Delstrigo · 4.8 Undesirable effects · 1

HOS-098617 · has-adverse-reaction-information · PDF-Seite 17

Summary of the safety profile In phase 3 clinical trials with doravirine plus 2 nucleoside reverse transcriptase inhibitors (NRTIs), the most frequently reported adverse reactions were nausea (4 %) and headache (3 %). Tabulated summary of adverse reactions The adverse reactions with doravirine plus 2 NRTIs from Phase 3 clinical trials (DRIVE-FORWARD, DRIVE-SHIFT and DRIVE-AHEAD) and post-marketing experience are listed below by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), or not known (cannot be estimated from the available data). Table 2: Tabulated summary of adverse reactions associated with doravirine/lamivudine/tenofovir disoproxil Frequency Adverse reactions Infections and infestations Rare rash pustular Blood and lymphatic systems disorders Uncommon neutropenia*, anaemia*, thrombocytopenia* Very rare pure red cell aplasia* Metabolism and nutrition disorders Uncommon hypophosphataemia, hypokalaemia* Rare hypomagnesaemia, lactic acidosis* Psychiatric disorders Common abnormal dreams, insomnia1, Uncommon nightmare, depression2, anxiety3, irritability, confusional state, suicidal ideation Rare aggression, hallucination, adjustment disorder, mood altered, somnambulism Nervous system disorders Common headache, dizziness, somnolence Uncommon disturbance in attention, memory impairment, paraesthesia, hypertonia, poor quality sleep Very rare peripheral neuropathy (or paraesthesia)* Vascular disorders Uncommon hypertension Respiratory, thoracic and mediastinal disorders Common

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HOS-098613 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Co-administration with medicinal products that are strong cytochrome P450 CYP3A enzyme inducers is contraindicated as significant decreases in doravirine plasma concentrations are expected to occur, which may decrease the effectiveness of Delstrigo (see sections 4.4 and 4.5). These medicinal products include, but are not limited to the following: • carbamazepine, oxcarbazepine, phenobarbital, phenytoin • rifampicin, rifapentine • St. John’s wort (Hypericum perforatum) • mitotane • enzalutamide • lumacaftor 3

HOS-098612 · has-indication-information · PDF-Seite 2

Delstrigo is indicated for the treatment of adults infected with human immunodeficiency virus type 1 (HIV-1) without past or present evidence of resistance to the non-nucleoside reverse transcriptase inhibitors (NNRTI) class, lamivudine, or tenofovir (see sections 4.4 and 5.1). Delstrigo is also indicated for the treatment of adolescents aged 12 years and older weighing at least 35 kg who are infected with HIV-1 without past or present evidence of resistance to the NNRTI class, lamivudine, or tenofovir and who have experienced toxicities which preclude the use of other regimens that do not contain tenofovir disoproxil (see sections 4.4 and 5.1).

HOS-098615 · has-interaction-information · PDF-Seite 6

Delstrigo is a complete regimen for the treatment of HIV-1 infection; therefore, Delstrigo should not be administered with other antiretroviral medicinal products. Information regarding potential medicinal product interactions with other antiretroviral medicinal products is not provided. Interaction studies have only been performed in adults. Delstrigo contains doravirine, lamivudine, and tenofovir disoproxil, therefore any interactions identified for these individually are relevant to Delstrigo and are presented in Table 1. Effects of other medicinal products on doravirine, lamivudine, and tenofovir disoproxil Doravirine Doravirine is primarily metabolised by CYP3A, and medicinal products that induce or inhibit CYP3A are expected to affect the clearance of doravirine (see section 5.2). Doravirine/lamivudine/tenofovir disoproxil should not be co-administered with medicinal products that are strong CYP3A enzyme inducers as significant decreases in doravirine plasma concentrations are expected to occur, which may decrease the effectiveness of doravirine/lamivudine/tenofovir disoproxil (see sections 4.3 and 5.2). Co-administration with the moderate CYP3A inducer rifabutin decreased doravirine concentrations (see Table 1). When Delstrigo is co-administered with rifabutin, a 100 mg dose of doravirine should be given daily, approximately 12 hours after doravirine/lamivudine/tenofovir disoproxil dose (see section 4.2). Co-administration of doravirine/lamivudine/tenofovir disoproxil with other moderate CYP3A inducers has not been evaluated, but decreased doravirine concentrations are expected. If co-administration with other moderate CYP3A inducers (e.g., debrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) cannot be avoided, a 100 mg dose of doravirine should be administered daily, approximately 12 hours after the administration of doravirine/lamivudine/tenofovir disoproxil dose (see section 4.2). Co-administration of doravirine/lamivudine/tenofovir disproxil and medicinal products that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine. However, no dose adjustment is needed when doravirine is co-administered with CYP3A inhibitors. 6 Lamivudine Because lamivudine is primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion (see section 5.2), co-administration of doravirine/lamivudi

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HOS-098616 · has-pregnancy-information · PDF-Seite 16

Pregnancy There are no or limited amount of data from the use of doravirine in pregnant women. A large amount of data on pregnant women (more than 3 000 outcomes from first trimester) taking the individual active component lamivudine in combination with other antiretrovirals indicates no malformative toxicity. A moderate amount of data on pregnant women (between 300-1 000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with tenofovir disoproxil. Antiretroviral pregnancy registry To monitor maternal-foetal outcomes in patients exposed to antiretroviral medicinal products while pregnant, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients in this registry. Animal studies with doravirine do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Animal studies with tenofovir disoproxil do not indicate direct or indirect harmful effects of tenofovir disoproxil with respect to reproductive toxicity (see section 5.3). Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not in rats (see section 5.3). Placental transfer of lamivudine has been shown to occur in humans. Lamivudine may inhibit cellular DNA replication (see section 5.3). The clinical relevance of this finding is unknown. As a precautionary measure, it is preferable to avoid the use of Delstrigo during pregnancy. Breast-feeding It is unknown whether doravirine is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of doravirine in milk (see section 5.3). Lamivudine has been identified in breast-fed newborns/infants of treated women. Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breast-fed infants of mothers treated for HIV are very low (< 4 % of maternal serum concentrations) and progressively decrease to undetectable levels when breast-fed infants reach 24 weeks of age. There are no data available on the safety of lamivudine when administered to babies less than three months old. Tenofovir is excreted in human milk. There is insufficient information on the effects of tenofovir in newborns/infants. It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV. Fertility No human data on the effect of Delstrigo on fertility are available. Animal studies do not ind

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HOS-098614 · has-warning-information · PDF-Seite 4

NNRTI substitutions and use of doravirine Doravirine has not been evaluated in patients with previous virologic failure to any other antiretroviral therapy. NNRTI-associated mutations detected at screening were part of exclusion criteria in the Phase 2b/3-studies. A breakpoint for a reduction in susceptibility, yielded by various NNRTI substitutions, that is associated with a reduction in clinical efficacy has not been established (see section 5.1). There is not sufficient clinical evidence to support the use of doravirine in patients infected with HIV-1 with evidence of resistance to the NNRTI class. Severe cutaneous adverse reactions (SCARs) Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported during the post-marketing experience with doravirine-containing regimens (see section 4.8). In addition, drug reaction with eosinophilia and systemic symptoms (DRESS) was reported in a clinical trial with a two-drug regimen containing doravirine (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, Delstrigo should be withdrawn immediately and an alternative treatment considered (as appropriate). Clinical status should be closely monitored, and appropriate therapy should be initiated. If the patient has developed a serious reaction such as SJS/TEN or DRESS with the use of Delstrigo, treatment with Delstrigo must not be restarted in this patient at any time. Severe acute exacerbation of hepatitis B in patients co-infected with HIV-1 and HBV All patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy. Severe acute exacerbations of hepatitis B (e.g., liver decompensated and liver failure) have been reported in patients who are co-infected with HIV-1 and HBV, and have discontinued lamivudine or tenofovir disoproxil, two of the components of Delstrigo. Patients who are co-infected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with Delstrigo. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failur

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