Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Efavirenz has been studied in over 9,000 patients. In a subset of 1,008 adult patients who received 600 mg efavirenz daily in combination with PIs and/or NRTIs in controlled clinical studies, the most frequently reported adverse reactions of at least moderate severity reported in at least 5 % of patients were rash (11.6 %), dizziness (8.5 %), nausea (8.0 %), headache (5.7 %) and fatigue (5.5 %). The most notable adverse reactions associated with efavirenz are rash and nervous system symptoms. Nervous system symptoms usually begin soon after therapy onset and generally resolve after the first 2 - 4 weeks. Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; psychiatric adverse reactions including severe depression, death by suicide, and psychosis like behaviour; and seizures have been reported in patients treated with efavirenz. The administration of efavirenz with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions (see section 4.4).

The long-term safety profile of efavirenz-containing regimens was evaluated in a controlled trial (006) in which patients received efavirenz + zidovudine + lamivudine (n = 412, median duration 180 weeks), efavirenz + indinavir (n = 415, median duration 102 weeks), or indinavir + zidovudine + lamivudine (n = 401, median duration 76 weeks). Long-term use of efavirenz in this study was not associated with any new safety concerns.

Tabulated list of adverse reactions

Adverse reactions of moderate or greater severity with at least possible relationship to treatment regimen (based on investigator attribution) reported in clinical trials of efavirenz at the recommended dose in combination therapy (n = 1,008) are listed below. Also listed in italics are adverse reactions observed post-marketing in association with efavirenz-containing antiretroviral treatment regimens.
Frequency is defined using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); or not known (cannot be estimated from the available data).


Immune system disorders uncommon                                      hypersensitivity

Metabolism and nutrition disorders common                                        hypertriglyceridaemia*
 uncommon                                      hypercholesterolaemia*
Psychiatric disorders common                                        abnormal dreams, anxiety, depression, insomnia*  uncommon                                      affect lability, aggression, confusional state, euphoric mood, hallucination, mania, paranoia,
psychosis‡, suicide attempt, suicide ideation,
catatonia*
 rare                                          delusion‡‡, neurosis‡‡, completed suicide‡‡* 
Nervous system disorders common                                        cerebellar coordination and balance disturbances‡, disturbance in attention (3.6 %),
dizziness (8.5 %), headache (5.7 %), somnolence
(2.0 %)*
 uncommon                                      agitation, amnesia, ataxia, coordination abnormal, convulsions, thinking abnormal, tremor‡
 not known                                     encephalopathy
Eye disorders uncommon                                      vision blurred

Ear and labyrinth disorders uncommon                                      tinnitus‡, vertigo
Vascular disorders uncommon                                      flushing‡

Gastrointestinal disorders common                                        abdominal pain, diarrhoea, nausea, vomiting  uncommon                                      pancreatitis

Hepatobiliary disorders common                                        aspartate aminotransferase (AST) increased*, alanine aminotransferase (ALT) increased*,
gamma-glutamyltransferase (GGT) increased*
 uncommon                                      hepatitis acute
 rare                                          hepatic failure‡‡*
Skin and subcutaneous tissue disorders very common                                   rash (11.6 %)*


common                                                   pruritus
 uncommon                                                 erythema multiforme, Stevens-Johnson syndrome*
 rare                                                     photoallergic dermatitis‡ 
Reproductive system and breast disorders uncommon                                                 gynaecomastia 
General disorders and administration site conditions common                                               fatigue

*,‡ ,‡‡ See section Description of selected adverse reactions for more details.
Description of selected adverse reactions

Information regarding post-marketing surveillance
‡
These adverse reactions were identified through post-marketing surveillance; however the frequencies were determined using data from 16 clinical trials (n=3,969).
‡‡
These adverse reactions were identified through post-marketing surveillance but not reported as drug-related events for efavirenz-treated patients in 16 clinical trials. The frequency category of "rare" was defined per A Guideline on Summary of Product Characteristics (SmPC) (rev. 2, Sept 2009) on the basis of an estimated upper bound of the 95 % confidence interval for 0 events given the number of patients treated with efavirenz in these clinical trials (n=3,969).

Rash
In clinical studies, 26 % of patients treated with 600 mg of efavirenz experienced skin rash compared with 17 % of patients treated in control groups. Skin rash was considered treatment related in 18 % of patients treated with efavirenz. Severe rash occurred in less than 1 % of patients treated with efavirenz, and 1.7 % discontinued therapy because of rash. The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0.1%.

Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first two weeks of initiating therapy with efavirenz. In most patients rash resolves with continuing therapy with efavirenz within one month. Efavirenz can be reinitiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when efavirenz is restarted.

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Reported rates of recurrent rash following a switch from nevirapine to efavirenz therapy, primarily based on retrospective cohort data from published literature, range from 13 to 18 %, comparable to the rate observed in patients treated with efavirenz in clinical studies. (See section 4.4.) 
Psychiatric symptoms
Serious psychiatric adverse reactions have been reported in patients treated with efavirenz. In controlled trials the frequency of specific serious psychiatric events were: 

Efavirenz regimen                    Control regimen
(n=1,008)                           (n=635)
- severe depression                               1.6 %                              0.6 % - suicidal ideation                               0.6 %                              0.3 % - non-fatal suicide attempts                      0.4 %                               0% - aggressive behaviour                            0.4 %                              0.3 % - paranoid reactions                              0.4 %                              0.3 % - manic reactions                                 0.1 %                               0% 
Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse reactions with frequencies of each of the above events ranging from 0.3 % for manic reactions to 2.0 % for both severe depression and suicidal ideation. There have also been post-marketing reports of death by suicide, delusions, psychosis-like behaviour and catatonia.

Nervous system symptoms
In clinical controlled trials, frequently reported adverse reactions included, but were not limited to: dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming. Nervous system symptoms of moderate-to-severe intensity were experienced by 19 % (severe 2.0 %) of patients compared to 9 % (severe 1 %) of patients receiving control regimens. In clinical studies 2 % of patients treated with efavirenz discontinued therapy due to such symptoms.

Nervous system symptoms usually begin during the first one or two days of therapy and generally resolve after the first 2 - 4 weeks. In a study of uninfected volunteers, a representative nervous system symptom had a median time to onset of 1 hour post-dose and a median duration of 3 hours. Nervous system symptoms may occur more frequently when efavirenz is taken concomitantly with meals possibly due to increased efavirenz plasma levels (see section 5.2). Dosing at bedtime seems to improve the tolerability of these symptoms and can be recommended during the first weeks of therapy and in patients who continue to experience these symptoms (see section 4.2). Dose reduction or splitting the daily dose has not been shown to provide benefit.

Analysis of long-term data showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated patients were generally similar to those in the control arm.

Ataxia and encephalopathy associated with high levels of efavirenz, occurring months to years after beginning efavirenz therapy have been reported post-marketing (see section 4.4).

Hepatic failure
A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death.

Immune Reactivation 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 (CART).
The frequency of this is unknown (see section 4.4).

Laboratory test abnormalities
Liver enzymes: elevations of AST and ALT to greater than five times the upper limit of the normal range (ULN) were seen in 3 % of 1,008 patients treated with 600 mg of efavirenz (5-8 % after long- term treatment in study 006). Similar elevations were seen in patients treated with control regimens (5 % after long-term treatment). Elevations of GGT to greater than five times ULN were observed in 4 % of all patients treated with 600 mg of efavirenz and 1.5 - 2 % of patients treated with control regimens (7 % of efavirenz-treated patients and 3 % of control-treated patients after long-term treatment). Isolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction.
In the long-term study (006), 1 % of patients in each treatment arm discontinued because of liver or biliary system disorders.

Amylase: in the clinical trial subset of 1,008 patients, asymptomatic increases in serum amylase levels greater than 1.5 times the upper limit of normal were seen in 10 % of patients treated with efavirenz and 6 % of patients treated with control regimens. The clinical significance of asymptomatic increases in serum amylase is unknown.

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

Paediatric population

Undesirable effects in children were generally similar to those of adult patients. Rash was reported more frequently in children (in a clinical study including 57 children who received efavirenz during a 48-week period, rash was reported in 46 %) and was more often of higher grade than in adults (severe rash was reported in 5.3 % of children). Prophylaxis with appropriate antihistamines prior to initiating therapy with efavirenz in children may be considered. Although nervous system symptoms are difficult for young children to report, they appear to be less frequent in children and were generally mild. In the study of 57 children, 3.5 % of patients experienced nervous system symptoms of moderate intensity, predominantly dizziness. No child had severe symptoms or had to discontinue because of nervous system symptoms.

Other special populations

Liver enzymes in hepatitis B or C co-infected patients
In the long-term data set from study 006, 137 patients treated with efavirenz-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among co-infected patients in study 006, elevations in AST to greater than five times ULN developed in 13 % of efavirenz treated patients and in 7 % of controls, and elevations in ALT to greater than five times ULN developed in 20 % and 7 % respectively. Among co-infected patients, 3 % of those treated with efavirenz and 2 % in the control arm discontinued because of liver disorders (see section 4.4).

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: https://sideeffects.health.gov.il