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Risk-Management-Plan Summary PART VI SUMMARY OF THE RISK MANAGEMENT PLAN BY PRODUCT Summary of risk management plan for DELSTRIGO (doravirine + lamivudine + tenofovir disoproxil) This is a summary of the risk management plan (RMP) for DELSTRIGO. The RMP details important risks of DELSTRIGO and how more information will be obtained about DELSTRIGO’s risks and uncertainties (missing information). DELSTRIGO’s summary of product characteristics (SmPC) and its package leaflet give essential information to healthcare professionals and patients on how DELSTRIGO should be used. This summary of the RMP for DELSTRIGO 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 DELSTRIGO’s RMP. I. The Medicine and What it is Used For DELSTRIGO is indicated for the treatment of adults infected with HIV-1 without past or present evidence of resistance to the NNRTI class, lamivudine, or tenofovir. It contains doravirine (+) lamivudine (+) tenofovir disoproxil as the active substances and it is given only by mouth. Further information about the evaluation of DELSTRIGO’s benefits can be found in DELSTRIGO’s EPAR, including in its plain-language summary, available on the EMA website, under the medicine’s webpage: link to product’s EPAR summary landing page on the EMA webpage. http://www.ema.europa.eu/ema/index.jsp?curl=/pages/medicines/human/medicines/004746/h uman_med_002329.jsp&mid=WC0b01ac058001d124 II. Risks Associated With the Medicine and Activities to Minimise or Further Characterise the Risks Important risks of DELSTRIGO, together with measures to minimise such risks and the proposed studies for learning more about DOR/3TC/TDF'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 package leaflet and SmPC addressed to patients and healthcare professionals; Important advice on the medicine’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 (e.g. with or without prescription) can help to minimise its risks. Together, these measures constitute routine risk minimisation measures. If important information that may affect the safe use of DELSTRIGO is not yet available, it is listed under ‘missing information’ below. II.A List of Important Risks and Missing Information Important risks of DELSTRIGO 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 DELSTRIGO. 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 (e.g. on the long-term use of the medicine); Table II.A.1 List of Important Risks and Missing Information List of important risks and missing information Attributable Component of Safety Concern for DELSTRIGO DELSTRIGO Important identified risks 3TC,TDF Severe acute exacerbations of hepatitis B TDF New onset or worsening renal impairment/Renal toxicity TDF Decreases in bone mineral density (BMD)/bone events due to proximal renal tubulopathy Important potential risks None Missing information DOR,3TC,TDF Safety during pregnancy DOR,3TC,TDF Safety during lactation DOR,3TC,TDF Safety in elderly population DOR Long-term safety II.B Summary of Important Risks Table II.B.1 Important Identified Risk: Severe Acute Exacerbations of Hepatitis B Evidence for linking the risk to the Literature. medicine Lamivudine SmPC Tenofovir (VIREAD) SmPC Risk factors and risk groups Patients with diminished hepatic function are at a greater risk of more severe outcomes following post-treatment hepatic flares. Risk minimisation measures Routine risk minimisation measures Section 4.4 of the SmPC. What you need to know before you take DELSTRIGO and Possible side effects sections of the Package Leaflet Table II.B.2 Important Identified Risk: New Onset or Worsening Renal Impairment/Renal Toxicity Evidence for linking the risk to the Literature. medicine Tenofovir (VIREAD) SmPC Risk factors and risk groups Tenofovir is principally eliminated via the kidney. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of TDF in clinical practice. Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation. However, in some patients, declines in creatinine clearance did not completely resolve despite TDF discontinuation. Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients receiving concomitant nephrotoxic medications) are at increased risk of experiencing incomplete recovery of renal function despite TDF discontinuation. Risk minimisation measures Routine risk minimisation measures Section 4.2 Section 4.4, Section 4.8 and Section 5.2 of the SmPC. What you need to know before you take DELSTRIGO and Possible side effects sections of the Package Leaflet Table II.B.3 Important Identified Risk: Decreases in bone Mineral Density (BMD)/Bone Events due to Proximal Renal Tubulopathy Evidence for linking the risk to the Literature. medicine Tenofovir (VIREAD) SmPC Risk factors and risk groups In HIV infected patients, in a 144-week controlled clinical study that compared TDF with stavudine in combination with 3TC and EFV in antiretroviral-naïve adult patients, small decreases in bone mineral density (BMD) of the hip and spine were observed in both treatment groups. Decreases in BMD of spine and changes in bone biomarkers from baseline were significantly greater in the TDF treatment group at 144 weeks. Decreases in BMD of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks. In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen in patients treated with TDF as part of a regimen containing a boosted protease inhibitor. Alternative treatment regimens should be considered for patients with osteoporosis that are at a high risk for fractures. Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy. HIV infection is known to be associated with bone disease. A variety of bone disorders have been seen in patients with HIV-1 infection including osteoporosis, osteopenia, osteomalacia and osteonecrosis and there is evidence to suggest that the risk of these disorders is increased in HIV infection. The contributing factors to bone demineralization in HIV-1 infected patients are multifactorial. 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, cytokines, decreased physical activity, decreased bone acquisition, hypogonadism, amenorrhea, premature menopause, fat deposit in bone marrow, decreased muscle and fat mass, and medications {04Q7RX} {04Q7QC}. The importance of the influence of non-antiretroviral risk factors is shown by the greater than expected proportion of HIV uninfected MSM with low BMD, which has been associated with amphetamine and inhalant use {04Q7RX} {04Q7QC}, {04Q9LK}. Risk minimisation measures Routine risk minimisation measures Section 4.4 and Section 4.8 of the SmPC. What you need to know before you take DELSTRIGO and Possible side effects section of the Package Leaflet Table II.B.4 Missing Information: Safety During Pregnancy Risk minimisation measures Routine risk minimisation measures: Section 4.6 and Section 5.3 of the SmPC. What you need to know before you take DELSTRIGO section of the Package Leaflet Table II.B.5 Missing information: Safety during lactation Risk minimisation measures Routine risk minimisation measures: Section 4.6 and Section 5.3 of the SmPC. What you need to know before you take DELSTRIGO section of the Package Leaflet Table II.B.6 Missing Information: Safety in Elderly Population Risk minimisation measures Routine risk minimisation measures Section 4.2 and Section 5.2 of the SmPC. Table II.B.7 Missing Information: Long-term Safety Risk minimisation measures Routine risk minimisation measures: Section 4.8 of the SmPC. 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 DELSTRIGO. II.C.2 Other Studies in Post-authorisation Development Plan There are no studies required for DELSTRIGO. .
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