Pifeltro

HOS-098625 · has-adverse-reaction-information · PDF-Seite 13

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 postmarketing 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), or not known (cannot be estimated from the available data). Table 2: Tabulated summary of adverse reactions associated with doravirine used in combination with other antiretrovirals Frequency Adverse reactions Infections and infestations Rare rash pustular 13 Frequency Adverse reactions Metabolism and nutrition disorders Uncommon hypophosphataemia Rare hypomagnesaemia 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 Vascular disorders Uncommon hypertension Respiratory, thoracic and mediastinal disorders Rare dyspnoea, tonsillar hypertrophy Gastroint

Auszug; vollständigen Abschnitt im Original lesen.

HOS-098621 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance 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 Pifeltro (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

HOS-098620 · has-indication-information · PDF-Seite 2

Pifeltro is indicated, in combination with other antiretroviral medicinal products, for the treatment of adults, and adolescents aged 12 years and older weighing at least 35 kg 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 (see sections 4.4 and 5.1).

HOS-098623 · has-interaction-information · PDF-Seite 4

Effects of other medicinal products on 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 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 (see sections 4.3 and 5.2). Co-administration with the moderate CYP3A inducer rifabutin decreased doravirine concentrations (see Table 1). When doravirine is co-administered with rifabutin, the doravirine dose should be increased to 100 mg twice daily (the doses should be taken approximately 12 hours apart) (see section 4.2). Co-administration of doravirine 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., dabrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) cannot be avoided, the doravirine dose should be increased to 100 mg twice daily (the doses should be taken approximately 12 hours apart) (see section 4.2). Co-administration of doravirine 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. 4 Effects of doravirine on other medicinal products Doravirine at a dose of 100 mg once daily is not likely to have a clinically relevant effect on the plasma concentrations of medicinal products that are dependent on transport proteins for absorption and/or elimination or that are metabolised by CYP enzymes. However, co-administration of doravirine and the sensitive CYP3A substrate midazolam resulted in a 18 % decrease in midazolam exposure, suggesting that doravirine may be a weak CYP3A inducer. Therefore caution should be used when co-administering doravirine with medicinal products that are sensitive CYP3A substrates that also have a narrow therapeutic window (e.g., tacrolimus and sirolimus). Interactions table Table 1 shows the established and other potential medicinal product interactions with doravirine but is not all inclusive (increase is indicated as , decrease is indicated as ↓, and no change as ↔). Table 1: Interactions of doravi

Auszug; vollständigen Abschnitt im Original lesen.

HOS-098624 · has-pregnancy-information · PDF-Seite 12

Pregnancy There are no or limited amount of data from the use of doravirine in pregnant women. 12 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). As a precautionary measure, it is preferable to avoid the use of doravirine 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). 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 doravirine on fertility are available. Animal studies do not indicate harmful effects of doravirine on fertility at exposure levels higher than the exposure in humans at the recommended clinical dose (see section 5.3).

HOS-098622 · has-warning-information · PDF-Seite 3

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 postmarketing 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 3 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, Pifeltro 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 Pifeltro, treatment with Pifeltro must not be restarted in this patient at any time. Use with CYP3A inducers Caution should be given to prescribing doravirine with medicinal products that may reduce the exposure of doravirine (see sections 4.3 and 4.5). Immune reactivation syndrome Immune reactivation syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, autoimmune hepatitis, polymyositis, and Guillain- Barré syndrome) have also been reported to occur in the setting of imm

Auszug; vollständigen Abschnitt im Original lesen.