Rilpivirine

At supra-therapeutic doses (75 and 300 mg once daily), rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG). Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Rilpivirine should be used with caution when co-administered with medicinal products with a known risk of Torsade de Pointes.

In patients with severe renal impairment or end-stage renal disease, rilpivirine should be used with caution. In patients with severe renal impairment or end-stage renal disease, the combination of rilpivirine with a strong CYP3A inhibitor (e.g. ritonavir-boosted HIV protease inhibitor) should only be used if the benefit outweighs the risk.

Treatment with rilpivirine resulted in an early small increase of mean serum creatinine levels which remained stable over time and is not considered clinically relevant.

Rilpivirine should be used with caution in patients with moderate hepatic impairment.

Rilpivirine has not been studied in patients with severe hepatic impairment (Child-Pugh score C). Therefore, rilpivirine is not recommended in patients with severe hepatic impairment.

Antacids (e.g. aluminium or magnesium hydroxide, calcium carbonate): Significant decreases in rilpivirine plasma concentrations are expected (reduced absorption due to gastric pH increase).

The combination of rilpivirine and antacids should be used with particular caution. Antacids should only be administered either at least 2 hours before or at least 4 hours after rilpivirine.

The combination of rilpivirine and H₂-receptor antagonists should be used with particular caution. Only H₂-receptor antagonists that can be dosed once daily should be used. A strict dosing schedule, with intake of H₂-receptor antagonists at least 12 hours before or at least 4 hours after rilpivirine should be used.

Rilpivirine is primarily metabolised by cytochrome P450 (CYP)3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Co-administration of rilpivirine and medicinal products that induce CYP3A has been observed to decrease the plasma concentrations of rilpivirine, which could reduce the therapeutic effect of rilpivirine.

Rilpivirine is primarily metabolised by cytochrome P450 (CYP)3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Co-administration of rilpivirine and medicinal products that inhibit CYP3A has been observed to increase the plasma concentrations of rilpivirine.

Increased exposure of rilpivirine is expected (inhibition of CYP3A enzymes).

Where possible, alternatives such as azithromycin should be considered.

The combination of rilpivirine and dabigatran etexilate should be used with caution.

A risk for increases in dabigatran plasma concentrations cannot be excluded (inhibition of intestinal P-gp).

No dose adjustment is required. Didanosine should be administered at least two hours before or at least four hours after rilpivirine.

No dose adjustments are required when initiating co-administration of methadone with rilpivirine. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

Throughout co-administration of rilpivirine with rifabutin, the rilpivirine dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin co-administration is stopped, the rilpivirine dose should be decreased to 25 mg once daily.

Patients with hepatitis B co-infection were excluded from studies with rilpivirine. It is not recommended to initiate rilpivirine in patients with hepatitis B co-infection. In patients co-infected with hepatitis B receiving oral rilpivirine, the incidence of hepatic enzyme elevation was higher than in patients receiving oral rilpivirine who were not hepatitis B co-infected. Physicians should refer to current treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus.

Limited data is available in patients with hepatitis C co-infection. In patients co-infected with hepatitis C receiving oral rilpivirine, the incidence of hepatic enzyme elevation was higher than in patients receiving oral rilpivirine who were not hepatitis C co-infected. The pharmacokinetic exposure of oral and injectable rilpivirine in co-infected patients was comparable to that in patients without hepatitis C co-infection. Monitoring of liver function is recommended in patients with hepatitis C co-infection.

The effect of rilpivirine on human pregnancy is unknown.

A moderate amount of data with oral rilpivirine in pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or foetal/neonatal toxicity of rilpivirine.

A study of 19 pregnant women treated with oral rilpivirine in combination with a background regimen during the second and third trimesters, and postpartum, showed lower exposures of oral rilpivirine during pregnancy, therefore viral load should be monitored closely if rilpivirine is used during pregnancy.

Animal studies do not indicate reproductive toxicity.

Rilpivirine is not recommended during pregnancy unless the expected benefit justifies the potential risk.

An alternative oral regimen should be considered in line with current treatment guidelines. After discontinuation of rilpivirine, rilpivirine may remain in systemic circulation for up to 4 years in some patients.

It is expected that rilpivirine will be secreted into human milk based on animal data, although this has not been confirmed in humans. Rilpivirine may be present in human milk for up to 4 years in some patients after discontinuation of rilpivirine.

It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

Fertility

No human data on the effect of rilpivirine on fertility are available. No clinically relevant effects on fertility were seen in animal studies.

Patients should be informed that fatigue, dizziness and somnolence could occur when treated with rilpivirine.

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). Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100).

Tabulated summary of adverse reactions¹:

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.

Paediatric population

Based on data from the week 16 (Cohort 1; n=25) and week 24 (Cohort 2; n=144) analyses of the MOCHA study (IMPAACT 2017), no new safety concerns were identified in adolescents (aged at least 12 years and weighing 35 kg or more) when compared with the safety profile established in adults.