General security profile
Generally efavirenz well tolerated in clinical studies. In the subgroup of patients who took efavirenz in a dose of 600 mg once daily in combination with HIV protease inhibitors and / or NRTIs, skin rashes (11.6%), dizziness (8, 5%), nausea (8.0%), headache (5.7%) and fatigue (5.5%).
The most noticeable adverse events associated with taking efavirenz were a skin rash and symptoms from the nervous system. Symptoms from the nervous system usually appeared shortly after the initiation of therapy and, as a rule, disappeared after the first 2-4 weeks of therapy. Also in patients who took efavirenzsevere skin reactions, such as Stevens-Johnson syndrome and multiform erythema exudative, have been observed; mental disorders, including severe depression, death due to suicide and psychotic behavior, as well as convulsive seizures. With the use of the drug Stockrin simultaneously with food, the systemic exposure of efavirenz can increase, which can lead to an increase in the frequency of undesirable reactions (see SPECIAL INSTRUCTIONS).
Safety profile for long-term therapy, including efavirenzwere evaluated in a controlled trial in which patients took either efavirenz + zidovudine + 3TC for 180 weeks, or efavirenz + indinavir for 102 weeks, or indinavir + zidovudine + 3TC for 76 weeks. Long-term use of efavirenz in this study was not accompanied by the appearance of any new safety data.
The following are moderate and severe adverse reactions, for which a possible causal relationship was established with the treatment regimen used (according to the researchers) and which were observed during clinical trials of efavirenz used in the recommended dose in combination ARVT.
Italic events are identified that were registered during the post-registration period of the use of efavirenz in combination therapy. The incidence of adverse events is given in the following classification: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥ 1/1000, <1/100); rarely (≥ 1/10000, <1/1000); very rarely (<1/10000).
Immune system disorders
Infrequent: hypersensitivity.
Disorders from the metabolism and nutrition
Often: hypertriglyceridemia *.
Infrequently: hypercholesterolemia *.
Disorders of the psyche
Often: pathological dreams, anxiety, depression, insomnia *.
Infrequently: a tendency to affect, aggressiveness, confusion, mood with a propensity for euphoria, hallucinations, mania, paranoid behavior, psychosis‡ suicide attempts, suicidal intentions.
Rarely: rave‡‡, neurosis‡‡, death by suicide‡‡*.
Disturbances from the nervous system
Often: disorders of cerebellar coordination and balance‡, attention disorder (3.6%), dizziness (8.5%), headaches (5.7%), drowsiness (2.0%) *.
Infrequently: anxiety, amnesia, ataxia, impaired coordination of movements, convulsions, impaired thinking, tremor‡.
Disturbances on the part of the organ of sight
Infrequent: blurred vision.
Hearing disorders and labyrinthine disorders
Infrequently: noise in ears‡, Vertigo.
Vascular disorders
Infrequently: "tides" of blood to the skin of the face‡.
Disorders from the gastrointestinal tract
Often: abdominal pain, diarrhea, nausea, vomiting.
Infrequently: pancreatitis.
Disturbances from the liver and bile ducts
Often: increased activity of aspartate aminotransferase (ACT)*, alanine aminotransferase (ALT) * and gamma-glutamyl transferase (GGT) *.
Infrequently: acute hepatitis.
Rarely: liver failure‡‡*.
Disturbances from the skin and subcutaneous tissues
Very often: skin rash (11.6%) *.
Often: itchy skin.
Infrequently: multiforme exudative erythema, Stevens-Johnson syndrome *.
Rarely: photoallergic dermatitis‡.
Violations of the genitals and mammary gland
Infrequently: gynecomastia.
General disorders
Often: increased fatigue.
* - For a more detailed description, see below.
‡ - These undesirable reactions were recorded in the post-registration period of observation; the frequency of these reactions was determined using data from 16 clinical trials (3,969 patients).
‡‡ - These adverse reactions were recorded in the post-registration period of observation, however, in patients who took efavirenz in 16 clinical trials, they were not reported as phenomena associated with the use of the drug. According to the frequency classification, these side effects were regarded as "rarely observed" (based on an upper bound estimate of 95% confidence interval for 0 events, based on the number of patients taking efavirenz in the course of these clinical studies (n = 3969)).
Description of individual undesirable phenomena
Skin rash: In clinical trials, skin rash was observed in 26% of patients taking efavirenz in a dose of 600 mg, compared with 17% of patients in control groups. In 18% of patients, the skin rash was associated with efavirenz, while 1.7% of patients were discontinued due to skin rash. The incidence of multiforme exudative erythema and Stevens-Johnson syndrome was approximately 0.1%.
Cases of skin rash were recorded in 58 of 182 children (32%) who received efavirenz treatment in 3 clinical trials with an average duration of 123 weeks.In 6 children, the rash was severe. Before the beginning of efavirenz therapy in children, they can be recommended appropriate antihistamine therapy as a prophylaxis. Usually, mild or moderately expressed maculopapular skin rash develops, which appear within the first two weeks after initiation of efavirenz therapy. In most patients, a skin rash disappears when continuing with efavirenz therapy for one month. Efavirenz can be re-assigned to patients who stopped taking it because of a skin rash. When resuming efavirenz therapy, it is also recommended to take appropriate blockers H1histamine receptors and / or corticosteroids.
There is limited experience with efavirenz in patients who discontinued therapy with other antiretroviral drugs from the NNRTI group. The incidence of recurrence of skin rash after switching from nevirapine therapy to efavirenz therapy, generally estimated from published retrospective data, was 13% to 18%, and comparable to the frequency found in patients taking efavirenz in clinical trials (see SPECIAL INSTRUCTIONS).
Symptoms from the side of the psyche: in some patients who took efavirenz, there were serious undesirable phenomena on the part of the psyche. In controlled clinical trials, the incidence of certain serious adverse events from the psyche was as follows: severe depression 1.6% in the group of patients taking combined ARVT with efavirenz; 0,6% in the control group of patients, suicidal intentions (0,6%, 0,3%), suicide attempts without a lethal outcome (0,4%, 0%), aggressive behavior (0,4%, 0,3% ), paranoid reactions (0.4%, 0.3%), manic reactions (0.1%, 0%), respectively.
Patients with a history of mental disorders are at increased risk of developing these serious adverse events from the psyche with a frequency of occurrence of each of the above events from 0.3% for manic reactions to 2.0% for severe depression and suicidal intentions. Also in the post-marketing period, reports of deaths as a result of suicide, delusional disorders and psychotic behavior have been reported.
Symptoms from the nervous system: in patients taking efavirenz in a dose of 600 mg in controlled clinical trials, the following adverse reactions were often observed: dizziness, insomnia, drowsiness, attention disorder, nightmares. Other undesirable phenomena were also observed. Severe and severe symptoms from the nervous system were observed in 19% (severe - in 2%) patients, whereas in patients receiving control therapy, this indicator was 9% (severe - 1%). In clinical trials, 2% of patients who took efavirenz, discontinued therapy because of the above symptoms.
Symptoms from the nervous system are usually observed during the first or second day after the initiation of therapy and in most cases disappear within the first 2-4 weeks. In a study involving uninfected volunteers, a representative symptom from the nervous system arose on average 1 hour after taking the drug and lasted an average of 3 hours. Symptoms from the nervous system developed more often if efavirenz taken during meals. Perhaps this is due to an increase in the concentration of efavirenz in the blood plasma under such conditions (see PHARMACOKINETICS).To improve the tolerability of the drug for these symptoms during the first weeks of therapy, it is recommended to take the drug at bedtime. This regimen is also recommended for patients who continue to have these symptoms (see DOSAGE AND ADMINISTRATION). Dose reduction or fractional intake of a daily dose usually do not give a favorable effect.
Analysis of data on long-term use of the drug showed that after 24 weeks of therapy the incidence of first-time symptoms from the nervous system in patients taking efavirenz, was generally similar to that in the control group.
Liver failure: in the post-registration period of observation, several cases of hepatic insufficiency, including cases without evidence of liver disease in the anamnesis, and without other identified risk factors, have been reported. These cases were characterized by a lightning current; in a number of cases liver transplantation was required or the death of the patient was reported.
Immunodeficiency Syndrome: In HIV-infected patients with severe immunodeficiency, the onset of combined ARV therapy may increase the risk of inflammatory reactions toinactive or residual opportunistic infections (see SPECIAL INSTRUCTIONS).
Lipodystrophy and metabolic disorders: combined ARVT is associated with the redistribution of adipose tissue (lipodystrophy) in HIV-infected patients, including depletion of peripheral and facial subcutaneous fat, its accumulation in the intraperitoneal space, internal organs, posterior neck ("buffalo buffalo") and mammary hypertrophy.
Combined ARVT can cause metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia (see SPECIAL INSTRUCTIONS).
Osteonecrosis: there were cases of osteonecrosis, mainly in patients with well-known risk factors, with long-term HIV infection, as well as in patients who took long-term combined ARVT. However, the frequency of this complication is not established (see SPECIAL INSTRUCTIONS).
Laboratory indicators
"Hepatic" enzymes: increased activity ACT and ALT more than 5 times higher than the upper limit of the norm (VGN) was observed in 3% of patients from 1008 who took efavirenz in a dose of 600 mg per day (5-8% with prolonged ARVT with efavirenz).A similar increase was observed in the control group (5% with prolonged ARVT without efavirenz). The increase in GGT activity was more than 5-fold higher than ULN observed in 4% of all patients taking 600 mg of efavirenz and 1.5-2% of patients in the control group (7% with prolonged ARVT with efavirenz and 3% with prolonged ARV without efavirenz ). Isolated increase in GGT activity in patients taking efavirenz, can indicate the induction of enzymes. In a clinical study with prolonged ARVT, about 1% of patients in each study group discontinued therapy due to violations from the liver and bile ducts.
Amylase: an asymptomatic increase in serum amylase activity, more than 1.5 times that of UHN, was detected in 10% of patients taking efavirenz, and in 6% of patients in control groups. The clinical significance of the asymptomatic increase in serum amylase activity is unknown.
Lipids: an increase in the concentration of total cholesterol (OCS) by 10-20% was observed in uninfected volunteers who took efavirenz. In clinical studies of the use of different combination ARVT with efavirenz in patients,previously untreated ARVT, during the 48 weeks of treatment, an increase in the concentration of OXC by 21-31%, high density lipoprotein cholesterol (HDL cholesterol) by 23-34% and triglycerides by 23-49% was observed. The proportion of patients who had a ratio of OXC / HDL cholesterol greater than 5 did not change. The magnitude of changes in lipid concentrations can be due to factors such as the duration of therapy and the intake of other drugs in combination ARVT.
Interaction in the test for cannabinoids: efavirenz does not communicate with cannabinoid receptors, but there are reports of false positive urine tests for cannabinoids in uninfected volunteers and in HIV-infected patients who were taking efavirenz. The positive result of the cannabinoid screening test is recommended to be confirmed using special methods such as gas chromatography or mass spectrometry.
Children and teens
The type and incidence of adverse events in children are generally comparable to those observed in adult patients, with the exception of skin rash, which is more common in children (46% of children) than in adults and more severe (a severe skin rash was seen in 5.3% of children ).
For the purpose of prophylaxis of the rash, it may be advisable to designate appropriate blockers H1-gystamine receptors for children before the initiation of efavirenz therapy.
Although the symptoms of the nervous system in young children are difficult to identify, it is believed that such symptoms are more rare in children and usually are mild. In 3.5% of patients, symptoms of moderate severity from the nervous system were observed, mainly dizziness. No child had severe symptoms and did not need to cancel therapy because of symptoms from the nervous system.
Other special patient groups
Activity of "hepatic" enzymes in patients simultaneously infected with hepatitis B or C
Among patients seropositive for hepatitis B and / or C, increased activity ACT more than 5 times higher than ULN observed in 13% of patients who took efavirenz, and 7% of patients in the control group, and an increase in ALT activity was more than 5 times higher than ULN observed in 20% and 7% of patients, respectively. Among patients with co-infection, 3% of patients who took efavirenz, and 2% of patients from the control group discontinued therapy because of violations of the liver (see SPECIAL INSTRUCTIONS).