Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most frequently reported adverse reaction (ARs) from monthly dosing studies were headache (up to 12%) and pyrexia4 (10%).
The most frequently reported ARs, considered by the investigator as causally related, from ATLAS- 2M every 2 month dosing were headache (7%) and pyrexia4 (7%).

Tabulated list of adverse reactions

The ARs identified for cabotegravir and rilpivirine are listed in Table 3 by body system organ class and 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 3         Tabulated summary of adverse reactions1

MedDRA System Organ              Frequency              ARs for Vocabria + rilpivirine regimen Class (SOC)                      Category

Immune system disorders          Uncommon               Hypersensitivity* 
Psychiatric disorders            Common                 Depression
Anxiety
Abnormal dreams
Insomnia
Uncommon               Suicide attempt; Suicidal ideation
(particularly in patients with a pre-existing history of psychiatric illness)
Nervous system disorders         Very common            Headache

Common                 Dizziness
Uncommon               Somnolence

Gastrointestinal disorders       Common                 Nausea
Vomiting
Abdominal pain2
Flatulence
Diarrhoea

Hepatobiliary Disorders          Uncommon               Hepatotoxicity 
Skin and subcutaneous tissue     Common                 Rash3 disorders
Uncommon               Urticaria*
Angioedema*
Musculoskeletal and              Common                 Myalgia connective tissue disorders

General disorders and              Very common             Pyrexia4 administrative site conditions

Common                  Fatigue
Asthenia
Malaise

Investigations                     Common                  Weight increased 
Uncommon                Transaminase increased
Blood bilirubin increased
1
The frequency of the identified ARs are based on all reported occurrences of the events and are not limited to those considered at least possibly related by the investigator.
2
Abdominal pain includes the following grouped MedDRA preferred term: upper abdominal pain.
3
Rash includes the following grouped MedDRA preferred terms: rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic.
4
Pyrexia includes the following grouped MedDRA preferred terms: feeling hot, body temperature increased. The majority of pyrexia events were reported within one week of injections.
*
Please refer to section 4.4

The overall safety profile at Week 96 and Week 124 in the FLAIR study was consistent with that observed at Week 48, with no new safety findings identified. In the extension phase of the FLAIR study, initiating the CAB LA + RPV LA regimen with Direct to Injection did not identify any new safety concerns related to omitting the oral lead-in phase (see section 5.1).

Description of selected adverse reactions

Weight increased
At the Week 48 time point, subjects in studies FLAIR and ATLAS, who received Vocabria plus rilpivirine gained a median of 1.5 kg in weight; subjects continuing on their current antiretroviral therapy (CAR) gained a median of 1.0 kg (pooled analysis). In the individual studies FLAIR and ATLAS, the median weight gains in the Vocabria plus rilpivirine arms were 1.3 kg and 1.8 kg respectively, compared to 1.5 kg and 0.3 kg in the CAR arms.

At the 48 week timepoint, in ATLAS-2M the median weight gain in both the monthly and 2-monthly Vocabria plus rilpivirine dosing arms was 1.0 kg.

Changes in laboratory chemistries
Small, non-progressive increases in total bilirubin (without clinical jaundice) were observed with treatment with Vocabria plus rilpivirine. These changes are not considered clinically relevant as they likely reflect competition between cabotegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1).

Elevated transaminases (ALT/AST) were observed in subjects receiving Vocabria plus rilpivirine during clinical studies. These elevations were primarily attributed to acute viral hepatitis. A few subjects on oral therapy had transaminase elevations attributed to suspected drug-related hepatotoxicity; these changes were reversible upon discontinuation of treatment (see section 4.4).

Elevated lipases were observed during clinical trials with Vocabria plus rilpivirine; Grade 3 and 4 lipase increases occurred at a higher incidence with Vocabria plus rilpivirine compared with CAR.
These elevations were generally asymptomatic and did not lead to Vocabria plus rilpivirine discontinuation. One case of fatal pancreatitis with Grade 4 lipase and confounding factors (including history of pancreatitis) has been reported in study ATLAS-2M, for which causality to the injection regimen could not be ruled out.

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)