects, until Week 48. To evaluate long-term efficacy, resistance, and safety of the D/C/F/TAF FDC regimen (Week 96 and beyond). TMC114FD2HTX A Phase 3, randomized, active-controlled, double-blind study to evaluate efficacy and safety of D/C/F/TAF once daily fixed-dose combination regimen versus a regimen consisting of DRV/COBI FDC coadministered with FTC/TDF FDC in ARV treatmentnaïve HIV-1 infected subjects. Purpose of the study: Rationale for inclusion in pharmacovigilance plan: Study the long-term efficacy, resistance and safety of the D/C/F/TAF FDC to address the long-term safety of Symtuza, which is considered missing information. Study objectives: To demonstrate non-inferiority in efficacy of D/C/F/TAF FDC vs. DRV/COBI FDC coadministered with FTC/TDF FDC in HIV-1-infected subjects until Week 48. To evaluate long-term efficacy, resistance, and safety of the D/C/F/TAF FDC regimen (Week 96 and beyond). GS-US A Phase 2/3, Open-Label Study of the Pharmacokinetics, Safety, and Antiviral Activity of the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Single Tablet Regimen (STR) in HIV-1 Infected Antiretroviral Treatment-Naive Adolescents and Virologically Suppressed Children.

17 Purpose of the study: Rationale for inclusion in pharmacovigilance plan: Study the PK, safety and antiviral activity of the COBI and F/TAF components to address the long-term safety of Symtuza and its use in children, which is considered missing information. Study objective: To evaluate the PK, safety, tolerability, and antiviral activity of E/C/F/TAF in HIV-infected, ART-naïve adolescents and virologically suppressed HIV-infected children. GS-US A Phase 3, Open-Label Study to Evaluate Switching from a TDF-Containing Combination Regimen to a TAF-Containing Combination Single Tablet Regimen (STR) in Virologically-Suppressed, HIV-1 Positive Subjects. Purpose of the study: Rationale for inclusion in pharmacovigilance plan: Study the efficacy and safety of the TAF component to address the long-term safety of Symtuza, which is considered missing information. Study objective: To evaluate switching from a TDF-containing combination regimen to a TAFcontaining combination single tablet regimen in virologically suppressed, HIV-1-positive subjects. GS-US A Phase 3b, Randomized, Double-Blind, Switch Study to Evaluate F/TAF in HIV-1 Positive Subjects who are Virologically Suppressed on Regimens containing ABC/3TC. Purpose of the study: Rationale for inclusion in pharmacovigilance plan: Study the efficacy and safety of the F/TAF component to address the long-term safety of Symtuza, which is considered missing information. Study objective: To collect information on the efficacy of switching abacavir (ABC)/lamivudine (3TC) to F/TAF vs. maintaining ABC/3TC in HIV-1-infected subjects who are virologically suppressed on regimens containing ABC/3TC as determined by the proportion of subjects with HIV-1 RNA <50 copies/ml at Week 48.