Adverse reactions : תופעות לוואי

4.8    Undesirable effects
Summary of the safety profile

In randomised clinical trials raltegravir 400 mg twice daily was administered in combination with fixed or optimised background treatment regimens to treatment-naïve (N=547) and treatment- experienced (N=462) adults for up to 96 weeks. A further 531 treatment-naïve adults have received raltegravir 1,200 mg once daily with emtricitabine and tenofovir disoproxil fumarate for up to 96 weeks. See section 5.1.

The most frequently reported adverse reactions during treatment were headache, nausea and abdominal pain. The most frequently reported serious adverse reaction was immune reconstitution syndrome and rash. The rates of discontinuation of raltegravir due to adverse reactions were 5% or less in clinical trials.

Rhabdomyolysis was an uncommonly reported serious adverse reaction in post-marketing use of raltegravir 400 mg twice daily.

Tabulated summary of adverse reactions

Adverse reactions considered by investigators to be causally related to raltegravir (alone or in combination with other ART), as well as adverse reactions established in post-marketing experience, are listed below by System Organ Class. Frequencies are defined as common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and not known (cannot be estimated from the available data).

System Organ Class             Frequency                      Adverse reactions Raltegravir (alone or in combination with other
ART)
Infections and infestations        Uncommon       genital herpes, folliculitis, gastroenteritis, herpes simplex, herpes virus infection, herpes zoster,
influenza, lymph node abscess, molluscum contagiosum, nasopharyngitis, upper respiratory tract infection
Neoplasms benign, malignant        Uncommon       skin papilloma and unspecified (including cysts and polyps)
Blood and lymphatic system         Uncommon       anaemia, iron deficiency anaemia, lymph node pain, disorders                                         lymphadenopathy, neutropenia, thrombocytopenia 

Immune system disorders            Uncommon       immune reconstitution syndrome, drug hypersensitivity, hypersensitivity
Metabolism and nutrition           Common         decreased appetite disorders
Uncommon       cachexia, diabetes mellitus, dyslipidaemia,
hypercholesterolaemia, hyperglycaemia,
hyperlipidaemia, hyperphagia, increased appetite,
polydipsia, body fat disorder
Psychiatric disorders              Common         abnormal dreams, insomnia, nightmare, depression 

Uncommon       mental disorder, suicide attempt, anxiety,
confusional state, depressed mood, major depression, middle insomnia, mood altered, panic attack, sleep disorder, suicidal ideation, suicidal behaviour (particularly in patients with a pre- existing history of psychiatric illness)


System Organ Class          Frequency                   Adverse reactions Raltegravir (alone or in combination with other
ART)
Nervous system disorders         Common      dizziness, headache

Uncommon    amnesia, carpal tunnel syndrome, cognitive disorder, disturbance in attention, dizziness postural, dysgeusia, hypersomnia, hypoaesthesia,
lethargy, memory impairment, migraine,
neuropathy peripheral, paraesthesia, somnolence,
tension headache, tremor, poor quality sleep
Eye disorders                    Uncommon    visual impairment
Ear and labyrinth disorders      Common      vertigo

Uncommon    tinnitus
Cardiac disorders                Uncommon    palpitations, sinus bradycardia, ventricular extrasystoles
Vascular disorders               Uncommon    hot flush, hypertension
Respiratory, thoracic and        Uncommon    dysphonia, epistaxis, nasal congestion mediastinal disorders
Gastrointestinal disorders       Common      abdominal distention, abdominal pain, diarrhoea, flatulence, nausea, vomiting, dyspepsia

Uncommon    gastritis, abdominal discomfort, abdominal pain upper, abdominal tenderness, anorectal discomfort,
constipation, dry mouth, epigastric discomfort,
erosive duodenitis, eructation, gastroesophageal reflux disease, gingivitis, glossitis, odynophagia,
pancreatitis acute, peptic ulcer, rectal haemorrhage
Hepato-biliary disorders         Uncommon    hepatitis, hepatic steatosis, hepatitis alcoholic, hepatic failure


Skin and subcutaneous tissue     Common      rash disorders
Uncommon    acne, alopecia, dermatitis acneiforme, dry skin,
erythema, facial wasting, hyperhidrosis,
lipoatrophy, lipodystrophy acquired,
lipohypertrophy, night sweats, prurigo, pruritus,
pruritus generalised, rash macular, rash maculo- papular, rash pruritic, skin lesion, urticaria,
xeroderma, Stevens Johnson syndrome , drug rash with eosinophilia and systemic symptoms (DRESS)

Musculoskeletal and connective   Uncommon    arthralgia, arthritis, back pain, flank pain, tissue disorders                             musculoskeletal pain, myalgia, neck pain, osteopenia, pain in extremity, tendonitis,
rhabdomyolysis


Renal and urinary disorders      Uncommon    renal failure, nephritis, nephrolithiasis, nocturia, renal cyst, renal impairment, tubulointerstitial nephritis
Reproductive system and breast   Uncommon    erectile dysfunction, gynaecomastia, menopausal disorders                                    symptoms


System Organ Class             Frequency                       Adverse reactions Raltegravir (alone or in combination with other
ART)
General disorders and              Common          asthenia, fatigue, pyrexia administration site conditions
Uncommon        chest discomfort, chills, face oedema, fat tissue increased, feeling jittery, malaise, submandibular mass, oedema peripheral, pain
Investigations                     Common          alanine aminotransferase increased, atypical lymphocytes, aspartate aminotransferase increased,
blood triglycerides increased, lipase increased,
blood pancreatic amylase increased

Uncommon        absolute neutrophil count decreased, alkaline phosphatase increased, blood albumin decreased,
blood amylase increased, blood bilirubin increased,
blood cholesterol increased, blood creatinine increased, blood glucose increased, blood urea nitrogen increased, creatine phosphokinase increased, fasting blood glucose increased, glucose urine present, high density lipoprotein increased,
international normalised ratio increased, low density lipoprotein increased, platelet count decreased, red blood cells urine positive, waist circumference increased, weight increased, white blood cell count decreased
Injury, poisoning and              Uncommon        accidental overdose procedural complications


Description of selected adverse reactions
Cancers were reported in treatment-experienced and treatment-naïve patients who initiated raltegravir in conjunction with other antiretroviral agents. The types and rates of specific cancers were those expected in a highly immunodeficient population. The risk of developing cancer in these studies was similar in the groups receiving raltegravir and in the groups receiving comparators.

Grade 2-4 creatine kinase laboratory abnormalities were observed in patients treated with raltegravir.
Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinal products associated with these conditions (see section 4.4).

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).

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).

For each of the following clinical adverse reactions there was at least one serious occurrence: genital herpes, anaemia, immune reconstitution syndrome, depression, mental disorder, suicide attempt, gastritis, hepatitis, renal failure, accidental overdose.

In clinical studies of treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing raltegravir and darunavir compared to those containing raltegravir without darunavir or darunavir without raltegravir. Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section 4.4).

Patients co-infected with hepatitis B and/or hepatitis C virus
In clinical trials, there were 79 patients co-infected with hepatitis B, 84 co-infected with hepatitis C, and 8 patients co-infected with hepatitis B and C who were treated with raltegravir in combination with other agents for HIV-1. In general, the safety profile of raltegravir in patients with hepatitis B and/or hepatitis C virus co-infection was similar to that in patients without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were somewhat higher in the subgroup co-infected with hepatitis B and/or hepatitis C virus.

At 96-weeks, in treatment-experienced patients, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29 %, 34 % and 13 %, respectively, of co-infected patients treated with raltegravir as compared to 11 %, 10 % and 9 % of all other patients treated with raltegravir. At 240-weeks, in treatment-naïve patients, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 22 %, 44 % and 17 %, respectively, of co-infected patients treated with raltegravir as compared to 13 %, 13 % and 5 % of all other patients treated with raltegravir.

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/