Leaflet REKAMBYS 900mg long-release injection suspension

REKAMBYS 600 mg prolonged-release suspension for injection

REKAMBYS 900 mg prolonged-release suspension for injection

2 mL vial

Each vial contains 600 mg rilpivirine3 mL vial

Each vial contains 900 mg rilpivirine

For the full list of excipients, see section 6.1.

Prolonged-release suspension for injection

White to off-white suspension.

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

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

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

Following discontinuation of REKAMBYS in combination with cabotegravir injection, it is essentialto adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the lastevery 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.

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 tothe initiation of rilpivirine injections to assess tolerability (see Table 1), or proceed directly torilpivirine 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 withcabotegravir oral tablets, should be taken for approximately 1 month (at least 28 days) to assesstolerability to rilpivirine and cabotegravir. One rilpivirine 25-mg tablet should be taken with a mealwith 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 dailya 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 injectiondose 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 single600 mg monthly intramuscular injection. Patients may be given injections up to 7 days before or afterthe date of the monthly injection schedule.

Table 2 Recommended monthly intramuscular injection dosing schedule

Initiation injection Continuation injections

Initiate injection on the last day of

Medicinaleither current ART therapy or oral One month after initiation injection

Productlead-in (if used) 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 rilpivirineinjection dose is a single 900 mg intramuscular injection.

One month later, a second 900 mg intramuscular injection should be administered. Patients may begiven 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 single900 mg intramuscular injection administered every 2 months. Patients may be given injections up to7 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

Initiate injection on the last day ofeither current ART therapy or oral

Two months after last initiation

Medicinal lead-in (if used). One month later, ainjection and every 2 months

Product second initiation injection should beonwardsadministered.

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 continuationinjection schedule should receive a single 900 mg intramuscular injection of REKAMBYS one monthafter the last 600 mg REKAMBYS continuation injection dose and then 900 mg every 2 monthsthereafter.

Dosing recommendations when switching from every 2 months to monthly injections

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

Patients who miss an injection visit should be clinically reassessed to ensure resumption of therapy isappropriate. 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 rilpivirinetablet [25 mg] and one cabotegravir tablet [30 mg]) may be used to replace up to 2 consecutivemonthly injection visits. Limited data is available on oral bridging with other fully suppressiveantiretroviral 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 forpatients on monthly injection dosing

Time since last injection Recommendation≤ 2 months: Continue with the monthly 600 mg injection schedule as soon aspossible.> 2 months: Re-initiate the patient on the 900 mg dose, and then continue to followthe 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 (onerilpivirine tablet [25 mg] and one cabotegravir tablet [30 mg]) may be used to replace one ‘every2 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 lastinjection doses of REKAMBYS and cabotegravir. Injection dosing should be resumed on the day oraldosing 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 injectionof REKAMBYS.

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

Missed Injection Time since Recommendation (all injections are 3 mL)

Visit last injection

Injection 2 ≤ 2 months Continue with the 900 mg injection as soon as possible andcontinue with every 2 months injection schedule.> 2 months Re-initiate the patient on the 900 mg dose, followed by asecond 900 mg initiation injection one month later. Thenfollow the every 2 months injection schedule.

Injection 3 or ≤ 3 months Continue with the 900 mg injection as soon as possible andlater continue with every 2 months injection schedule.

> 3 months Re-initiate the patient on the 900 mg dose, followed by asecond 900 mg initiation injection one month later. Thenfollow the every 2 months injection schedule.

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

No dose adjustment is required in patients with mild or moderate renal impairment. In patients withsevere 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 estimatedcreatinine clearance < 50 mL/min/1.73 m2 were not included in the Phase 3 studies. No data areavailable in subjects receiving dialysis although differences in pharmacokinetics are not expected inthis population (see section 5.2).

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pughscore A or B), but caution is advised in patients with moderate hepatic impairment. No data areavailable in patients with severe hepatic impairment (Child-Pugh score C); therefore REKAMBYS isnot recommended in these patients (see section 5.2).

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

For intramuscular use.

Care should be taken to avoid inadvertent injection of REKAMBYS into a blood vessel. Thesuspension 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 instructionsshould be carefully followed when preparing the suspension for injection to avoid leakage.

REKAMBYS should always be co-administered with a cabotegravir injection. REKAMBYS andcabotegravir 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 bodymass index (BMI) of the patient to ensure that the needle length is sufficient to reach the gluteusmuscle. 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 invertedand the resuspension should be checked. It should look uniform. If the suspension is not uniform, thevial should be shaken again. It is normal to see small air bubbles.

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

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

Co-administration 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).

Risk of resistance following treatment discontinuation

To minimise the risk of developing viral resistance it is essential to adopt an alternative, fullysuppressive antiretroviral regimen no later than one month after the last every 1 month injection ofrilpivirine 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 prolongedperiods (up to 4 years in some patients) and should be considered upon discontinuation of rilpivirine(see sections 4.5, pct. 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 acombination of at least 2 of the following baseline factors may be associated with an increased risk ofvirological 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 aretreated 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 (seesection 5.1).

Post-injection reactions

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

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

Rilpivirine should be used with caution when co-administered with a medicinal product with a knownrisk of Torsade de Pointes. At supra-therapeutic doses (75 and 300 mg once daily), oral rilpivirine hasbeen associated with prolongation of the QTc interval of the electrocardiogram (ECG) (seesections 4.5, pct. 4.8 and 5.2). Oral rilpivirine at the recommended dose of 25 mg once daily is notassociated with a clinically relevant effect on QTc. Plasma rilpivirine concentrations after rilpivirineinjections 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 notrecommended to initiate rilpivirine in patients with hepatitis B co-infection. In patients co-infectedwith hepatitis B receiving oral rilpivirine, the incidence of hepatic enzyme elevation was higher thanin patients receiving oral rilpivirine who were not hepatitis B co-infected. Physicians should refer tocurrent 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 patientsreceiving oral rilpivirine who were not hepatitis C co-infected. The pharmacokinetic exposure of oraland injectable rilpivirine in co-infected patients was comparable to that in patients without hepatitis Cco-infection. Monitoring of liver function is recommended in patients with hepatitis C co-infection.

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

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

In HIV-infected patients with severe immune deficiency at the time of institution of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticpathogens 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 andtreatment instituted when necessary. Autoimmune disorders (such as Graves’ disease and autoimmunehepatitis) have also been reported to occur in the setting of immune reconstitution, however, thereported time to onset is more variable and these events can occur many months after initiation oftreatment.

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

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

Rilpivirine, in combination with cabotegravir injection, is intended for use as a complete regimen forthe treatment of HIV-1 infection and should not be administered with other antiretroviral medicinalproducts for the treatment of HIV-1. Therefore, information regarding drug-drug interactions withother antiretroviral medicinal products is not provided. From a drug interaction perspective, there areno 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 rilpivirinetreatment, 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 orinhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2). Co-administration ofrilpivirine and medicinal products that induce CYP3A has been observed to decrease the plasmaconcentrations of rilpivirine, which could reduce the therapeutic effect of rilpivirine.

Co-administration of rilpivirine and medicinal products that inhibit CYP3A has been observed toincrease 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 productsmetabolised by CYP enzymes.

Rilpivirine inhibits P-glycoprotein in vitro (IC50 is 9.2 μM). In a clinical study, oral rilpivirine (25 mgonce 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 clinicalimplications of this finding are currently unknown.

Selected established and theoretical interactions between rilpivirine and co-administered medicinalproducts are listed in Table 6 and are based on the studies conducted with oral rilpivirine or arepotential 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 Interaction Recommendations concerningtherapeutic areas Geometric mean change (%)Ω co-administration

ANTIVIRAL AGENTS

Cabotegravir cabotegravir AUC ↔ No dose adjustment is required.cabotegravir Cmin↔cabotegravir Cmax ↔rilpivirine AUC ↔rilpivirine Cmin ↓ 8%rilpivirine Cmax ↔

Ribavirin Not studied. No clinically relevant No dose adjustment is required.drug-drug interaction is expected.

ANTICONVULSANTS

Carbamazepine Not studied. Significant decreases in Rilpivirine must not be used in

Oxcarbazepine rilpivirine plasma concentrations are combination with these

Phenobarbital expected. anticonvulsants as

Phenytoin co-administration may result in loss(induction of CYP3A enzymes) of therapeutic effect of rilpivirine(see section 4.3).

AZOLE ANTIFUNGAL AGENTS

Ketoconazole*# ketoconazole AUC ↓ 24% No dose adjustment is required.400 mg once daily ketoconazole Cmin ↓ 66%ketoconazole Cmax ↔(induction of CYP3A due to highrilpivirine dose in the study)rilpivirine AUC ↑ 49%rilpivirine Cmin ↑ 76%rilpivirine Cmax ↑ 30%(inhibition of CYP3A enzymes)

Fluconazole Not studied. Concomitant use of No dose adjustment is required.

Itraconazole REKAMBYS with azole antifungal

Posaconazole agents may cause an increase in the

Voriconazole plasma concentrations of rilpivirine.

(inhibition of CYP3A enzymes)

ANTIMYCOBACTERIALS

Rifabutin*# rifabutin AUC ↔ Rilpivirine must not be used in300 mg once daily rifabutin Cmin ↔ combination with rifabutin asrifabutin Cmax ↔ specific dosing recommendations25-O-desacetyl-rifabutin AUC ↔ have not been established.25-O-desacetyl-rifabutin Cmin ↔ Co-administration is likely to result25-O-desacetyl-rifabutin Cmax ↔ in loss of therapeutic effect ofrilpivirine (see section 4.3).300 mg once daily rilpivirine AUC ↓ 42%(+ 25 mg once daily rilpivirine Cmin ↓ 48%rilpivirine) rilpivirine Cmax ↓ 31%300 mg once daily rilpivirine AUC ↑ 16%*(+ 50 mg once daily rilpivirine Cmin ↔*rilpivirine) rilpivirine Cmax ↑ 43%*

* compared to 25 mg once daily rilpivirinealone(induction of CYP3A enzymes)

Rifampicin*# rifampicin AUC ↔ Rilpivirine must not be used in600 mg once daily rifampicin Cmin NA combination with rifampicin asrifampicin Cmax ↔ co-administration is likely to result25-desacetyl-rifampicin AUC ↓ 9% in loss of therapeutic effect of25-desacetyl-rifampicin Cmin NA rilpivirine (see section 4.3).25-desacetyl-rifampicin Cmax ↔rilpivirine AUC ↓ 80%rilpivirine Cmin ↓ 89%rilpivirine Cmax ↓ 69%(induction of CYP3A enzymes)

Rifapentine Not studied. Significant decreases in Rilpivirine must not be used inrilpivirine plasma concentrations are combination with rifapentine asexpected. co-administration is likely to resultin loss of therapeutic effect of(induction of CYP3A enzymes) rilpivirine (see section 4.3).

MACROLIDE ANTIBIOTICS

Clarithromycin Not studied. Increased exposure of Where possible, alternatives such as

Erythromycin rilpivirine is expected. azithromycin should be considered.

(inhibition of CYP3A enzymes)

GLUCOCORTICOIDS OR CORTICOSTEROIDS

Dexamethasone Not studied. Dose dependent Rilpivirine should not be used in(systemic, except for decreases in rilpivirine plasma combination with systemicsingle dose use) concentrations are expected. dexamethasone (except as a singledose) as co-administration may(induction of CYP3A enzymes) result in loss of therapeutic effect ofrilpivirine (see section 4.3).

Alternatives should be considered,particularly for long-term use.

NARCOTIC ANALGESICS

Methadone* R(-) methadone AUC ↓ 16% No dose adjustments are required60-100 mg once daily, R(-) methadone Cmin ↓ 22% when initiating co-administration ofindividualised dose R(-) methadone Cmax ↓ 14% methadone with rilpivirine.

rilpivirine AUC ↔* However, clinical monitoring isrilpivirine Cmin ↔* recommended as methadonerilpivirine Cmax ↔* maintenance therapy may need to

* based on historic controls be adjusted in some patients.

ANTIARRHYTHMICS

Digoxin* digoxin AUC ↔ No dose adjustment is required.

digoxin Cmin NAdigoxin Cmax ↔

ANTIDIABETICS

Metformin* metformin AUC ↔ No dose adjustment is required.

metformin Cmin NAmetformin Cmax ↔

HERBAL PRODUCTS

St John's wort Not studied. Significant decreases in Rilpivirine must not be used in(Hypericum perforatum) rilpivirine plasma concentrations are combination with productsexpected. containing St. John’s wort asco-administration may result in loss(induction of CYP3A enzymes) of therapeutic effect of rilpivirine(see section 4.3).

ANALGESICS

Paracetamol*# paracetamol AUC ↔ No dose adjustment is required.500 mg single dose paracetamol Cmin NAparacetamol Cmax ↔rilpivirine AUC ↔rilpivirine Cmin ↑ 26%rilpivirine Cmax ↔

ORAL CONTRACEPTIVES

Ethinylestradiol* ethinylestradiol AUC ↔ No dose adjustment is required.0.035 mg once daily ethinylestradiol Cmin ↔

Norethindrone* ethinylestradiol Cmax ↑ 17%1 mg once daily norethindrone AUC ↔norethindrone Cmin ↔norethindrone Cmax ↔rilpivirine AUC ↔*rilpivirine Cmin ↔*rilpivirine Cmax ↔*

* based on historic controls

HMG CO-A REDUCTASE INHIBITORS

Atorvastatin*# atorvastatin AUC ↔ No dose adjustment is required.40 mg once daily atorvastatin Cmin ↓ 15%atorvastatin Cmax ↑ 35%rilpivirine AUC ↔rilpivirine Cmin ↔rilpivirine Cmax ↓ 9%

PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS

Sildenafil*# sildenafil AUC ↔ No dose adjustment is required.50 mg single dose sildenafil Cmin NAsildenafil Cmax ↔rilpivirine AUC ↔rilpivirine Cmin ↔rilpivirine Cmax ↔

Vardenafil Not studied. No dose adjustment is required.

Tadalafil

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-druginteractions shown are predicted.

# This interaction study has been performed with a dose higher than the recommended dose for rilpivirine assessing themaximal effect on the co-administered medicinal product. The dosing recommendation is applicable to therecommended 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 clinicallyrelevant effect on QTc. Rilpivirine plasma concentrations after rilpivirine injections at therecommended dose of 600 mg monthly or 900 mg every 2 months, are comparable to those achievedwith oral rilpivirine at a dose of 25 mg qd. In a study of healthy subjects, supratherapeutic doses oforal rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTcinterval of the ECG (see section 5.1). Rilpivirine should be used with caution when co-administeredwith a medicinal product with a known risk of Torsade de Pointes (see section 4.4).

The effect of rilpivirine on human pregnancy is unknown.

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

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

Animal studies do not indicate reproductive toxicity (see section 5.3).

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

An alternative oral regimen should be considered in line with current treatment guidelines. Afterdiscontinuation of rilpivirine, rilpivirine may remain in systemic circulation for up to 4 years in somepatients (see section 4.4).

It is expected that rilpivirine will be secreted into human milk based on animal data, although this hasnot been confirmed in humans. Rilpivirine may be present in human milk for up to 4 years in somepatients after discontinuation of rilpivirine.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV donot breast-feed.

No human data on the effect of rilpivirine on fertility are available. No clinically relevant effects onfertility were seen in animal studies (see section 5.3).

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

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

The ARs identified for rilpivirine and/or cabotegravir are listed by system organ class (SOC) andfrequency (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, decreasedsystem disorders haemoglobin2, decreased platelet count2

Immune System Disorders Uncommon immune reactivation syndrome2

Metabolism and nutrition Very common increased total cholesterol (fasted)2, increased LDLdisorders 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 toinjections)

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 rash4tissue disorders

Musculoskeletal and Common myalgiaconnective tissue disorders

General disorders and Very common injection site reactions (pain and discomfort, nodule,administrative site induration), pyrexia5conditions 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 increased1 The frequency of the identified ARs are based on all reported occurrences of the events and are not limited to thoseconsidered 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, rashmacular, 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 thatobserved at week 48, with no new safety findings identified. In the extension phase of the FLAIRstudy, initiating the rilpivirine plus cabotegravir injection regimen without oral lead-in (direct toinjection) was not associated with any new safety concerns related to omitting the oral lead-in phase.

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 rilpivirineplus cabotegravir gained a median of 1.5 kg in weight; subjects continuing on their currentantiretroviral 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 pluscabotegravir arms were 1.3 kg and 1.8 kg, respectively, compared to 1.5 kg and 0.3 kg in the CARarms.

At the 48 week timepoint, in ATLAS-2M the median weight gain in both the monthly and every2 months rilpivirine+cabotegravir dosing arms was 1.0 kg.

Changes in laboratory chemistry

Elevated transaminases (ALT/AST) were observed in subjects receiving rilpivirine plus cabotegravirduring the clinical studies. These elevations were primarily attributed to acute viral hepatitis. A fewsubjects on oral rilpivirine plus oral cabotegravir treatment had transaminase elevations attributed tosuspected drug-related hepatotoxicity; these changes were reversible upon discontinuation oftreatment.

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

Elevated lipases were observed during clinical trials with rilpivirine plus cabotegravir. Grade 3 and 4lipase 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 cabotegravirdiscontinuation. One case of fatal pancreatitis with Grade 4 lipase and confounding factors (includinghistory of pancreatitis) has been reported in study ATLAS-2M for which the causality to the injectionregimen could not be ruled out.

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 atleast 12 years and weighing 35 kg or more) when compared with the safety profile established inadults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Antiviral for systemic use, non-nucleoside reverse transcriptaseinhibitors, ATC code: J05AG05

Rilpivirine is a diarylpyrimidine NNRTI of HIV-1. Rilpivirine activity is mediated by non-competitiveinhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNApolymerases α, β and γ.

Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected

T-cell line with a median EC50 value for HIV-1/IIIB of 0.73 nM (0.27 ng/mL). Although rilpivirinedemonstrated limited in vitro activity against HIV-2 with EC50 values ranging from 2,510 to10,830 nM (920 to 3,970 ng/mL), treatment of HIV-2 infection with rilpivirine is not recommended inthe absence of clinical data.

Rilpivirine also demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B,

C, D, F, G, H) primary isolates with EC50 values ranging from 0.07 to 1.01 nM (0.03 to 0.37 ng/mL)and group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/mL).

Considering all of the available in vitro data and in vivo data generated with oral rilpivirine inpreviously untreated patients, the following resistance-associated mutations, when present at baseline,may affect the activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L,

Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, M230L, and the combination of L100I and

K103N.

Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of differentorigins and subtypes as well as NNRTI resistant HIV-1. The most commonly observedresistance-associated mutations that emerged included L100I, K101E, V108I, E138K, V179F, Y181C,

H221Y, F227C and M230I.

Virologically suppressed adults

The number of subjects who met confirmed virologic failure (CVF) criteria was low across the pooled

Phase 3 studies ATLAS and FLAIR. There were 7 CVFs on rilpivirine plus cabotegravir (7/591, 1.2%)and 7 CVFs on current antiretroviral regimen (7/591, 1.2%) through week 48. In the rilpivirine pluscabotegravir group in the pooled analysis, 5/591 (0.8%) subjects had resistance development: 5/591(0.8%) and 4/591 (0.7%) with resistance-associated mutations to rilpivirine (K101E [n=1],

E138A/E/K/T [n=1], E138A [n=1], or E138K [n=2]) and/or cabotegravir (G140R [n=1], Q148R[n=2], or N155H [n=1]), respectively. The 4 CVFs on cabotegravir plus rilpivirine in FLAIR had

HIV-1 subtype A1 (n=3) or AG (n=1). One CVF in FLAIR never received an injection. The 3 CVFson cabotegravir plus rilpivirine in ATLAS had HIV-1 subtype A, A1, or AG. In 2 of these 3 CVFs therilpivirine resistance-associated mutations observed at failure were also observed at baseline in PBMC

HIV-1 DNA.

In the ATLAS-2M study 10 subjects met CVF criteria through week 48: 8/522 (1.5%) in the Q8W armand 2/523 (0.4%) in the Q4W arm. In the Q8W group 5/522 (1.0%) had resistance development: 4/522(0.8%) and 5/522 (1.0%) with resistance-associated mutations to rilpivirine (E138A [n=1], E138K[n=1], K101E [n=2], or Y188L [n=1]) and/or cabotegravir (Q148R [n=3] or N155H [n=4]),respectively. In the Q4W group 2/523 (0.4%) had resistance development: 1/523 (0.2%) and 2/523(0.4%) had rilpivirine (K101E [n=1], M230L [n=1]) and/or cabotegravir (E138K [n=1], Q148R [n=1],or N155H [n=1]) resistance-associated mutations, respectively. At baseline in the Q8W arm, 5 subjectshad rilpivirine resistance-associated mutations and 1 of those subjects carried a cabotegravirresistance-associated mutation. Neither subject in the Q4W arm had any rilpivirine or cabotegravirresistance-associated mutation at baseline. The 10 CVFs on cabotegravir plus rilpivirine in ATLAS-2M had HIV-1 subtype A (n=1), A1 (n=2), B (n=4), C (n=2), or Complex (n=1).

Site-directed NNRTI mutant virus

In a panel of 67 HIV-1 recombinant laboratory strains with one mutation at RT positions associatedwith NNRTI resistance, including the most commonly found K103N and Y181C, rilpivirine showedantiviral activity against 64 (96%) of these strains. The single resistance-associated mutationsassociated with a loss of susceptibility to rilpivirine were: K101P, Y181I and Y181V. The K103Nmutation did not result in reduced susceptibility to rilpivirine by itself, but the combination of K103Nand L100I resulted in a 7-fold reduced susceptibility to rilpivirine.

Recombinant clinical isolates

Rilpivirine retained sensitivity (fold change ≤ biological cut-off) against 62% of 4,786 HIV-1recombinant clinical isolates resistant to efavirenz and/or nevirapine.

Virologically suppressed adults

In the week 48 analysis of the Phase 3 studies ATLAS and FLAIR, 5/7 CVFs had phenotypicresistance against rilpivirine at failure. Among these 5 patients, phenotypic cross-resistance wasobserved against efavirenz (n=4), etravirine (n=3), and nevirapine (n=4).

No effect on QTcF interval was shown for oral rilpivirine at the recommended dose of 25 mg oncedaily in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossoverstudy in 60 healthy adults, with 13 measurements over 24 hours at steady-state. Plasma rilpivirineconcentrations after REKAMBYS injections are comparable to those achieved with oral rilpivirine atdose of 25 mg qd. REKAMBYS at the recommended dose of 600 mg monthly or 900 mg every2 months is not associated with a clinically relevant effect on QTc.

When supratherapeutic doses of 75 mg once daily and 300 mg once daily of oral rilpivirine werestudied in healthy adults, the maximum mean time-matched (95% upper confidence bound)differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4)ms, respectively. Steady-state administration of oral rilpivirine 75 mg once daily and 300 mg oncedaily resulted in a mean Cmax approximately 4.4-fold and 11.6-fold, respectively, higher than the meansteady-state Cmax observed with the recommended 600 mg once monthly dose of REKAMBYS. Steadystate administration of oral rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean Cmaxapproximately 4.1-fold and 10.7-fold, respectively, higher than the mean steady state Cmax observedwith the recommended 900 mg every 2 months dose of REKAMBYS.

Every 1 month dosing

The efficacy of REKAMBYS plus cabotegravir injection has been evaluated in two Phase 3randomised, multicentre, active-controlled, parallel-arm, open-label, non-inferiority studies, FLAIR(201584) and ATLAS (201585). The primary analysis was conducted after all subjects completed theirweek 48 visit or discontinued the study prematurely.

Patients virologically suppressed (on prior dolutegravir-based regimen for 20 weeks)

In FLAIR, 629 HIV-1-infected, antiretroviral treatment (ART)-naive subjects received a dolutegravir

INI containing regimen for 20 weeks (either dolutegravir/abacavir/lamivudine or dolutegravir + 2other nucleoside reverse transcriptase inhibitors if subjects were HLA-B*5701 positive). Subjects whowere virologically suppressed (HIV-1 RNA < 50 copies per mL, n=566) were then randomised (1:1) toreceive either a rilpivirine plus cabotegravir regimen or remain on the CAR. Subjects randomised toreceive the rilpivirine plus cabotegravir regimen, initiated treatment with oral lead-in dosing with acabotegravir (30 mg) tablet plus a rilpivirine (25 mg) tablet once daily for at least 4 weeks, followedby treatment with cabotegravir injection (month 1: 600 mg, month 2 onwards: 400 mg injection) plusrilpivirine injection (month 1: 900 mg injection, month 2 onwards: 600 mg injection), monthly, for upto 96 weeks.

Patients virologically suppressed (stable on prior ART for at least 6 months)

In ATLAS, 616 HIV-1-infected, ART-experienced, virologically-suppressed (for at least 6 months)subjects (HIV-1 RNA < 50 copies per mL) were randomised (1:1) and received either a rilpivirine pluscabotegravir regimen or remained on the CAR. Subjects randomised to receive the rilpivirine pluscabotegravir regimen initiated treatment with oral lead-in dosing with a cabotegravir (30 mg) tabletplus a rilpivirine (25 mg) tablet once daily for at least 4 weeks, followed by treatment withcabotegravir injection (month 1: 600 mg, month 2 onwards: 400 mg injection) plus rilpivirine injection(month 1: 900 mg injection, month 2 onwards: 600 mg injection), monthly, for an additional 44 weeks.

In ATLAS, 50%, 17%, and 33% of subjects received an NNRTI, PI, or INI (respectively) as theirbaseline third treatment agent class prior to randomisation and this was similar between treatmentarms.

Pooled Phase 3 studies

At baseline, in the pooled analysis, in the rilpivirine plus cabotegravir arm the median age of subjectswas 38 years, 27% were female, 27% were non-white, 1% were ≥ 65 years and 7% had CD4+ cellcount less than 350 cells per mm3; these characteristics were similar between treatment arms.

The primary endpoint of both studies was the proportion of subjects with plasma HIV-1 RNA≥ 50 copies/mL at week 48 (snapshot algorithm for the ITT-E population).

In a pooled analysis of the two Phase 3 studies, rilpivirine plus cabotegravir was non-inferior to CARon the proportion of subjects having plasma HIV-1 RNA ≥ 50 c/mL (1.9% and 1.7%, respectively) atweek 48. The adjusted treatment difference between rilpivirine plus cabotegravir and CAR (0.2; 95%

CI: -1.4, 1.7) met the non-inferiority criterion (upper bound of the 95% CI below 4%) [See Table 8].

The primary endpoint and other week 48 outcomes, including outcomes by key baseline factors, for

FLAIR, ATLAS, and pooled data are shown in Table 8 and Table 9.

Table 8 Virologic outcomes of randomised treatment in FLAIR and ATLAS at week 48(Snapshot analysis)

FLAIR ATLAS Pooled Data

RPV+ RPV+

CAB CAR CAB CAR RPV+ CAB CAR

N=283 N=283 N=308 N=308 N=591 N=591

HIV-1

RNA ≥ 50 copies/mL† 6 (2.1) 7 (2.5) 5 (1.6) 3 (1.0) 11 (1.9) 10 (1.7)

Treatment Difference

- 0.4 (-2.8, 2.1) 0.7 (-1.2, 2.5) 0.2 (-1.4, 1.7)% (95% CI)*

HIV-1 RNA 265 (93.6) 264 (93.3) 285 (92.5) 294 (95.5) 550 (93.1) 558 (94.4)< 50 copies/mL

Treatment Difference 0.4 (-3.7, 4.5) -3.0 (-6.7, 0.7) -1.4 (-4.1, 1.4)% (95% CI)*

No virologic data at12 (4.2) 12 (4.2) 18 (5.8) 11 (3.6) 30 (5.1) 23 (3.9)week 48 window

Reasons

Discontinuedstudy/study drug8 (2.8) 2 (0.7) 11 (3.6) 5 (1.6) 19 (3.2) 7 (1.2)due to adverseevent or death

Discontinuedstudy/study drug 4 (1.4) 10 (3.5) 7 (2.3) 6 (1.9) 11 (1.9) 16 (2.7)for other reasons

Missing dataduring window but 0 0 0 0 0 0on study

* Adjusted for baseline stratification factors.† Includes subjects who discontinued for lack of efficacy, discontinued while not suppressed.

N=Number of subjects in each treatment group, CI=confidence interval, CAR=current antiretroviral regimen,

RPV=rilpivirine, CAB=cabotegravir.

Table 9 Proportion of subjects with plasma HIV-1 RNA ≥ 50 copies/mL at week 48 for keybaseline factors (Snapshot outcomes)

Pooled data from FLAIR and ATLAS

RPV+CAB CAR

Baseline factors

N=591 N=591n/N (%) n/N (%)

Baseline CD4+ < 350 0/42 2/54 (3.7)(cells/ mm3) ≥ 350 to < 500 5/120 (4.2) 0/117≥ 500 6/429 (1.4) 8/420 (1.9)

Gender Male 6/429 (1.4) 9/423 (2.1)

Female 5/162 (3.1) 1/168 (0.6)

Race White 9/430 (2.1) 7/408 (1.7)

Black African/American 2/109 (1.8) 3/133 (2.3)

Asian/Other 0/52 0/48

BMI < 30 kg/m2 6/491 (1.2) 8/488 (1.6)≥ 30 kg/m2 5/100 (5.0) 2/103 (1.9)

Age (years) < 50 9/492 (1.8) 8/466 (1.7)≥ 50 2/99 (2.0) 2/125 (1.6)

Baseline antiviral PI 1/51 (2.0) 0/54therapy at randomisation INI 6/385 (1.6) 9/382 (2.4)

NNRTI 4/155 (2.6) 1/155 (0.6)

BMI=body mass index, PI=Protease inhibitor, INI=Integrase inhibitor, NNRTI=non-nucleoside reversetranscriptase inhibitor, RPV=rilpivirine, CAB=cabotegravir, CAR=current antiretroviral regimen

In the FLAIR and ATLAS studies, treatment differences across baseline characteristics (CD4+ count,gender, age, race, BMI, baseline third agent treatment class) were comparable.

Week 96 FLAIR

In the FLAIR study at 96 weeks, the results remained consistent with the results at 48 weeks. Theproportion of subjects having plasma HIV-1 RNA ≥ 50 c/mL in rilpivirine plus cabotegravir (n=283)and CAR (n=283) was 3.2% and 3.2%, respectively (adjusted treatment difference between rilpivirineplus cabotegravir and CAR [0.0; 95% CI: -2.9, 2.9]). The proportion of subjects having plasma HIV-1

RNA < 50 c/mL in rilpivirine plus cabotegravir and CAR was 87% and 89%, respectively (adjustedtreatment difference between rilpivirine plus cabotegravir and CAR [-2.8; 95% CI: -8.2, 2.5]).

Week 124 FLAIR Direct to Injection versus Oral Lead-In

In the FLAIR study, an evaluation of safety and efficacy was performed at week 124 for patientselecting to switch at week 100 from abacavir/dolutegravir/lamivudine to rilpivirine plus cabotegravirin the Extension Phase. Subjects were given the option to switch with or without an oral lead-in phase,creating an oral lead-in group and a direct to injection group.

At week 124, the proportion of subjects having plasma HIV-1 RNA ≥ 50 c/mL was 1/121 (0.8%) and1/111 (0.9%) for the oral lead-in and direct to injection groups, respectively. The rates of virologicsuppression (HIV-1 RNA < 50 c/mL) were similar in both the oral lead-in group (113/121 [93.4%])and direct to injection group (110/111 [99.1%]).

Every 2 months dosing

Patients virologically suppressed (stable on prior ART for at least 6 months)

The efficacy and safety of rilpivirine injection given every 2 months, has been evaluated in one

Phase 3b randomised, multicentre, parallel-arm, open-label, non-inferiority study, ATLAS-2M(207966). The primary analysis was conducted after all subjects completed their week 48 visit ordiscontinued the study prematurely.

In ATLAS-2M, 1045 HIV-1 infected, ART-experienced, virologically suppressed subjects wererandomised (1:1) and received a rilpivirine plus cabotegravir injection regimen administered eitherevery 2 months or monthly. Subjects initially on non-cabotegravir/rilpivirine treatment received orallead-in treatment comprising one rilpivirine tablet (25 mg) plus one cabotegravir tablet (30 mg), daily,for at least 4 weeks. Subjects randomised to monthly rilpivirine injections (month 1: 900 mg injection,month 2 onwards: 600 mg injection) and cabotegravir injections (month 1: 600 mg injection, month 2onwards: 400 mg injection administered) received treatment for an additional 44 weeks. Subjectsrandomised to every 2 months rilpivirine injections (900 mg injection at months 1, 2, 4 and every2 months thereafter) and cabotegravir injections (600 mg injection at months 1, 2, 4 and every2 months thereafter) received treatment for an additional 44 weeks. Prior to randomisation, 63%, 13%and 24% of subjects received rilpivirine plus cabotegravir for 0 weeks, 1 to 24 weeks and > 24 weeks,respectively.

At baseline, the median age of subjects was 42 years, 27% were female, 27% were non-white, 4%were ≥65 years, and 6% had a CD4+ cell count less than 350 cells per mm3; these characteristics weresimilar between the treatment arms.

The primary endpoint in ATLAS-2M was the proportion of subjects with a plasma HIV-1 RNA≥50 c/mL at week 48 (snapshot algorithm for the ITT-E population).

In ATLAS-2M, rilpivirine plus cabotegravir administered every 2 months was non-inferior tocabotegravir and rilpivirine administered every month on the proportion of subjects having plasma

HIV-1 RNA ≥ 50 c/mL (1.7% and 1.0%, respectively) at week 48. The adjusted treatment differencebetween cabotegravir plus rilpivirine administered every 2 months and every month (0.8; 95%

CI: -0.6, 2.2) met the non-inferiority criterion (upper bound of the 95% CI below 4%).

Table 10 Virologic outcomes of randomised treatment of ATLAS-2M at 48 weeks(Snapshot analysis)

Every 2 months Dosing Monthly Dosing (Q4W)(Q8W)

N=522 (%) N=523 (%)

HIV-1 RNA≥ 50 copies/mL† 9 (1.7) 5 (1.0)

Treatment Difference % (95%0.8 (-0.6, 2.2)

CI)*

HIV-1 RNA < 50 copies/mL 492 (94.3) 489 (93.5)

Treatment Difference % (95%0.8 (-2.1, 3.7)

CI)*

No virologic data at week 48 21 (4.0) 29 (5.5)window

Reasons:

Discontinued study due to AE 9 (1.7) 13 (2.5)or death

Discontinued study for other 12 (2.3) 16 (3.1)reasons

On study but missing data in 0 0window

* Adjusted for baseline stratification factors.

† Includes subjects who discontinued for lack of efficacy, discontinued while not suppressed.

N=Number of subjects in each treatment group, CI=confidence interval, CAR=current antiretroviral regimen.

Table 11 Proportion of subjects with plasma HIV-1 RNA ≥ 50 copies/mL in ATLAS-2M atweek 48 for key baseline factors (Snapshot outcomes).

Number of HIV-1 RNA ≥ 50 c/mL/ Total Assessed (%)

Baseline factors Every 2 months dosing

Monthly dosing (Q4W)(Q8W)

Baseline CD4+ cell < 350 1/35 (2.9) 1/27 (3.7)count (cells/mm3) 350 to < 500 1/96 (1.0) 0/89≥ 500 7/391 (1.8) 4/407 (1.0)

Gender Male 4/385 (1.0) 5/380 (1.3)

Female 5/137 (3.5) 0/143

Race White 5/370 (1.4) 5/393 (1.3)

Non-White 4/152 (2.6) 0/130

Black/African4/101 (4.0) 0/ 90

American

Non-

Black/African 5/421 (1.2) 5/421 (1.2)

American

BMI < 30 kg/m2 3/409 (0.7) 3/425 (0.7)≥ 30 kg/m2 6/113 (5.3) 2/98 (2.0)

Age (years) < 35 4/137 (2.9) 1/145 (0.7)35 to < 50 3/242 (1.2) 2/239 (0.8)≥ 50 2/143 (1.4) 2/139 (1.4)

Prior exposure None 5/327 (1.5) 5/327 (1.5)

CAB/RPV 1-24 weeks 3/69 (4.3) 0/68> 24 weeks 1/126 (0.8) 0/128

BMI=body mass index, CAB=cabotegravir, RPV=rilpivirine

In the ATLAS-2M study, treatment differences on the primary endpoint across baseline characteristics(CD4+ lymphocyte count, gender, race, BMI, age and prior exposure to cabotegravir/rilpivirine) werenot clinically meaningful.

The efficacy results at week 96 are consistent with the results of the primary endpoint at week 48.

Rilpivirine plus cabotegravir injections administered every 2 months is non-inferior to rilpivirine andcabotegravir administered every month. The proportion of subjects having plasma HIV-1 RNA≥50 c/mL at week 96 in rilpivirine plus cabotegravir every 2 months dosing (n=522) and rilpivirineplus cabotegravir monthly dosing (n=523) was 2.1% and 1.1% respectively (adjusted treatmentdifference between rilpivirine plus cabotegravir every 2 months dosing and monthly dosing [1.0; 95%

CI: -0.6, 2.5]). The proportion of subjects having plasma HIV-1 RNA <50 c/mL at week 96 inrilpivirine plus cabotegravir every 2 months dosing and rilpivirine plus cabotegravir monthly dosingwas 91% and 90.2% respectively (adjusted treatment difference between rilpivirine plus cabotegravirevery 2 months dosing and monthly dosing [0.8; 95% CI: -2.8, pct. 4.3]).

The efficacy results at week 152 are consistent with the results of the primary endpoint at week 48 andat week 96. Rilpivirine plus cabotegravir injections administered every 2 months is non-inferior torilpivirine and cabotegravir administered every month. In an ITT analysis, the proportion of subjectshaving plasma HIV-1 RNA ≥50 c/mL at week 152 in rilpivirine plus cabotegravir every 2 monthsdosing (n=522) and rilpivirine plus cabotegravir monthly dosing (n=523) was 2.7% and 1.0%respectively (adjusted treatment difference between rilpivirine plus cabotegravir every 2 monthsdosing and monthly dosing [1.7; 95% CI: 0.1, 3.3]). In an ITT analysis, the proportion of subjectshaving plasma HIV-1 RNA <50 c/mL at week 152 in rilpivirine plus cabotegravir every 2 monthsdosing and rilpivirine plus cabotegravir monthly dosing was 87% and 86% respectively (adjustedtreatment difference between rilpivirine plus cabotegravir every 2 months dosing and monthly dosing[1.5; 95% CI: -2.6, 5.6]).

Post-hoc analyses

Multivariable analyses of pooled Phase 3 studies (ATLAS through 96 weeks, FLAIR through124 weeks, ATLAS-2M through 152 weeks) examined the influence of various factors on the risk of

CVF. The baseline factors analysis (BFA) examined baseline viral and participants characteristics anddosing regimen; and the multivariable analysis (MVA) included the baseline factors and incorporatedpost-baseline predicted plasma drug concentrations on CVF using regression modelling with a variableselection procedure. Following a total of 4291 person-years, the unadjusted CVF incidence rate was0.54 per 100 person-years; 23 CVFs were reported (1.4% of 1651 individuals in these studies).

The BFA demonstrated rilpivirine resistance mutations (incidence rate ratio IRR=21.65, p<0.0001),

HIV-1 subtype A6/A1 (IRR=12.87, p<0.0001), and body mass index IRR=1.09 per 1 unit increase,p=0.04; IRR=3.97 of ≥30 kg/m2, p=0.01) were associated with CVF. Other variables including Q4Wor Q8W dosing, female gender, or CAB/INI resistance mutations had no significant association with

CVF. A combination of at least 2 of the following key baseline factors was associated with anincreased risk of CVF: rilpivirine resistance associated mutations, HIV-1 subtype A6/A1, or BMI≥ 30 kg/m2 (Table 12).

Table 12 Virologic outcomes by presence of key baseline factors of rilpivirine resistancemutations, HIV-1 Subtype A6/A11 and BMI ≥ 30 kg/m2

Confirmed Virologic Failure

Baseline Factors (number) Virologic Successes2(%)30 844/970 (87.0) 4/970 (0.4)1 343/404 (84.9) 8/404 (2.0)4≥ 2 44/57 (77.2) 11/57 (19.3)5

TOTAL 1231/1431 (86/0) 23/1431 (1.6)6(95% Confidence Interval) (84.1%, 87.8%) (1.0%, 2.4%)1 HIV-1 subtype A1 or A6 classification based on Los Alamos National Library panel from HIV Sequence database(June 2020).2 Based on the FDA Snapshot algorithm of RNA <50 copies/mL at week 48 for ATLAS, at week 124 for FLAIR, atweek 152 for ATLAS-2M.3 Defined as two consecutive measurements of HIV RNA ≥200 copies/mL.4 Positive Predictive Value (PPV) <1%; Negative Predictive Value (NPV) 98.5%; sensitivity 34.8%; specificity 71.9%.5 PPV 19.3%; NPV 99.1%; sensitivity 47.8%; specificity 96.7%.6 Analysis dataset with all non-missing covariates for baseline factors (out of a total of 1651 individuals).

In patients with at least two of these risk factors, the proportion of subjects who had a CVF was higherthan observed in patients with none or one risk factor, with CVF identified in 6/24 patients [25.0%,95% CI (9.8%, 46.7%)] treated with the every 2 months dosing regimen and 5/33 patients [15.2%,95% CI (5.1%, 31.9%)] treated with the monthly dosing regimen.

Oral bridging with other ART

In a retrospective analysis of pooled data from 3 clinical studies (FLAIR, ATLAS-2M, and LATTE-2/study 200056), 29 subjects were included who received oral bridging for a median duration of 59days (25th and 75th percentile 53-135) with ART other than rilpivirine plus cabotegravir (alternativeoral bridging) during treatment with rilpivirine plus cabotegravir long-acting (LA) intramuscular (IM)injections. The median age of subjects was 32 years, 14% were female, 31% were non-white, 97%received an INI-based regimen for alternative oral bridging, 41% received an NNRTI as part of theiralternative oral bridging regimen (including rilpivirine in 11/12 cases) and 62% received an NRTI.

Three subjects withdrew during oral bridging or shortly following oral bridging for non-safety reasons.

The majority (≥96%) of subjects maintained virologic suppression (plasma HIV-1 RNA <50 c/mL).

During bridging with alternative oral bridging and during the period following alternative oralbridging (up to 2 rilpivirine plus cabotegravir injections following oral bridging), no cases of CVF(confirmed plasma HIV-1 RNA ≥200 c/mL) were observed.

The safety, acceptability, tolerability and pharmacokinetics of rilpivirine plus cabotegravir have beenevaluated in an ongoing Phase 1/2 multicentre, open-label, non-comparative study, MOCHA(IMPAACT 2017).

In Cohort 2 of this study, 144 virologically suppressed adolescents discontinued their pre-study cARTregimen and received one 25 mg rilpivirine tablet plus one 30 mg cabotegravir tablet daily for at least4 weeks followed by every 2 months rilpivirine IM injections (months 1 and 2: 900 mg injection, andthen 900 mg injection every 2 months) and cabotegravir IM injections (months 1 and 2: 600 mginjection, and then 600 mg injection every 2 months).

At baseline, the median age of participants was 15.0 years, the median weight was 48.5 kg (range:35.2, 100.9), the median BMI was 19.5 kg/m2 (range: 16.0, 34.3), 51.4% were female, 98.6% werenon-white, and 4 participants had a CD4+ cell count less than 350 cells per mm3.

Antiviral activity was assessed as a secondary objective, with 139 of the 144 participants (96.5%[snapshot algorithm]) remaining virologically suppressed (plasma HIV-1 RNA value <50 c/mL) atweek 24.

The European Medicines Agency has deferred the obligation to submit the results of studies withrilpivirine injection in one or more subsets of the paediatric population in the treatment of HIV-1infection (see section 4.2 for information on paediatric use).

The population pharmacokinetic properties of rilpivirine have been evaluated in healthy and HIV-1infected adults.

Table 13 Pharmacokinetic parameters of rilpivirine following once daily oral dosing, andafter initial, monthly, or every two months intramuscular injections of rilpivirinein adults

Geometric mean (5th; 95th Percentile)

Dosing phase Dose regimen AUC b(0-tau) Cmax C btau(ng*h/mL) (ng/mL) (ng/mL)25 mg PO 2,083 116 79

Oral Lead-Inconce daily (1,125; 3,748) (49; 244) (32; 177)900 mg IM 44,842 144 42

Initial Injectiona,dinitial dose (21,712; 87,575) (94; 221) (22; 79)a,e 600 mg IM 68,324 121 86

Monthly Injectionmonthly (39,042; 118,111) (68; 210) (50; 147)

Every 2 months 900 mg IM 132,450 138 69

Injectiona,e every 2 months (76,638; 221,783) (81; 228) (38; 119)a Based on individual post-hoc estimates from rilpivirine IM population pharmacokinetic model (pooled data FLAIR,

ATLAS and ATLAS-2M).b tau is dosing interval: 24 hours for oral; 1 or 2 months for monthly or every 2 months IM injections.c For oral rilpivirine, Ctau represents observed pooled data FLAIR, ATLAS and ATLAS-2M, AUC(0-tau) and Cmaxrepresent pharmacokinetic data from oral rilpivirine Phase 3 studies.d When administered with oral lead-in, initial injection Cmax primarily reflects oral dosing because the initial injectionwas administered on the same day as the last oral dose. When administered without oral lead-in (direct to injection,n=110), the rilpivirine observed geometric mean (5th; 95th percentile) Cmax (1 week post initial injection) was68 ng/mL (28, 220) and the Ctau was 49 ng/mL (18, 138).

e Week 48 data.

Rilpivirine prolonged-release injection exhibits absorption rate-limited kinetics (i.e., flip-floppharmacokinetics) resulting from slow absorption from the gluteal muscle into the systemic circulationresulting in sustained rilpivirine plasma concentrations.

Following a single intramuscular dose, rilpivirine plasma concentrations are detectable the first dayand gradually rise to reach maximum plasma concentrations after a median of 3-4 days. Rilpivirine hasbeen detected in plasma up to 52 weeks or longer after administration of a single dose of rilpivirine.

After 1 year of monthly or every 2 months injections, approximately 80% of the rilpivirinepharmacokinetic steady-state exposure is reached.

Plasma rilpivirine exposure increases in proportion or slightly less than in proportion to dose followingsingle and repeat IM injections of doses ranging from 300 to 1200 mg.

Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. Based onpopulation pharmacokinetics analysis, the typical apparent volume of the central compartment (Vc/F)for rilpivirine after IM administration was estimated to be 132 L, reflecting a moderate distribution toperipheral tissues.

Rilpivirine is present in cerebrospinal fluid (CSF). In HIV-1-infected subjects receiving a regimen ofrilpivirine injection plus cabotegravir injection, the median rilpivirine CSF to plasma concentrationratio (n=16) was 1.07 to 1.32% (range: not quantifiable to 1.69%). Consistent with therapeuticrilpivirine concentrations in the CSF, CSF HIV-1 RNA (n=16) was < 50 c/mL in 100% and < 2 c/mLin 15/16 (94%) of subjects. At the same time point, plasma HIV-1 RNA (n=18) was < 50 c/mL in100% and < 2 c/mL in 12/18 (66.7%) of subjects.

In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated bythe cytochrome P450 (CYP) 3A system.

The mean apparent half-life of rilpivirine following rilpivirine administration is absorption rate-limitedand was estimated to be 13-28 weeks.

The apparent plasma clearance (CL/F) of rilpivirine was estimated to be 5.08 L/h.

After single dose administration of oral 14C-rilpivirine, on average 85% and 6.1% of the radioactivitycould be retrieved in faeces and urine, respectively. In faeces, unchanged rilpivirine accounted for onaverage 25% of the administered dose. Only trace amounts of unchanged rilpivirine (< 1% of dose)were detected in urine.

No clinically relevant differences in the rilpivirine exposure after intramuscular (IM) administrationhave been observed between men and women.

No clinically relevant effect of race on the rilpivirine exposure after intramuscular administration hasbeen observed.

BMI

No clinically relevant effect of BMI on the rilpivirine exposure after intramuscular administration hasbeen observed.

No clinically relevant effect of age on the rilpivirine exposure after intramuscular administration hasbeen observed. Pharmacokinetic data for rilpivirine in subjects of > 65 years old are limited.

The pharmacokinetics of rilpivirine have not been studied in patients with renal insufficiency. Renalelimination of rilpivirine is negligible. No dose adjustment is needed for patients with mild ormoderate renal impairment. In patients with severe renal impairment or end-stage renal disease,rilpivirine should be used with caution, as plasma concentrations may be increased due to alteration ofdrug absorption, distribution and/or metabolism secondary to renal dysfunction. In patients with severerenal impairment or end-stage renal disease, the combination of rilpivirine with a strong CYP3Ainhibitor should only be used if the benefit outweighs the risk. As rilpivirine is highly bound to plasmaproteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis (seesection 4.2).

Rilpivirine is primarily metabolised and eliminated by the liver. In a study comparing 8 patients withmild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 patients with moderatehepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of oralrilpivirine was 47% higher in patients with mild hepatic impairment and 5% higher in patients withmoderate hepatic impairment. However, it may not be excluded that the pharmacologically active,unbound, rilpivirine exposure is significantly increased in moderate hepatic impairment. No doseadjustment is suggested but caution is advised 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 (see section 4.2).

HBV/HCV Co-infected Patients

Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had noclinically relevant effect on the rilpivirine exposure after oral rilpivirine intake.

The pharmacokinetics of rilpivirine in children less than 12 years of age and adolescents weighing lessthan 35 kg have not been established with rilpivirine.

Population pharmacokinetic analyses revealed no clinically relevant differences in exposure betweenadolescent participants (at least 12 years of age and weighing 35 kg or more) and HIV-1 infected anduninfected adult participants. Therefore, no dosage adjustment is needed for adolescents weighing≥35 kg.

Table 14 Pharmacokinetic parameters of rilpivirine following once daily oral dosing, andafter initial, monthly, or every two months intramuscular injections of rilpivirinein adolescents (aged 12 to less than 18 years and weighing ≥35 kg)

Geometric mean (5th; 95th Percentile)

Dose

Population Dosing phase AUC b C C bregimen (0-tau) max tau(ng*h/mL) (ng/mL) (ng/mL)

Adolescents 25 mg PO 2,389 144 76

Oral Lead-Inconce daily (1,259; 4,414) (81; 234) (28; 184)900 mg IM 35,259 135 37

Initial Injectiona,dinitial dose (20,301; 63,047) (86; 211) (22; 59)

Monthly 600 mg IM 84,280 146 109

Injectiona,e monthly (49,444; 156,987) (85; 269) (65; 202)900 mg IM

Every 2 monthsa,f every 110,686 108 62

Injection2 months (78,480; 151,744) (68; 164) (45; 88)a Based on individual post-hoc estimates from rilpivirine IM population pharmacokinetic model (MOCHA, IMPAACT2017).b tau is dosing interval: 24 hours for oral; 1 or 2 months for monthly or every 2 months IM injections.c OLI PK parameter values represent steady state.d When administered with oral lead-in, initial injection Cmax primarily reflects oral dosing because the initial injectionwas administered on the same day as the last oral dose; however, the AUCtau and the Ctau value at Week 4 reflect theinitial injection.

e Every month injection: 11th RPV LA IM Injection (40-44 weeks after initiation injection).f Every 2 months injection: 6th RPV LA IM Injection (36-44 weeks after initiation injection).

All studies were performed with rilpivirine for oral use except for the studies on local tolerance withrilpivirine injections.

Liver toxicity associated with liver enzyme induction was observed in rodents. In dogs,cholestasis-like effects were noted.

Reproductive toxicology studies

Studies in animals have shown no evidence of relevant embryonic or foetal toxicity or an effect onreproductive function. There was no teratogenicity with oral rilpivirine in rats and rabbits. Theexposures at the embryo-foetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbitswere respectively ≥ 12 times and ≥ 57 times the exposure in humans at the maximum recommendedhuman daily dose of 25 mg once daily in HIV-1 infected patients or 600 mg or 900 mg intramuscularinjection dose of rilpivirine long-acting injectable suspension.

Carcinogenesis and mutagenesis

Oral rilpivirine was evaluated for carcinogenic potential by oral gavage administration to mice and ratsup to 104 weeks. At the lowest tested doses in the carcinogenicity studies, the systemic exposures(based on AUC) to rilpivirine were ≥ 17 times (mice) and ≥ 2 times (rats) the exposure in humans atthe maximum recommended human daily dose of 25 mg once daily in HIV-1 infected patients or600 mg or 900 mg intramuscular injection dose of rilpivirine long-acting injectable suspension. In rats,there were no drug-related neoplasms. In mice, rilpivirine was positive for hepatocellular neoplasms inboth males and females. The observed hepatocellular findings in mice may be rodent-specific.

Rilpivirine has tested negative in the absence and presence of a metabolic activation system in thein vitro Ames reverse mutation assay and the in vitro clastogenicity mouse lymphoma assay.

Rilpivirine did not induce chromosomal damage in the in vivo micronucleus test in mice.

Local tolerance for rilpivirine

After long-term repeated IM administration of rilpivirine in dogs and minipigs, slight, short-lasting(i.e., 1-4 days in minipigs) erythema was observed, and white deposits were noted at the injection sitesat necropsy, accompanied by swelling and discolouration of draining lymph nodes. Microscopicexamination showed macrophage infiltration and eosinophilic deposits at the injection sites. Amacrophage infiltration response was also noted in the draining/regional lymph nodes. These findingswere considered to be a reaction to the deposited material rather than a manifestation of local irritation.

poloxamer 338citric acid monohydrate (E330)glucose monohydratesodium dihydrogen phosphate monohydratesodium hydroxide (E524) (to adjust pH and ensure isotonicity)water for injections

This medicinal product must not be mixed with other medicinal products or diluents.

3 years

Chemical and physical in-use stability has been demonstrated for 6 hours at 25 °C.

Once the suspension has been drawn into the syringe, the injection should be administered as soon aspossible, but may remain in the syringe for up to 2 hours. If 2 hours are exceeded, the medicine,syringe, and needle must be discarded.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Prior to administration, the vial should be brought to room temperature (not to exceed 25 °C). The vialmay remain in the carton at room temperature for up to 6 hours; do not put back into the refrigerator. Ifnot used within 6 hours, the vial must be discarded (refer to section 6.3).

Type I glass vial.

600 mg pack

Each pack contains one clear 4-mL glass vial, with a butyl elastomer stopper and an aluminiumoverseal with a plastic flip-off button, 1 syringe (0.2 mL graduation), 1 vial adaptor and 1 needle forinjection (23 gauge, 1½ inch).

900 mg pack

Each pack contains one clear 4-mL glass vial, with a butyl elastomer stopper and an aluminiumoverseal with a plastic flip-off button, 1 syringe (0.2 mL graduation), 1 vial adaptor and 1 needle forinjection (23 gauge, 1½ inch).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Full instructions for use and handling of REKAMBYS are provided in the package leaflet (see

Instructions for Use).

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

600 mg: EU/1/20/1482/001900 mg: EU/1/20/1482/002

Date of first authorisation: 17 December 2020

Date of latest renewal:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu