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.

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of rilpivirine. Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely.

Animal studies do not indicate reproductive toxicity.

The use of rilpivirine may be considered during pregnancy, if necessary.

It is not known whether rilpivirine is excreted in human milk. Rilpivirine is excreted in the milk of rats. Because of the potential for adverse reactions in breastfed infants, mothers should be instructed not to breast-feed if they are receiving rilpivirine.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed.

Fertility

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

Rilpivirine has no or negligible influence on the ability to drive and use machines. However, fatigue, dizziness and somnolence have been reported in some patients taking rilpivirine and should be considered when assessing a patient’s ability to drive or operate machinery.

Summary of the safety profile

During the clinical development program (1,368 patients in the Phase III controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE)), 55.7% of subjects experienced at least one adverse drug reaction. The most frequently reported adverse drug reactions (ADRs) (≥2%) that were at least of moderate intensity were depression (4.1%), headache (3.5%), insomnia (3.5%), rash (2.3%), and abdominal pain (2.0%). The most frequent serious treatment-related ADRs were reported in 7 (1.0%) patients receiving rilpivirine. The median duration of exposure for patients in the rilpivirine arm and efavirenz arm was 104.3 and 104.1 weeks, respectively. Most ADRs occurred in the first 48 weeks of treatment.

Selected treatment emergent clinical laboratory abnormalities (grade 3 or grade 4), considered as ADRs, reported in rilpivirine treated patients were increased pancreatic amylase (3.8%), increased AST (2.3%), increased ALT (1.6%), increased LDL cholesterol (fasted, 1.5%), decreased white blood cell count (1.2%), increased lipase (0.9%), increased bilirubin (0.7%), increased triglycerides (fasted, 0.6%), decreased haemoglobin (0.1%), decreased platelet count (0.1%), and increased total cholesterol (fasted, 0.1%).

Tabulated summary of adverse reactions

ADRs reported in adult patients treated with rilpivirine are summarised in the table below. The ADRs are listed by system organ class (SOC) and frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, ADRs are presented in order of decreasing frequency.

ADRs reported in antiretroviral treatment-naïve HIV-1 infected adult patients treated with Rilpivirine (pooled data from the week 96 analysis of the Phase III ECHO and THRIVE trials) N=686:

BR = background regimen
N = number of subjects

Laboratory abnormalities

In the rilpivirine arm in the week 96 analysis of the Phase III ECHO and THRIVE trials, mean change from baseline in total cholesterol (fasted) was 5 mg/dl, in HDL cholesterol (fasted) 4 mg/dl, in LDL cholesterol (fasted) 1 mg/dl, and in triglycerides (fasted) -7 mg/dl.

Description of selected adverse reactions

Immune reactivation 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.

Paediatric population (12 to less than 18 years of age)

The safety assessment is based on the week 48 analysis of the single-arm, open-label, Phase II trial, TMC278-C213, in which 36 antiretroviral treatment-naïve HIV-1 infected adolescent patients weighing at least 32 kg received rilpivirine (25 mg once daily) in combination with other antiretroviral agents. The median duration of exposure for patients was 63.5 weeks. There were no patients who discontinued treatment due to ADRs. No new ADRs were identified compared to those seen in adults.

Most ADRs were Grade 1 or 2. The most common ADRs (all grades, greater than or equal to 10%) were headache (19.4%), depression (19.4%), somnolence (13.9%), and nausea (11.1%). No grade 3-4 laboratory abnormalities for AST/ALT or grade 3-4 ADRs of transaminase increased were reported.

There were no new safety concerns identified in the Week 240 analysis of the TMC278-C213 trial in adolescents.

The safety and efficacy of rilpivirine in children aged <12 years have not yet been established. No data are available.

Other special populations

Patients co-infected with hepatitis B and/or hepatitis C virus

In patients co-infected with hepatitis B or C virus receiving rilpivirine, the incidence of hepatic enzyme elevation was higher than in patients receiving rilpivirine who were not co-infected. This observation was the same in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in co-infected patients was comparable to that in patients without co-infection.