4.1. Therapeutic indications

REKAMBYS is indicated, in combination with cabotegravir injection, for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection in adults and adolescents (at least 12 years of age and weighing at least 35 kg) who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with, agents of the non-nucleoside reverse transcriptase inhibitor (NNRTI) and integrase inhibitor (INI) class (see sections 4.2, 4.4 and 5.1).

4.2. Posology and method of administration

Therapy should be prescribed by a physician experienced in the management of HIV infection. Each injection should be administered by a healthcare professional.

Prior to starting REKAMBYS, the healthcare professional should carefully select patients who agree to the required injection schedule and counsel patients about the importance of adherence to scheduled dosing visits to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance associated with missed doses.

Following discontinuation of REKAMBYS in combination with cabotegravir injection, it is essential to adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the last every 1 month injection, or two months after the last every 2 months injection (see section 4.4).

The prescribing information for cabotegravir injection should be consulted for recommended dosing.

Posology

REKAMBYS (rilpivirine injection) may be initiated with oral lead-in or without (direct to injection).

The healthcare professional and patient may decide to use rilpivirine tablets as an oral lead-in prior to the initiation of rilpivirine injections to assess tolerability (see Table 1), or proceed directly to rilpivirine injections (see Tables 2 and 3, for monthly and every 2 months dosing recommendations, respectively).

Adults and adolescents (at least 12 years of age and weighing at least 35 kg)

Oral lead-in

When used for oral lead-in prior to the initiation of REKAMBYS, rilpivirine oral tablets, together with cabotegravir oral tablets, should be taken for approximately 1 month (at least 28 days) to assess tolerability to rilpivirine and cabotegravir. One rilpivirine 25‑mg tablet should be taken with a meal with one cabotegravir 30‑mg tablet once daily (see Table 1).

Table 1 Oral Lead-in Dosing Schedule

Oral Lead-In

Drug

For one month (at least 28 days), followed by the Initiation Injectiona

Rilpivirine

25 mg once daily with a meal

Cabotegravir

30 mg once daily

a see Table 2 for monthly injection dosing schedule and Table 3 for every 2 months injection dosing schedule.

Every 1 month dosing

Initiation injection (900 mg corresponding to 3 mL)

On the final day of current antiretroviral therapy or oral lead-in, the recommended initiation injection dose of rilpivirine is a single 900 mg intramuscular injection.

Continuation injection (600 mg corresponding to 2 mL)

After the initiation injection, the recommended continuation injection dose of rilpivirine is a single 600 mg monthly intramuscular injection. Patients may be given injections up to 7 days before or after the date of the monthly injection schedule.

Table 2 Recommended monthly intramuscular injection dosing schedule

Medicinal Product

Initiation injection

Continuation injections

Initiate injection on the last day of either current ART therapy or oral lead-in (if used)

One month after initiation injection and monthly onwards

Rilpivirine

900 mg

600 mg

Cabotegravir

600 mg

400 mg

Every 2 months dosing

Initiation Injections –1 month apart (900 mg corresponding to 3 mL)

On the final day of current antiretroviral therapy or oral lead-in, the recommended initial rilpivirine injection dose is a single 900 mg intramuscular injection.

One month later, a second 900 mg intramuscular injection should be administered. Patients may be given the second 900 mg injection up to 7 days before or after the scheduled dosing date.

Continuation Injections – 2 months apart (900 mg corresponding to 3 mL)

After the initiation injections, the recommended rilpivirine continuation injection dose is a single 900 mg intramuscular injection administered every 2 months. Patients may be given injections up to 7 days before or after the date of the every 2 months injection schedule.

Table 3 Recommended every 2 months intramuscular injection dosing schedule

Initiation injections

Continuation injections

Medicinal Product

Initiate injection on the last day of either current ART therapy or oral lead-in (if used). One month later, a second initiation injection should be administered.

Two months after last initiation injection and every 2 months onwards

Rilpivirine

900 mg

900 mg

Cabotegravir

600 mg

600 mg

Dosing recommendations when switching from monthly to every 2 months injections

Patients switching from a monthly continuation injection schedule to an every 2 months continuation injection schedule should receive a single 900 mg intramuscular injection of REKAMBYS one month after the last 600 mg REKAMBYS continuation injection dose and then 900 mg every 2 months thereafter.

Dosing recommendations when switching from every 2 months to monthly injections

Patients switching from an every 2 months continuation injection schedule to a monthly continuation injection schedule should receive a single 600 mg intramuscular injection of REKAMBYS two months after the last 900 mg REKAMBYS continuation injection dose and then 600 mg monthly thereafter.

Missed doses

Patients who miss an injection visit should be clinically reassessed to ensure resumption of therapy is appropriate. See Table 4 and 5 for dosing recommendations after a missed injection.

Missed every 1 month injection (Oral Dosing to Replace Up to 2 Consecutive Monthly Injections)

If a patient plans to miss a scheduled injection by more than 7 days, daily oral therapy (one rilpivirine tablet [25 mg] and one cabotegravir tablet [30 mg]) may be used to replace up to 2 consecutive monthly injection visits. Limited data is available on oral bridging with other fully suppressive antiretroviral therapy (ART) (mainly INI-based), see section 5.1.

The first dose of oral therapy should be taken 1 month (± 7 days) after the last injection doses of REKAMBYS and cabotegravir. Injection dosing should be resumed on the day oral dosing completes, as recommended in Table 4.

In case more than two months need to be covered for, i.e., missing more than two monthly injections, an alternative oral regimen should be initiated one month (± 7 days) after the final injection of REKAMBYS.

Table 4 REKAMBYS dosing recommendations after missed injections or oral therapy for patients on monthly injection dosing

Time since last injection

Recommendation

≤ 2 months:

Continue with the monthly 600 mg injection schedule as soon as possible.

> 2 months:

Re-initiate the patient on the 900 mg dose, and then continue to follow the monthly 600 mg injection schedule.

Missed every 2 months injection (Oral Dosing to Replace 1 Every 2 Months Injection)

If a patient plans to miss a scheduled injection visit by more than 7 days, daily oral therapy (one rilpivirine tablet [25 mg] and one cabotegravir tablet [30 mg]) may be used to replace one 'every 2 months' injection visit. Limited data is available on oral bridging with other fully suppressive ART (mainly INI-based), see section 5.1.

The first dose of oral therapy should be taken approximately two months (±7 days) after the last injection doses of REKAMBYS and cabotegravir. Injection dosing should be resumed on the day oral dosing completes, as recommended in Table 5.

In case more than two months need to be covered for, i.e., missing more than one 'every 2 months' injection, an alternative oral regimen should be initiated two months (± 7 days) after the final injection of REKAMBYS.

Table 5 REKAMBYS dosing recommendations after missed injections or oral therapy for patients on every 2 months injection dosing

Missed Injection Visit

Time since last injection

Recommendation (all injections are 3 mL)

Injection 2

≤ 2 months

Continue with the 900 mg injection as soon as possible and continue with every 2 months injection schedule.

> 2 months

Re-initiate the patient on the 900 mg dose, followed by a second 900 mg initiation injection one month later. Then follow the every 2 months injection schedule.

Injection 3 or later

≤ 3 months

Continue with the 900 mg injection as soon as possible and continue with every 2 months injection schedule.

> 3 months

Re-initiate the patient on the 900 mg dose, followed by a second 900 mg initiation injection one month later. Then follow the every 2 months injection schedule.

Special populations

Elderly

There is limited information regarding the use of REKAMBYS in patients > 65 years of age. No dose adjustment of REKAMBYS is required in older patients (see sections 5.1 and 5.2).

Renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment. In patients with severe renal impairment or end stage renal disease, the combination of REKAMBYS with a strong CYP3A inhibitor should only be used if the benefit outweighs the risk. Subjects with estimated creatinine clearance < 50 mL/min/1.73 m2 were not included in the Phase 3 studies. No data are available in subjects receiving dialysis although differences in pharmacokinetics are not expected in this population (see section 5.2).

Hepatic impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh score A or B), but caution is advised in patients with moderate hepatic impairment. No data are available in patients with severe hepatic impairment (Child-Pugh score C); therefore REKAMBYS is not recommended in these patients (see section 5.2).

Paediatric population

The safety and efficacy of REKAMBYS in children aged less than 12 years and adolescents weighing less than 35 kg have not been established. No data are available.

Method of administration

For intramuscular use.

Care should be taken to avoid inadvertent injection of REKAMBYS into a blood vessel. The suspension should be injected slowly (see section 4.4).

Prior to administration, the REKAMBYS vial should be brought to room temperature.

For instructions on administration, see “Instructions for Use” in the package leaflet. These instructions should be carefully followed when preparing the suspension for injection to avoid leakage.

REKAMBYS should always be co-administered with a cabotegravir injection. REKAMBYS and cabotegravir injections should be administered at separate gluteal injection sites during the same visit. The order of injections is not important.

When administering REKAMBYS, the healthcare professional should take into consideration the body mass index (BMI) of the patient to ensure that the needle length is sufficient to reach the gluteus muscle. The pack contains 1 injection needle (see section 6.5).

The vial should be held firmly and shaken vigorously for a full 10 seconds. The vial should be inverted and the resuspension should be checked. It should look uniform. If the suspension is not uniform, the vial should be shaken again. It is normal to see small air bubbles.

Injections must be administered to the ventrogluteal (recommended) or the dorsogluteal sites.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co‑administered with the following medicinal products (see section 4.5):

- the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin

- the antimycobacterials rifabutin, rifampicin, rifapentine

- the systemic glucocorticoid dexamethasone, except as a single dose treatment

- St John's wort (Hypericum perforatum).

4.4. Special warnings and precautions for use

Risk of resistance following treatment discontinuation

To minimise the risk of developing viral resistance it is essential to adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the last every 1 month injection of rilpivirine or two months after the last every 2 months injection of rilpivirine.

If virologic failure is suspected, an alternative regimen should be adopted as soon as possible.

Long-acting properties of rilpivirine injection

Residual concentrations of rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 4 years in some patients) and should be considered upon discontinuation of rilpivirine (see sections 4.5, 4.6, 4.7, 4.9).

Baseline factors associated with virological failure

Before starting the regimen, it should be taken into account that multivariable analyses indicate that a combination of at least 2 of the following baseline factors may be associated with an increased risk of virological failure: archived rilpivirine resistance mutations, HIV-1 subtype A6/A1, or BMI ≥ 30 kg/m2. Available data suggest that virologic failure occurs more often when these patients are treated according to the every 2 months dosing schedule as compared to the monthly dosing regimen. In patients with an incomplete or uncertain treatment history without pre-treatment resistance analyses, caution is warranted in the presence of either BMI ≥ 30 kg/m2 or HIV‑1 subtype A6/A1 (see section 5.1).

Post-injection reactions

Accidental intravenous administration may result in Adverse Reactions due to temporarily high plasma concentrations. In clinical studies, serious post-injection reactions were reported within minutes after the injection of rilpivirine. These events included symptoms such as dyspnoea, bronchospasm, agitation, abdominal cramping, rash/urticaria, dizziness, flushing, sweating, oral numbness, changes in blood pressure, and pain (e.g., back and chest). These events were very rare and began to resolve within minutes after the injection. Some of the patients received symptomatic treatment, at the discretion of the treating physician.

Carefully follow the Instructions for Use when preparing and administering rilpivirine (see section 4.2). Patients should be briefly observed (approximately 10 minutes) after the injection. If a patient experiences a post-injection reaction, monitoring and treatment should be provided as clinically indicated.

Cardiovascular

Rilpivirine should be used with caution when co‑administered with a medicinal product with a known risk of Torsade de Pointes. At supra‑therapeutic doses (75 and 300 mg once daily), oral rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG) (see sections 4.5, 4.8 and 5.2). Oral rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Plasma rilpivirine concentrations after rilpivirine injections are comparable to those during such oral rilpivirine therapy.

HBV/HCV co-infection

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.

Interactions with other medicinal products

Rilpivirine should not be administered with other antiretroviral medicinal products, except for cabotegravir injection for the treatment of HIV-1 infection (see section 4.5).

Pregnancy

There are limited data of rilpivirine in pregnant women. Rilpivirine is not recommended during pregnancy unless the expected benefit justifies the potential risk. Lower exposures of oral rilpivirine were observed when rilpivirine 25 mg once daily was taken during pregnancy. In the Phase 3 studies with oral rilpivirine, lower rilpivirine exposure, similar to that seen during pregnancy, has been associated with an increased risk of virological failure, therefore viral load should be monitored closely. Alternatively, switching to another ART regimen could be considered (see sections 4.6, 5.1 and 5.2).

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution, however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Opportunistic infections

Patients should be advised that rilpivirine or any other antiretroviral therapy does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per injection, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Rilpivirine, in combination with cabotegravir injection, is intended for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral medicinal products for the treatment of HIV-1. Therefore, information regarding drug-drug interactions with other antiretroviral medicinal products is not provided. From a drug interaction perspective, there are no limitations on the use of other antiretroviral medicinal products after discontinuing rilpivirine.

For the oral lead-in rilpivirine treatment and in case missed doses are replaced by oral rilpivirine treatment, refer to the oral rilpivirine tablet SmPC for information about drug interactions.

Medicinal products that affect rilpivirine exposure

Rilpivirine is primarily metabolised by cytochrome P450 (CYP)3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2). 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.Co‑administration of rilpivirine and medicinal products that inhibit CYP3A has been observed to increase the plasma concentrations of rilpivirine.

When using oral rilpivirine, proton pump inhibitors are contraindicated (see rilpivirine tablet SmPC, section 4.3).

Medicinal products that are affected by the use of rilpivirine

Rilpivirine is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.

Rilpivirine inhibits P‑glycoprotein in vitro (IC50 is 9.2 μM). In a clinical study, oral rilpivirine (25 mg once daily) did not significantly affect the pharmacokinetics of digoxin.

Rilpivirine is an in vitro inhibitor of the transporter MATE‑2K with an IC50 of < 2.7 nM. The clinical implications of this finding are currently unknown.

Interaction table

Selected established and theoretical interactions between rilpivirine and co-administered medicinal products are listed in Table 6 and are based on the studies conducted with oral rilpivirine or are potential drug interactions that may occur (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, not applicable as “NA”, confidence interval as “CI”).

Table 6 Interactions and dose recommendations with other medicinal products

Medicinal products by therapeutic areas

Interaction

Geometric mean change (%)Ω

Recommendations concerning co‑administration

ANTIVIRAL AGENTS

Cabotegravir

cabotegravir AUC ↔

cabotegravir Cmin↔

cabotegravir Cmax ↔

rilpivirine AUC ↔

rilpivirine Cmin ↓ 8%

rilpivirine Cmax ↔

No dose adjustment is required.

Ribavirin

Not studied. No clinically relevant drug-drug interaction is expected.

No dose adjustment is required.

ANTICONVULSANTS

Carbamazepine

Oxcarbazepine

Phenobarbital

Phenytoin

Not studied. Significant decreases in rilpivirine plasma concentrations are expected.

(induction of CYP3A enzymes)

Rilpivirine must not be used in combination with these anticonvulsants as co‑administration may result in loss of therapeutic effect of rilpivirine (see section 4.3).

AZOLE ANTIFUNGAL AGENTS

Ketoconazole*#

400 mg once daily

ketoconazole AUC ↓ 24%

ketoconazole Cmin ↓ 66%

ketoconazole Cmax ↔

(induction of CYP3A due to high rilpivirine dose in the study)

rilpivirine AUC ↑ 49%

rilpivirine Cmin ↑ 76%

rilpivirine Cmax ↑ 30%

(inhibition of CYP3A enzymes)

No dose adjustment is required.

Fluconazole

Itraconazole

Posaconazole

Voriconazole

Not studied. Concomitant use of REKAMBYS with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine.

(inhibition of CYP3A enzymes)

No dose adjustment is required.

ANTIMYCOBACTERIALS

Rifabutin*#

300 mg once daily

300 mg once daily

(+ 25 mg once daily rilpivirine)

300 mg once daily

(+ 50 mg once daily rilpivirine)

rifabutin AUC ↔

rifabutin Cmin ↔

rifabutin Cmax ↔

25‑O‑desacetyl‑rifabutin AUC ↔

25‑O‑desacetyl‑rifabutin Cmin ↔

25‑O‑desacetyl‑rifabutin Cmax ↔

rilpivirine AUC ↓ 42%

rilpivirine Cmin ↓ 48%

rilpivirine Cmax ↓ 31%

rilpivirine AUC ↑ 16%*

rilpivirine Cmin ↔*

rilpivirine Cmax ↑ 43%*

* compared to 25 mg once daily rilpivirine alone

(induction of CYP3A enzymes)

Rilpivirine must not be used in combination with rifabutin as specific dosing recommendations have not been established. Co‑administration is likely to result in loss of therapeutic effect of rilpivirine (see section 4.3).

Rifampicin*#

600 mg once daily

rifampicin AUC ↔

rifampicin Cmin NA

rifampicin Cmax ↔

25‑desacetyl‑rifampicin AUC ↓ 9%

25‑desacetyl‑rifampicin Cmin NA

25‑desacetyl‑rifampicin Cmax ↔

rilpivirine AUC ↓ 80%

rilpivirine Cmin ↓ 89%

rilpivirine Cmax ↓ 69%

(induction of CYP3A enzymes)

Rilpivirine must not be used in combination with rifampicin as co‑administration is likely to result in loss of therapeutic effect of rilpivirine (see section 4.3).

Rifapentine

Not studied. Significant decreases in rilpivirine plasma concentrations are expected.

(induction of CYP3A enzymes)

Rilpivirine must not be used in combination with rifapentine as co‑administration is likely to result in loss of therapeutic effect of rilpivirine (see section 4.3).

MACROLIDE ANTIBIOTICS

Clarithromycin

Erythromycin

Not studied. Increased exposure of rilpivirine is expected.

(inhibition of CYP3A enzymes)

Where possible, alternatives such as azithromycin should be considered.

GLUCOCORTICOIDS OR CORTICOSTEROIDS

Dexamethasone (systemic, except for single dose use)

Not studied. Dose dependent decreases in rilpivirine plasma concentrations are expected.

(induction of CYP3A enzymes)

Rilpivirine should not be used in combination with systemic dexamethasone (except as a single dose) as co‑administration may result in loss of therapeutic effect of rilpivirine (see section 4.3). Alternatives should be considered, particularly for long‑term use.

NARCOTIC ANALGESICS

Methadone*

60‑100 mg once daily, individualised dose

R(‑) methadone AUC ↓ 16%

R(‑) methadone Cmin ↓ 22%

R(‑) methadone Cmax ↓ 14%

rilpivirine AUC ↔*

rilpivirine Cmin ↔*

rilpivirine Cmax ↔*

* based on historic controls

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.

ANTIARRHYTHMICS

Digoxin*

digoxin AUC ↔

digoxin Cmin NA

digoxin Cmax ↔

No dose adjustment is required.

ANTIDIABETICS

Metformin*

metformin AUC ↔

metformin Cmin NA

metformin Cmax ↔

No dose adjustment is required.

HERBAL PRODUCTS

St John's wort (Hypericum perforatum)

Not studied. Significant decreases in rilpivirine plasma concentrations are expected.

(induction of CYP3A enzymes)

Rilpivirine must not be used in combination with products containing St. John's wort as co‑administration may result in loss of therapeutic effect of rilpivirine (see section 4.3).

ANALGESICS

Paracetamol*#

500 mg single dose

paracetamol AUC ↔

paracetamol Cmin NA

paracetamol Cmax ↔

rilpivirine AUC ↔

rilpivirine Cmin ↑ 26%

rilpivirine Cmax ↔

No dose adjustment is required.

ORAL CONTRACEPTIVES

Ethinylestradiol*

0.035 mg once daily

Norethindrone*

1 mg once daily

ethinylestradiol AUC ↔

ethinylestradiol Cmin ↔

ethinylestradiol Cmax ↑ 17%

norethindrone AUC ↔

norethindrone Cmin ↔

norethindrone Cmax ↔

rilpivirine AUC ↔*

rilpivirine Cmin ↔*

rilpivirine Cmax ↔*

* based on historic controls

No dose adjustment is required.

HMG CO‑A REDUCTASE INHIBITORS

Atorvastatin*#

40 mg once daily

atorvastatin AUC ↔

atorvastatin Cmin ↓ 15%

atorvastatin Cmax ↑ 35%

rilpivirine AUC ↔

rilpivirine Cmin ↔

rilpivirine Cmax ↓ 9%

No dose adjustment is required.

PHOSPHODIESTERASE TYPE 5 (PDE‑5) INHIBITORS

Sildenafil*#

50 mg single dose

sildenafil AUC ↔

sildenafil Cmin NA

sildenafil Cmax ↔

rilpivirine AUC ↔

rilpivirine Cmin ↔

rilpivirine Cmax ↔

No dose adjustment is required.

Vardenafil

Tadalafil

Not studied.

No dose adjustment is required.

Ω % increase/decrease based on Drug-Drug Interaction studies with oral rilpivirine

* The interaction between rilpivirine and the medicinal product was evaluated in a clinical study. All other drug‑drug interactions shown are predicted.

# This interaction study has been performed with a dose higher than the recommended dose for rilpivirine assessing the maximal effect on the co‑administered medicinal product. The dosing recommendation is applicable to the recommended dose of rilpivirine of 25 mg once daily.

QT prolonging medicinal products

Oral rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Rilpivirine plasma concentrations after rilpivirine injections at the recommended dose of 600 mg monthly or 900 mg every 2 months, are comparable to those achieved with oral rilpivirine at a dose of 25 mg qd. In a study of healthy subjects, supratherapeutic doses of oral rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the ECG (see section 5.1). Rilpivirine should be used with caution when co‑administered with a medicinal product with a known risk of Torsade de Pointes (see section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy

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 (see section 5.3).

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 (see section 4.4).

Breast‑feeding

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.

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 (see section 5.3).

4.7. Effects on ability to drive and use machines

Patients should be informed that fatigue, dizziness and somnolence could occur when treated with rilpivirine (see section 4.8).

4.8. Undesirable effects

Adults

Summary of the safety profile

The most frequently reported ARs were injection site reactions, headache and pyrexia.

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 Class (SOC)

Frequency Category

ARs for rilpivirine + cabotegravir regimen

Blood and lymphatic system disorders

Common

decreased white blood cell count2, decreased haemoglobin2, decreased platelet count2

Immune System Disorders

Uncommon

immune reactivation syndrome2

Metabolism and nutrition disorders

Very common

increased total cholesterol (fasted)2, increased LDL 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 tissue disorders

Common

rash4

Musculoskeletal and connective tissue disorders

Common

myalgia

General disorders and administrative site conditions

Very common

injection site reactions (pain and discomfort, nodule, induration), pyrexia5

Common

injection site reactions (swelling, erythema, pruritis, 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.

Paediatric population

Based on data from the week 16 (Cohort 1) and week 24 (Cohort 2) analyses of the MOCHA study, 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medical product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is currently limited experience with rilpivirine overdose. If overdose occurs, the patient should be treated supportively and as clinically indicated, with monitoring of vital signs and ECG (QT interval), as necessary. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance.