Adverse reactions : תופעות לוואי

4.8    Undesirable effects
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Summary of the safety profile

The most frequently reported adverse reactions are headache (3%), diarrhoea (2%), nausea (2%) and insomnia (2%).

The most severe adverse reaction reported with dolutegravir was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4).

Tabulated list of adverse reactions

The adverse reactions from clinical study and post-marketing experience are listed in Table 2 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), not known (cannot be estimated from the available data).

Table 2:        Tabulated summary of adverse reactions to Dovato based on clinical study and post- marketing experience with Dovato and its individual components
Frequency              Adverse reaction
Blood and lymphatic systems disorders:
Uncommon:                   neutropenia, anaemia, thrombocytopenia
Very rare:                  pure red cell aplasia
Immune system disorders:
Uncommon:                   hypersensitivity (see section 4.4), immune reconstitution syndrome (see section 4.4)
Metabolism and nutrition disorders:
Very rare:                  lactic acidosis
Psychiatric disorders:
Common:                     depression, anxiety, insomnia, abnormal dreams Uncommon:                   suicidal ideation*, suicide attempt*, panic attack 
*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 disorders:
Very common:                headache
Common:                     dizziness, somnolence
Very rare:                  peripheral neuropathy, paraesthesia
Gastrointestinal disorders:
Very common:                nausea, diarrhoea
Common:                     vomiting, flatulence, abdominal pain/ discomfort Rare:                       pancreatitis
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Hepatobiliary disorders:
Common:                     alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations
Uncommon:                   hepatitis
Rare:                       acute hepatic failure1, increased bilirubin2 Skin and subcutaneous tissue disorders:
Common:                     rash, pruritus, alopecia
Rare:                       angioedema
Musculoskeletal and connective tissue disorders:
Common:                     arthralgia, muscle disorders (including myalgia) Rare:                       rhabdomyolysis
General disorders and administration site conditions:
Common:                     fatigue
Investigations:
Common:                     creatine phosphokinase (CPK) elevations, weight increased Rare:                       amylase elevations
1
This adverse reaction was identified through post-marketing surveillance for dolutegravir in combination with other ARVs. The frequency category of rare was estimated based on post-marketing reports.
2
In combination with increased transaminases.

Description of selected adverse reactions

Changes in laboratory biochemistries
Dolutegravir has been associated with an increase in serum creatinine occuring in the first week of treatment when administered with other antiretroviral medicinal products. Increases in serum creatinine occurred within the first four weeks of treatment with dolutegravir plus lamivudine and remained stable through 48 weeks. In the pooled GEMINI studies a mean change from baseline of 10.3 µmol/L (range: -36.3 µmol/L to 55.7 µmol/L) was observed after 48 weeks of treatment. These changes are linked to the inhibiting effect of dolutegravir on renal tubular transporters of creatinine. The changes are not considered to be clinically relevant and do not reflect a change in glomerular filtration rate.

Co-infection with Hepatitis B or C
In the Phase III studies for the dolutegravir single agent, 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).

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

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

Immune response 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).

Paediatric population

There are no clinical study data on the effects of Dovato in the paediatric population. Individual components have been investigated in adolescents (12 to 17 years).

Based on limited available data with the dolutegravir single entity or lamivudine single entity used in combination with other antiretroviral agents to treat adolescents (12 to 17 years), 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).