Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most severe adverse reaction, seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4). The most commonly seen treatment emergent adverse reactions were nausea (13%), diarrhoea (18%) and headache (13%).

Tabulated list of adverse reactions

The adverse reactions considered at least possibly related to dolutegravir are listed by body system, organ class and absolute frequency. Frequencies are defined as very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000).



Table 4 Adverse Reactions
Immune system          Uncommon             Hypersensitivity (see section 4.4) disorders              Uncommon             Immune Reconstitution Syndrome (see section 4.4)** Psychiatric disorders Common                Insomnia
Common               Abnormal dreams
Common               Depression
Common               Anxiety
Uncommon             Panic attack
Uncommon             Suicidal ideation*, suicide attempt*
*particularly in patients with a pre-existing history of depression or psychiatric illness.
Rare              Completed suicide*
*particularly in patients with a pre-existing history of depression or psychiatric illness.
Nervous system            Very common       Headache disorders                 Common            Dizziness
Gastrointestinal          Very common       Nausea disorders                 Very common       Diarrhoea
Common            Vomiting
Common            Flatulence
Common            Upper abdominal pain
Common            Abdominal pain
Common            Abdominal discomfort
Hepatobiliary             Common            Alanine aminotransferase (ALT) and/or Aspartate disorders                                   aminotransferase (AST) elevations Uncommon          Hepatitis
Rare              Acute hepatic failure, increased bilirubin***
Skin and                  Common            Rash subcutaneous tissue       Common            Pruritus disorders
Musculoskeletal and       Uncommon          Arthralgia connective tissue         Uncommon          Myalgia disorders
General disorders         Common            Fatigue and administration site conditions
Investigations            Common            Creatine phosphokinase (CPK) elevations, weight increased

**see below under Description of selected adverse reactions.
***in combination with increased transaminases.

Description of selected adverse reactions
Changes in laboratory biochemistries
Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained stable through 48 weeks. A mean change from baseline of 9.96 mol/L was observed after 48 weeks of treatment. Creatinine increases were comparable by various background regimens. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate.

Co-infection with Hepatitis B or C
In Phase III studies patients with hepatitis B and/or C co-infection were permitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN). Overall, the safety profile in patients co-infected with hepatitis B and/or C was similar to that observed in patients without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C co-infection for all treatment groups. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C co-infection at the start of dolutegravir therapy, particularly in those whose anti-hepatitis B therapy was withdrawn (see section 4.4).

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).

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

Paediatric population
Based on available data from the ongoing P1093 (ING112578) and ODYSSEY (201296) studies in 172 infants, children and adolescents (aged 4 weeks and above, to less than 18 years, and weighing at least 3 kg), who received the recommended doses of dispersible tablets or film-coated tablets once daily, there were no additional types of adverse reactions beyond those observed in the adult population.

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

Additionally, you should also report to GSK Israel (il.safety@gsk.com ).