Intelence · 4.4 Special warnings and precautions for use · 1

HOS-095012 · has-adverse-reaction-information · PDF-Seite 15

Summary of the safety profile The most frequent (incidence ≥ 10%) adverse reactions of all intensities reported for etravirine were rash, diarrhoea, nausea and headache. In the Phase III studies, the rates of discontinuation due to any adverse reaction were 7.2% in patients receiving etravirine. The most common adverse reaction leading to discontinuation was rash. Tabulated list of adverse reactions Adverse reactions reported in patients treated with etravirine are summarised in Table 3. The adverse reactions are listed by system organ class (SOC) and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000). Table 3: Adverse reactions observed with etravirine in clinical trials and post-marketing experience System Organ Class Frequency Adverse Reaction (SOC) category Blood and lymphatic common thrombocytopaenia, anaemia, decreased neutrophils 15  system disorders uncommon decreased white blood cell count Immune system common drug hypersensitivity disorders uncommon immune reconstitution syndrome Metabolism and common diabetes mellitus, hyperglycaemia, nutrition disorders hypercholesterolaemia, increased low density lipoprotein (LDL), hypertriglyceridaemia, hyperlipidaemia, dyslipidaemia, anorexia Psychiatric disorders common anxiety, insomnia, sleep disorders uncommon confusional state, disorientation, nightmares, nervousness, abnormal dreams Nervous system very common headache disorders common peripheral neuropathy, paraesthesia, hypoaesthesia, amnesia, somnolence uncommon convulsion, syncope, tremor, hypersomnia, disturbance

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HOS-095008 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with elbasvir/grazoprevir (see section 4.5).

HOS-095007 · has-indication-information · PDF-Seite 3

INTELENCE, in combination with a boosted protease inhibitor and other antiretroviral medicinal products, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients and in antiretroviral treatment-experienced paediatric patients from 2 years of age (see sections 4.4, 4.5 and 5.1).

HOS-095010 · has-interaction-information · PDF-Seite 6

Medicinal products that affect etravirine exposure Etravirine is metabolised by CYP3A4, CYP2C9 and CYP2C19 followed by glucuronidation of the metabolites by uridine diphosphate glucuronosyl transferase (UDPGT). Medicinal products that 6 induce CYP3A4, CYP2C9 or CYP2C19 may increase the clearance of etravirine, resulting in lowered plasma concentrations of etravirine. Co-administration of etravirine and medicinal products that inhibit CYP3A4, CYP2C9 or CYP2C19 may decrease the clearance of etravirine and may result in increased plasma concentrations of etravirine. Medicinal products that are affected by the use of etravirine Etravirine is a weak inducer of CYP3A4. Co-administration of etravirine with medicinal products primarily metabolised by CYP3A4 may result in decreased plasma concentrations of such medicinal products, which could decrease or shorten their therapeutic effects. Etravirine is a weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein. Co-administration with medicinal products primarily metabolised by CYP2C9 or CYP2C19, or transported by P-glycoprotein, may result in increased plasma concentrations of such medicinal products, which could increase or prolong their therapeutic effect or alter their adverse events profile. Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in table 2. The table is not all-inclusive. Interaction table Interactions between etravirine and co-administered medicinal products are listed in table 2 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, not done as “ND”, confidence interval as “CI”). Table 2: Interactions and dose recommendations with other medicinal products Medicinal products by Effects on drug levels Recommendations therapeutic areas Least Squares Mean Ratio concerning (90% CI; 1.00 = No effect) co-administration ANTI-INFECTIVES Antiretrovirals NRTIs Didanosine didanosine No significant effect on 400 mg once daily AUC ↔ 0.99 (0.79-1.25) didanosine and etravirine PK Cmin ND parameters is seen. Cmax ↔ 0.91 (0.58-1.

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HOS-095011 · has-pregnancy-information · PDF-Seite 15

Pregnancy As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women, and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account in order to characterise the safety for the foetus. Placental transfer has been seen in pregnant rats, but it is not known whether placental transfer of etravirine also occurs in pregnant women. Studies in animals do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Based on animal data the malformative risk is unlikely in humans. The clinical data do not raise safety concern but are very limited. Breast-feeding Etravirine is excreted in human milk. Because of the potential for adverse events in nursing infants, women should be instructed not to breastfeed if they are receiving INTELENCE. It is recommended that women living with HIV do not breastfeed in order to avoid transmission of HIV. Fertility No human data on the effect of etravirine on fertility are available. In rats, there was no effect on mating or fertility with etravirine treatment (see section 5.3).

HOS-095009 · has-warning-information · PDF-Seite 4

INTELENCE should optimally be combined with other antiretrovirals that exhibit activity against the patient’s virus (see section 5.1). A decreased virologic response to etravirine was observed in patients with viral strains harbouring 3 or more among the following mutations V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, and G190A/S (see section 5.1). Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results. No data other than drug-drug interaction data (see section 4.5) are available when etravirine is combined with raltegravir or maraviroc. Severe cutaneous and hypersensitivity reactions Severe cutaneous adverse reactions have been reported with etravirine. In clinical trials, Stevens-Johnson Syndrome and erythema multiforme have been rarely (< 0.1%) reported. Treatment with INTELENCE should be discontinued if a severe cutaneous reaction develops. The clinical data are limited and an increased risk of cutaneous reactions in patients with a history of NNRTI-associated cutaneous reactions cannot be excluded. Caution should be observed in such patients, especially in case of history of a severe cutaneous drug reaction. Cases of severe hypersensitivity syndromes, including DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and TEN (toxic epidermal necrolysis), sometimes fatal, have been reported with the use of etravirine (see section 4.8). The DRESS syndrome is characterised by rash, fever, 4 eosinophilia and systemic involvement (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and eosinophilia). Time to onset is usually around 3-6 weeks and the outcome in most cases is favourable upon discontinuation and after initiation of corticosteroid therapy. Patients should be informed to seek medical advice if severe rash or hypersensitivity reactions occur. Patients who are diagnosed with a hypersensitivity reaction whilst on therapy must discontinue INTELENCE immediately. Delay in stopping INTELENCE treatment after the onset of severe rash may result in a life-threatening reaction. Patients who have stopped treatment due to hypersensitivity reactions should not restart therapy with INTELEN

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