Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most frequently reported adverse reactions (ARs) from monthly dosing studies were injection site reactions (up to 84%), headache (up to 12%) and pyrexia4 (10%).
The most frequently reported ARs from ATLAS-2M every 2 month dosing were injection site reactions (76%), headache (7%) and pyrexia4 (7%).

Tabulated list of adverse reactions

The ARs identified for cabotegravir or rilpivirine are listed in Table 7 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 7          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
Vasovagal reactions (in response to injections)
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             Injection site reactions (pain and discomfort, administrative site conditions                             nodule, induration) Pyrexia4
Common                  Injection site reactions (swelling, erythema, pruritus, bruising, warmth, haematoma)
Fatigue
Asthenia
Malaise
Uncommon                Injection site reactions (cellulitis, abscess, anaesthesia, haemorrhage, discolouration)
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: abdominal pain, 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 Vocabria and rilpivirine injection 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

Local injection site reactions (ISRs)
Up to 1% of subjects discontinued treatment with Vocabria plus rilpivirine because of ISRs. When dosing monthly, up to 84% of subjects reported injection site reactions; out of 30393 injections, 6815 ISRs were reported. When dosing every 2 months, 76% of patients reported injection site reactions; out of 8470 injections, 2507 ISRs were reported.

The severity of reactions was generally mild (Grade 1, 70%-75% of subjects) or moderate (Grade 2, 27%-36% of subjects). 3-4% of subjects experienced severe (Grade 3) ISRs. The median duration of overall ISR events was 3 days. The percentage of subjects reporting ISRs decreased over time.

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)