Special Warning : אזהרת שימוש

4.4    Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

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; 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, 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 INTELENCE.

Rash
Rash has been reported with etravirine. Most frequently, rash was mild to moderate, occurred in the second week of therapy and was infrequent after week 4. Rash was mostly self-limiting and generally resolved within 1 to 2 weeks on continued therapy. When prescribing INTELENCE to females, prescribers should be aware that the incidence of rash was higher in females (see section 4.8).

Elderly
Experience in geriatric patients is limited: In the Phase III trials, 6 patients aged 65 years or older and 53 patients aged 56-64 years received etravirine. The type and incidence of adverse reaction in patients > 55 years of age were similar to the ones in younger patients (see sections 4.2 and 5.2).

Pregnancy
Given the increased etravirine exposure during pregnancy, caution should be applied for those pregnant patients that require concomitant medicinal products or have comorbidities that may further increase etravirine exposure.

Patients with coexisting conditions
Hepatic impairment
Etravirine is primarily metabolised and eliminated by the liver and highly bound to plasma proteins. Effects on unbound exposure could be expected (has not been studied) and therefore caution is advised in patients with moderate hepatic impairment. etravirine has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and its use is therefore not recommended in this group of patients (see sections 4.2 and 5.2).

Co-infection with HBV (hepatitis B virus) or HCV (hepatitis C virus)
Caution should be exercised in patients co-infected with hepatitis B or C virus due to the current limited data available. A potential increased risk of liver enzymes increase cannot be excluded.

Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Immune reconstitution syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis ) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable, and these events can occur many months after initiation of treatment (see section 4.8).

Osteonecrosis
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Interactions with medicinal products
It is not recommended to combine etravirine with tipranavir/ritonavir, due to a marked pharmacokinetic interaction (76% decrease of etravirine AUC) that could significantly impair the virologic response to etravirine.

The combination of etravirine with simeprevir, daclatasvir, atazanavir/cobicistat or darunavir/cobicistat is not recommended (see section 4.5).

For further information on interactions with medicinal products see section 4.5.

Lactose intolerance and lactase deficiency
INTELENCE 100 mg

Each tablet contains 160 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Effects on Driving

4.7    Effects on ability to drive and use machines

INTELENCE has minor influence on the ability to drive and use machines. No studies on the effects of INTELENCE on the ability to drive or operate machines have been performed.
Adverse reactions such as somnolence and vertigo have been reported in etravirine treated patients and should be considered when assessing a patient’s ability to drive or operate machinery (see section 4.8).