Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most frequently reported ARs from every 1-month dosing studies were injection site reactions (up to 84%), headache (up to 12%) and pyrexia (10%).
The most frequently reported ARs from every 2 months dosing were injection site reactions (76%), headache (7%) and pyrexia (7%).

Tabulated summary of adverse reactions
The ARs identified for rilpivirine and/or cabotegravir are listed by system organ class (SOC) and frequency (see Table 7). Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100).

Table 7      Tabulated summary of adverse reactions1
MedDRA System Organ        Frequency       ARs for rilpivirine + cabotegravir regimen Class (SOC)                Category
Blood and lymphatic        Common          decreased white blood cell count2, decreased system disorders                           haemoglobin2, decreased platelet count2 Immune System Disorders Uncommon           immune reactivation syndrome2 Metabolism and nutrition   Very common increased total cholesterol (fasted)2, increased LDL disorders                                  cholesterol (fasted)2
Common          decreased appetite2, increased triglycerides (fasted)2 Psychiatric disorders      Common          depression, anxiety, abnormal dreams, insomnia, sleep disorder2, depressed mood2
Nervous system disorders   Very common headache
Common          dizziness
Uncommon        somnolence, vasovagal reactions (in response to injections)
Gastrointestinal disorders Very common increased pancreatic amylase2
Common              nausea, vomiting, abdominal pain3, flatulence,
diarrhoea, abdominal discomfort2, dry mouth2,
increased lipase2

Hepatobiliary disorders           Uncommon            hepatotoxicity
Skin and subcutaneous             Common              rash4 tissue disorders
Musculoskeletal and               Common              myalgia connective tissue disorders
General disorders and             Very common         injection site reactions (pain and discomfort, nodule, administrative site                                   induration), pyrexia5 conditions                        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   Additional adverse reactions seen with oral rilpivirine in other studies.
3   Abdominal pain includes the following grouped MedDRA preferred term: abdominal pain, upper abdominal pain.
4   Rash includes the following grouped MedDRA preferred terms: rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic.
5   Pyrexia includes the following grouped MedDRA preferred terms: pyrexia, feeling hot, body temperature increased.
The majority of pyrexia events were reported within one week of injections.

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 rilpivirine plus cabotegravir injection regimen without oral lead-in (direct to injection) was not associated with any new safety concerns related to omitting the oral lead-in phase.


Description of selected adverse reactions

Local Injection Site Reactions (ISRs)
Up to 1% of subjects discontinued treatment with rilpivirine and cabotegravir injections because of ISRs.

Injection site reactions were 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
ISR events was 3 days. The percentage of subjects reporting ISRs decreased over time.

Weight increased
At the Week 48 time point, subjects in Phase 3 Studies FLAIR and ATLAS, who received rilpivirine plus cabotegravir gained a median of 1.5 kg in weight; subjects continuing on their current antiretroviral regimen (CAR) group gained a median of 1.0 kg (pooled analysis).

In the individual studies FLAIR and ATLAS, the median weight gains in the rilpivirine plus cabotegravir 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 every 2 months rilpivirine+cabotegravir dosing arms was 1.0 kg.

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

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

Elevated lipases were observed during clinical trials with rilpivirine plus cabotegravir. Grade 3 and 4 lipase increases occurred at a higher incidence with rilpivirine plus cabotegravir compared with CAR.
These elevations were generally asymptomatic and did not lead to rilpivirine plus cabotegravir 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 the 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 reactions should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il.