Adverse reactions : תופעות לוואי

4.8    Undesirable effects
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 2. 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 2:     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 system disorders                       neutrophils 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           headache disorders               common common         peripheral neuropathy, paraesthesia, hypoaesthesia,
amnesia, somnolence uncommon       convulsion, syncope tremor, hypersomnia,
disturbance in attention
Eye disorders           common         blurred vision
Ear and labyrinth       uncommon       vertigo disorders
Cardiac disorders       common         myocardial infarction uncommon       atrial fibrillation, angina pectoris
Vascular disorders      common         hypertension
                                   rare                 haemorrhagic strokea
Respiratory, thoracic           common               exertional dyspnoea and mediastinal                 uncommon             bronchospasm disorders
Gastrointestinal                very                 diarrhoea, nausea disorders                       common common               gastrooesophageal reflux disease, vomiting,
abdominal pain, abdominal distension, flatulence,
gastritis, constipation, dry mouth, stomatitis, lipase increased, blood amylase increased uncommon             pancreatitis, haematemesis, retching
Hepatobiliary                   common               increased alanine aminotransferase (ALT), disorders                                            increased aspartate aminotransferase (AST) uncommon             hepatitis, hepatic steatosis, cytolytic hepatitis, hepatomegaly
Skin and                        very                 rash subcutaneous tissue             common disorders                       common               night sweats, dry skin, prurigo uncommon             angioneurotic oedemaa, swelling face,
hyperhidrosis rare                 Stevens-Johnson Syndromea, erythema multiformea very rare            toxic epidermal necrolysisa, DRESSb
Renal and urinary               common               renal failure, blood creatinine increased disorders
Reproductive system             uncommon             gynaecomastia and breast disorders
General disorders and           common               fatigue administration site             uncommon             sluggishness conditions a
These adverse reactions were observed in other clinical trials than DUET-1 and DUET-2.
b
These adverse reactions have been identified through postmarketing experience with etravirine.


Description of selected adverse reactions
Rash
Rash was most frequently mild to moderate, generally macular to maculopapular or erythematous, mostly occurred in the second week of therapy, and was infrequent after week 4.
Rash was mostly self-limiting, and generally resolved within 1-2 weeks on continued therapy (see section 4.4). The incidence of rash was higher in women compared to men in the etravirine arm in the DUET trials (rash ≥ grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations due to rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men) (see section 4.4). There was no gender difference in severity or treatment discontinuation due to rash. The clinical data are limited and an increased risk of cutaneous reactions in patients with a history of NNRTI-associated cutaneous reaction cannot be excluded (see section 4.4).


Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4)

Immune reconstitution syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Osteonecrosis
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy.
The frequency of this is unknown (see section 4.4).

Other special populations
Patients co-infected with hepatitis B and/or hepatitis C virus
In the pooled analysis for DUET-1 and DUET-2, the incidence of hepatic events tended to be higher in co-infected subjects treated with INTELENCE compared to co-infected subjects in the placebo group. INTELENCE should be used with caution in these patients (see also sections 4.4 and 5.2).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectM edic@moh.gov.il