SUMMARY OF PRODUCT CHARACTERISTICS

400 mg

Vocabria 400 mg prolonged-release suspension for injection 600 mg

Vocabria 600 mg prolonged-release suspension for injection

400 mg

Each vial contains 400 mg cabotegravir in 2 mL. 600 mg

Each vial contains 600 mg cabotegravir in 3 mL. For the full list of excipients, see section 6.1.

Prolonged-release suspension for injection. White to light pink suspension.

4.1         Therapeutic indications

Vocabria injection is indicated, in combination with rilpivirine injection, for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults 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 NNRTI and INI class (see sections 4.2, 4.4 and 5.1).

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

Vocabria injection is indicated for the treatment of HIV-1 in combination with rilpivirine injection, therefore, the prescribing information for rilpivirine injection should be consulted for recommended dosing.

of adherence to scheduled dosing visits to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance with missed doses.

Following discontinuation of Vocabria and rilpivirine injection, it is essential to adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the final injection of Vocabria when dosed monthly and no later than two months after the final injection of Vocabria when dosed every 2 months (see section 4.4).

Posology

Adults

Oral lead-in

Prior to the initiation of Vocabria injection, oral cabotegravir together with oral rilpivirine should be taken for approximately one month (at least 28 days) to assess tolerability to cabotegravir and rilpivirine (see section 4.4). One cabotegravir 30 mg tablet should be taken with one rilpivirine 25 mg tablet, once daily. When administered with rilpivirine, cabotegravir tablets should be taken with a meal (see cabotegravir tablet prescribing information).

Monthly dosing

Initiation injection (600 mg corresponding to 3 mL dose)

On the final day of oral lead in therapy, the recommended initial dose of Vocabria injection in adults is a single 600 mg intramuscular injection. Vocabria injection and rilpivirine injection should be

administered at separate gluteal injection sites at the same visit.

Continuation injection (400 mg corresponding to 2 mL dose)

After the initiation injection, the continuation injection dose of Vocabria in adults is a single 400 mg monthly intramuscular injection. Vocabria injection and rilpivirine injection should be administered at

separate gluteal injection sites at the same visit. Patients may be given injections up to 7 days before or after the date of the monthly 400 mg injection schedule.

Every 2 Month Dosing

Initiation Injections – one month apart(600 mg)

On the final day of oral lead-in therapy, the recommended initial Vocabria injection in adults is a single 600 mg intramuscular injection (month 2).

One month later (month 3), a second Vocabria 600 mg intramuscular injection should be administered. Patients may be given the second 600 mg initiation injection up to 7 days before or after the scheduled dosing date.

Vocabria injection and rilpivirine injection should be administered at separate gluteal injection sites at the same visit.

Continuation Injections – 2 months apart(600 mg)

After the initiation injections, the recommended Vocabria continuation injection dose in adults is a single 600 mg intramuscular injection (month 5) administered every 2 months. Vocabria injection and

rilpivirine injection should be administered at separate gluteal injection sites at the same visit. Patients

may be given injections up to 7 days before or after the date of the every 2 month, 600 mg injection schedule.

Dosing recommendations when switching from monthly to every 2 month injections

Patients switching from a monthly continuation injection schedule to an every 2 month continuation injection schedule should receive a single 600 mg intramuscular injection of cabotegravir one month after the last 400 mg continuation injection dose and then 600 mg every 2 months thereafter.

Dosing recommendations when switching from every 2 month to monthly injections

Patients switching from an every 2 month continuation injection schedule to a monthly continuation dosing schedule should receive a single 400 mg intramuscular injection of cabotegravir 2 months after the last 600 mg continuation injection dose and then 400 mg monthly thereafter.

Missed doses

Patients who miss a scheduled injection visit should be clinically reassessed to ensure resumption of therapy remains appropriate. See Table 3 for dosing recommendations after a missed injection.

Missed monthly injection

If a patient plans to miss a scheduled injection visit by more than 7 days, oral therapy (one 30 mg cabotegravir tablet and one 25 mg rilpivirine tablet once daily) may be used to replace up to 2

consecutive monthly injection visits. For oral therapy durations greater than two months, an alternative

oral regimen is recommended.

The first dose of oral therapy should be taken one month (+/- 7 days) after the last injection doses of Vocabria and rilpivirine. Injection dosing should be resumed on the day oral dosing completes, as recommended in Table 3.

Missed 2 month injection

If a patient plans to miss a scheduled Vocabria injection visit by more than 7 days, oral therapy (one 30 mg cabotegravir tablet and one 25 mg rilpivirine tablet, once daily) may be used to replace one, 2-

monthly injection visit. For oral therapy durations greater than two months, an alternative oral regimen

is recommended.

The first dose of oral therapy should be taken approximately two months (+/- 7 days) after the last injection doses of cabotegravir and rilpivirine. Injection dosing should be resumed on the day oral dosing completes, as recommended in Table 4.

Elderly

No dose adjustment is required in elderly patients. There are limited data available on the use of cabotegravir in patients aged 65 years and over (see section 5.2).

Renal impairment

No dosage adjustment is required in patients with mild to severe renal impairment (CrCl <30 mL/min and not on dialysis [see section 5.2]). Cabotegravir has not been studied in patients with end-stage  renal disease on renal replacement therapy. As cabotegravir is greater than 99% protein bound, dialysis is not expected to alter exposures of cabotegravir. If administered in a patient on renal replacement therapy, cabotegravir should be used with caution.

Hepatic impairment

No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). Cabotegravir has not been studied in patients with severe hepatic impairment (Child- Pugh score C, [see section 5.2]). If administered in a patient with severe hepatic impairment, cabotegravir should be used with caution.

Paediatric population

The safety and efficacy of Vocabria in children and adolescents aged under 18 years have not been established. No data are available.

Method of administration

For intramuscular use. Care should be taken to avoid inadvertent injection into a blood vessel.

Vocabria injection should be administered by a healthcare professional. For instructions on administration, see “Instructions for Use” in the package leaflet.

Vocabria injection should always be co-administered with rilpivirine injection. The order of injections is not important. The prescribing information for rilpivirine injection should be consulted for recommended dosing.

When administering Vocabria injection, healthcare professionals 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.

Hold the vial firmly and vigorously shake for a full 10 seconds. Invert the vial and check the resuspension. It should look uniform. If the suspension is not uniform, shake the vial 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. Concomitant use with rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenytoin or

phenobarbital (see section 4.5).

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 final injection of Vocabria when dosed monthly and no later than two months after the final injection of Vocabria when dosed every 2 months.

If virologic failure is suspected, an alternative regimen should be adopted as soon as possible. Long acting properties of Vocabria injection

Residual concentrations of cabotegravir may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer), therefore, physicians should take the prolonged release characteristics of Vocabria injection into consideration when the medicinal product is discontinued (see sections 4.5, 4.6, 4.7 and 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. 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 A6/A1 subtype (see section 5.1).

Hypersensitivity reactions

Hypersensitivity reactions have been reported in association with other integrase inhibitors. These reactions were characterised by rash, constitutional findings and sometimes organ dysfunction, including liver injury. While no such reactions have been observed to date in association with Vocabria, physicians should remain vigilant and should discontinue Vocabria and other suspected medicinal products immediately, should signs or symptoms of hypersensitivity develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia or angioedema). Clinical status, including liver aminotransferases should be monitored and appropriate therapy  initiated. Administration of oral lead-in is recommended to help identify patients who may be at risk of a hypersensitivity reaction (see section 4.2, and Long acting properties of Vocabria injection).

Hepatoxicity

Hepatotoxicity has been reported in a limited number of patients receiving Vocabria with or without known pre-existing hepatic disease (see section 4.8).

Monitoring of liver chemistries is recommended and treatment with Vocabria should be discontinued

if hepatotoxicity is suspected (see Long acting properties of Vocabria injection). HBV/HCV co-infection

Patients with hepatitis B co-infection were excluded from studies with Vocabria. It is not recommended to initiate Vocabria in patients with hepatitis B co-infection. 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. Monitoring of liver function is recommended in patients with hepatitis C co-infection.

Interactions with medicinal products

Caution should be given to prescribing Vocabria injection with medicinal products that may reduce its exposure (see Section 4.5).

Concomitant use of Vocabria injection with rifabutin is not recommended (see section 4.5). Transmission of HIV

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

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 Vocabria or any other antiretroviral therapy do 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.

Vocabria injection, in combination with rilpivirine injection, is indicated for the treatment of HIV-1, therefore, the prescribing information for rilpivirine injection should be consulted for associated interactions.

Effect of other medicinal products on the pharmacokinetics of cabotegravir

Cabotegravir is primarily metabolised by uridine diphosphate glucuronosyl transferase (UGT) 1A1 and to a lesser extent by UGT1A9. Medicinal products which are strong inducers of UGT1A1 or UGT1A9 are expected to decrease cabotegravir plasma concentrations leading to lack of efficacy (see section 4.3 and table 5 below). In poor metabolizers of UGT1A1, representing a maximum clinical UGT1A1 inhibition, the mean AUC, Cmax and Ctau of oral cabotegravir increased by up to 1.5-fold. The impact of an UGT1A1 inhibitor may be slightly more pronounced, however, considering the safety margins of cabotegravir, this increase is not expected to be clinically relevant. No dosing adjustments for  Vocabria are, therefore, recommended in the presence of UGT1A1 inhibitors (e.g. atazanavir,  erlotinib, sorafenib).

Cabotegravir is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), however, because of its high permeability, no alteration in absorption is expected when co- administered with either P-gp or BCRP inhibitors.

Effect of cabotegravir on the pharmacokinetics of other medicinal products

In vivo, cabotegravir did not have an effect on midazolam, a cytochrome P450 (CYP) 3A4 probe. Invitro, cabotegravir did not induce CYP1A2, CYP2B6, or CYP3A4.

In vitrocabotegravir inhibited organic anion transporters (OAT) 1 (IC50=0.81 µM) and OAT3 (IC50=0.41 µM). Therefore, caution is advised when co-dosing with narrow therapeutic index OAT1/3 substrate drugs (e.g. methotrexate).

Vocabria and rilpivirine injections are 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. The following information regarding drug-drug interactions with other antiretroviral medicinal products is provided in the event that Vocabria and rilpivirine injections are stopped and initiation of an alternative antiviral therapy is necessary (see section 4.4). Based on the in vitro and clinical drug interaction profile, cabotegravir is not expected to alter concentrations of other anti- retroviral medications including protease inhibitors, nucleoside reverse transcriptase inhibitors, non- nucleoside reverse transcriptase inhibitors, integrase inhibitors, entry inhibitors or ibalizumab.

No drug interaction studies have been performed with cabotegravir injection. The drug interaction data provided in Table 5 is obtained from studies with oral cabotegravir (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus time curve as “AUC”, maximum observed concentration as “Cmax”, concentration at end of dosing interval as “Cτ”).

4.6         Fertility, pregnancy and lactation

Pregnancy

There are a limited amount of data from the use of cabotegravir in pregnant women. The effect of Vocabria on human pregnancy is unknown.

Cabotegravir was not teratogenic when studied in pregnant rats and rabbits but, exposures higher than the therapeutic dose showed reproductive toxicity in animals (see section 5.3). The relevance to human pregnancy is unknown.

Vocabria injection is not recommended during pregnancy unless the expected benefit justifies the potential risk to the foetus.

Cabotegravir has been detected in systemic circulation for up to 12 months or longer after an injection (see section 4.4).

Breast-feeding

It is expected that cabotegravir will be secreted into human milk based on animal data, although this has not been confirmed in humans. Cabotegravir may be present in human milk for up to 12 months or longer after the last cabotegravir injection.

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

Fertility

There are no data on the effects of cabotegravir on human male or female fertility. Animal studies indicate no effects of cabotegravir on male or female fertility (see section 5.3).

Patients should be informed that dizziness, fatigue and somnolence has been reported during treatment with Vocabria injection. The clinical status of the patient and the adverse reaction profile of Vocabria injection should be borne in mind when considering the patient’s ability to drive or operate machinery.

Summary of the safety profile

The most frequently reported adverse reactions (ARs) from monthly dosing studies were injection site reactions (up to 84%), headache (up to 12%) and pyrexia4 (10%).

The most frequently reported ARs from ATLAS-2M every 2 month dosing were injection site reactions (76%), headache (7%) and pyrexia4 (7%).

Tabulated list of adverse reactions

The ARs identified for cabotegravir or rilpivirine are listed in Table 6 by body system organ class and frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

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  Abdominal pain includes the following grouped MedDRA preferred term: abdominal pain, upper abdominal pain.

3  Rash includes the following grouped MedDRA preferred terms: rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic.

4  Pyrexia includes the following grouped MedDRA preferred terms: feeling hot, body temperature increased.

Description of selected adverse reactions

Local injection site reactions (ISRs)

Up to 1% of subjects discontinued treatment with Vocabria plus rilpivirine because of ISRs. When dosing monthly, up to 84% of subjects reported injection site reactions; out of 30393 injections, 6815 ISRs were reported. When dosing every 2 months, 76% of patients reported injection site reactions; out of 8470 injections, 2507 ISRs were reported.

The severity of reactions was 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 overall ISR events was 3 days. The percentage of subjects reporting ISRs decreased over time.

Weight increased

At the Week 48 time point, subjects in studies FLAIR and ATLAS, who received Vocabria plus rilpivirine gained a median of 1.5 kg in weight subjects continuing on their current antiretroviral therapy (CAR) gained a median of 1.0 kg (pooled analysis). In the individual studies FLAIR and ATLAS, the median weight gains in the Vocabria plus rilpivirine 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 2-monthly Vocabria plus rilpivirine dosing arms was 1.0 kg.

Changes in laboratory chemistries

Small, non-progressive increases in total bilirubin (without clinical jaundice) were observed with treatment with Vocabria plus rilpivirine. These changes are not considered clinically relevant as they

likely reflect competition between cabotegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1).

Elevated transaminases (ALT/AST) were observed in subjects receiving Vocabria plus rilpivirine during clinical studies. These elevations were primarily attributed to acute viral hepatitis. A few subjects on oral therapy had transaminase elevations attributed to suspected drug-related hepatotoxicity; these changes were reversible upon discontinuation of treatment (see section 4.4).

Elevated lipases were observed during clinical trials with Vocabria plus rilpivirine; Grade 3 and 4 lipase increases occurred at a higher incidence with Vocabria plus rilpivirine compared with CAR. These elevations were generally asymptomatic and did not lead to Vocabria plus rilpivirine 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 causality to the injection regimen could not be ruled out.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

There is no specific treatment for Vocabria overdose. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.

Cabotegravir is known to be highly protein bound in plasma; therefore, dialysis is unlikely to be helpful in removal of medicinal product from the body. Management of overdose with Vocabria injection should take into consideration the prolonged exposure to the medicine following an injection.

5.1         Pharmacodynamic properties

Pharmacotherapeutic group: Antiviral for systemic use, integrase inhibitor, ATC code: J05AJ04. Mechanism of action

Cabotegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle.

Pharmacodynamic effects

Antiviral activity in cell culture

Cabotegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean concentration of cabotegravir necessary to reduce viral replication by 50 percent (EC50) values of

0.22 nM in peripheral blood mononuclear cells (PBMCs), 0.74 nM in 293T cells and 0.57 nM in MT-4 cells. Cabotegravir demonstrated antiviral activity in cell culture against a panel of 24 HIV-1 clinical isolates (three in each group of M clades A, B, C, D, E, F, and G, and 3 in group O) with EC50 values ranging from 0.02 nM to 1.06 nM for HIV-1. Cabotegravir EC50 values against three HIV-2 clinical isolates ranged from 0.10 nM to 0.14 nM. No clinical data is available in patients with HIV-2.

Antiviral Activity in combination with other medicinal products

No medicines with inherent anti-HIV activity were antagonistic to cabotegravir’s antiretroviral activity (in vitro assessments were conducted in combination with rilpivirine, lamivudine, tenofovir and

emtricitabine).

Resistance in vitro

Isolation from wild-type HIV-1 and activity against resistant strains: Viruses with >10-fold increase in cabotegravir EC50 were not observed during the 112-day passage of strain IIIB. The following integrase (IN) mutations emerged after passaging wild type HIV-1 (with T124A polymorphism) in the presence of cabotegravir: Q146L (fold-change [FC] range 1.3-4.6), S153Y (FC range 3.6-8.4), and I162M (FC = 2.8). As noted above, the detection of T124A is selection of a pre-existing minority variant that does not have differential susceptibility to cabotegravir. No amino acid substitutions in the integrase region were selected when passaging the wild-type HIV-1 NL-432 in the presence of 6.4 nM of cabotegravir through Day 56.

Among the multiple mutants, the highest FC was observed with mutants containing Q148K or Q148R. E138K/Q148H resulted in a 0.92-fold decrease in susceptibility to cabotegravir but E138K/Q148R resulted in a 12-fold decrease in susceptibility and E138K/Q148K resulted in an 81-fold decrease in susceptibility to cabotegravir. G140C/Q148R and G140S/Q148R resulted in a 22- and 12-fold decrease in susceptibility to cabotegravir, respectively. While N155H did not alter susceptibility to cabotegravir, N155H/Q148R resulted in a 61-fold decrease in susceptibility to cabotegravir. Other multiple mutants, which resulted in a FC between 5 and 10, are: T66K/L74M (FC=6.3), G140S/Q148K (FC=5.6), G140S/Q148H (FC=6.1) and E92Q/N155H (FC=5.3).

Resistance in vivo

The number of subjects who met Confirmed Virologic Failure (CVF) criteria was low across the pooled FLAIR and ATLAS trials. In the pooled analysis, there were 7 CVFs on cabotegravir plus

rilpivirine (7/591, 1.2%) and 7 CVFs on current antiretroviral regimen (7/591, 1.2%). The three CVFs

on cabotegravir plus rilpivirine in FLAIR with resistance data had Subtype A1. In addition, 2 of the 3 CVFs had treatment-emergent integrase inhibitor resistance associated substitution Q148R while one

of the three had G140R with reduced phenotypic susceptibility to cabotegravir. All 3 CVFs carried one

rilpivirine resistance-associated substitution: K101E, E138E/A/K/T or E138K, and two of the three showed reduced phenotypic susceptibility to rilpivirine. The 3 CVFs in ATLAS had subtype A, A1 and AG. One of the three CVFs carried the INI resistance-associated substitution N155H at failure with reduced cabotegravir phenotype susceptibility. All three CVFs carried one rilpivirine resistance- associated substitution at failure: E138A, E138E/K or E138K, and showed reduced phenotypic susceptibility to rilpivirine. In two of these three CVFs, the rilpivirine resistance-associated substitutions observed at failure were also observed at baseline in PBMC HIV-1 DNA. The seventh CVF (FLAIR) never received an injection.

The substitutions associated with resistance to long-acting cabotegravir injection, observed in the pooled ATLAS and FLAIR trials were G140R (n=1), Q148R (n=2), and N155H (n=1).

In the ATLAS-2M study 10 subjects met CVF criteria through Week 48: 8 subjects (1.5%) in the Q8W arm and 2 subjects (0.4%) in the Q4W arm. Eight subjects met CVF criteria at or before the Week 24 timepoint.

At Baseline in the Q8W arm, 5 subjects had rilpivirine resistance-associated mutations of Y181Y/C + H221H/Y, Y188Y/F/H/L, Y188L, E138A or E138E/A and 1 subject contained cabotegravir resistance mutation, G140G/R (in addition to the above Y188Y/F/H/L rilpivirine resistance-associated mutation). At the suspected virologic failure (SVF) timepoint in the Q8W arm, 6 subjects had rilpivirine resistance-associated mutations with 2 subjects having an addition of K101E and 1 subject having an addition of E138E/K from Baseline to SVF timepoint. Rilpivirine FC was above the clinical cut-off for 7 subjects and ranged from 2.4 to 15. Five of the 6 subjects with rilpivirine resistance-associated substitution, also had INSTI resistance-associated substitutions, N155H (n=2); Q148R; Q148Q/R+N155N/H (n=2). INSTI substitution, L74I, was seen in 4/7 subjects. The Integrase genotype and phenotype assay failed for one subject and cabotegravir phenotype was unavailable for another. FCs for the Q8W subjects ranged from 0.6 to 9.1 for cabotegravir, 0.8 to 2.2 for dolutegravir and 0.8 to

1.7 for bictegravir.

In the Q4W arm, neither subject had any rilpivirine or INSTI resistance-associated substitutions at Baseline. One subject had the NNRTI substitution, G190Q, in combination with the NNRTI polymorphism, V189I. At SVF timepoint, one subject had on-treatment rilpivirine resistance- associated mutations, K101E + M230L and the other retained the G190Q + V189I NNRTI substitutions with the addition of V179V/I. Both subjects showed reduced phenotypic susceptibility to rilpivirine. Both subjects also had INSTI resistance-associated mutations, either Q148R + E138E/K or N155N/H at SVF and 1 subject had reduced susceptibility to cabotegravir. Neither subject had the INSTI substitution, L74I. FCs for the Q4W subjects were 1.8 and 4.6 for cabotegravir, 1.0 and 1.4 for dolutegravir and 1.1 and 1.5 for bictegravir.

Clinical efficacy and safety

The efficacy of Vocabria plus rilpivirine has been evaluated in two Phase III randomised, multicentre, active-controlled, parallel-arm, open-label, non-inferiority studies, FLAIR (study 201584) and ATLAS (study 201585). The primary analysis was conducted after all subjects completed their Week 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 integrase strand transfer inhibitor (INSTI) containing regimen for 20 weeks (either dolutegravir/abacavir/lamivudine or dolutegravir plus 2 other nucleoside reverse transcriptase inhibitors if subjects were HLA-B*5701 positive). Subjects who were virologically suppressed (HIV-1 RNA <50 copies per mL, n=566) were then randomised (1:1) to receive either the Vocabria plus rilpivirine regimen or remain on the current antiretroviral (CAR) regimen. Subjects randomised to receive the Vocabria plus rilpivirine regimen, initiated treatment with oral lead-in dosing with one 30 mg Vocabria tablet plus one 25 mg rilpivirine tablet, daily, for at least 4 weeks, followed by treatment with Vocabria injection (month 1: 600 mg injection, month 2 onwards: 400 mg injection) plus rilpivirine injection (month 1: 900 mg injection, month 2 onwards: 600 mg injection) every month for an additional 44 weeks. This study was extended to 96 weeks.

Patients virologically suppressed (stable on prior ARV therapy 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 the Vocabria

plus rilpivirine regimen or remained on the CAR regimen. Subjects randomised to receive the Vocabria plus rilpivirine regimen, initiated treatment with oral lead-in dosing with one 30 mg

Vocabria tablet plus one 25 mg rilpivirine tablet, daily for at least 4 weeks, followed by treatment with Vocabria injection (month 1: 600 mg injection, month 2 onwards: 400 mg injection) plus rilpivirine injection (month 1: 900 mg injection, month 2 onwards: 600 mg injection) every month for

an additional 44 weeks. In ATLAS, 50%, 17%, and 33% of subjects received an NNRTI, PI, or INI (respectively) as their baseline third treatment medicine class prior to randomisation and this was

similar between treatment arms.

Pooled data

At baseline, in the pooled analysis, for the Vocabria plus rilpivirine arm, the median age of subjects was 38 years, 27% were female, 27% were non-white, 1% were ≥ 65 years and 7% had CD4+ cell count 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 pivotal studies, Vocabria plus rilpivirine was non-inferior to CAR on the proportion of subjects having plasma HIV-1 RNA ≥50 c/mL (1.9% and 1.7% respectively) at Week 48. The adjusted treatment difference between Vocabria plus rilpivirine and CAR (0.2; 95% CI:

-1.4, 1.7) for the pooled analysis met the non-inferiority criterion (upper bound of the 95% CI below 4%).

The primary endpoint and other week 48 outcomes, including outcomes by key baseline factors, for FLAIR and ATLAS are shown in Tables 7 and 8.

*   Adjusted for baseline stratification factors.

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

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

BMI= body mass index PI= Protease inhibitor INI= Integrase inhibitor

NNRTI= non-nucleoside reverse transcriptase inhibitor

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

In the FLAIR study at 96 Weeks, the results remained consistent with the results at 48 Weeks. The

proportion of subjects having plasma HIV-1 RNA ≥50 c/mL in Vocabria plus rilpivirine (n=283) and

CAR (n=283) was 3.2% and 3.2% respectively (adjusted treatment difference between Vocabria plus rilpivirine and CAR [0.0; 95% CI: -2.9, 2.9]). The proportion of subjects having plasma HIV-1 RNA

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

Every 2 month dosing

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

The efficacy and safety of Vocabria injection given every 2 months, has been evaluated in one Phase IIIb 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 or discontinued the study prematurely.

In ATLAS-2M, 1045 HIV-1 infected, ART experienced, virologically suppressed subjects were randomised (1:1) and received a Vocabria plus rilpivirine injection regimen administered either every

2 months or monthly. Subjects initially on non-cabotegravir/rilpivirine treatment received oral lead-in

treatment comprising one 30 mg Vocabria tablet plus one 25 mg rilpivirine tablet, daily, for at least 4 weeks. Subjects randomised to monthly Vocabria injections (month 1: 600 mg injection, month 2 onwards: 400 mg injection) and rilpivirine injections (month 1: 900 mg injection, month 2 onwards: 600 mg injection) received treatment for an additional 44 weeks. Subjects randomised to every 2 month Vocabria injections (600 mg injection at months 1, 2, 4 and every 2 months thereafter) and rilpivirine injections (900 mg injection at months 1, 2, 4 and every 2 months thereafter) received treatment for an additional 44 weeks. Prior to randomisation, 63%, 13% and 24% of subjects received Vocabria plus rilpivirine 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 were similar 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, Vocabria and rilpivirine administered every 2 months was non-inferior to Vocabria 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 difference between Vocabria and 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%).

*   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 antiviral regimen.

BMI= body mass index

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) were not clinically meaningful.

Post-hoc analysis

Multivariable analyses of pooled phase 3 studies (ATLAS, FLAIR and ATLAS-2M), including data from 1039 HIV-infected adults with no prior exposure to Vocabria plus rilpivirine, examined the influence of baseline viral and participant characteristics, dosing regimen, and post-baseline plasma drug concentrations on confirmed virologic failure (CVF) using regression modelling with a variable selection procedure. Through Week 48 in these studies, 13/1039 (1.25%) participants had CVF while receiving cabotegravir and rilpivirine.

Four covariates were significantly associated (P<0.05 for each adjusted odds ratio) with increased risk of CVF: rilpivirine resistance mutations at baseline identified by proviral DNA genotypic assay, HIV- 1 subtype A6/A1 (associated with integrase L74I polymorphism), rilpivirine trough concentration 4 weeks following initial injection dose, body mass index of at least 30 kg/m2 (associated with cabotegravir pharmacokinetics). Other variables including Q4W or Q8W dosing, female gender, or other viral subtypes (non A6/A1) had no significant association with CVF. No baseline factor, when present in isolation, was predictive of virologic failure. However, a combination of at least 2 of the following baseline factors was associated with an increased risk of CVF: rilpivirine resistance mutations, HIV-1 subtype A6/A1, or BMI≥30 kg/m2 (see Table 11).

1 HIV-1 subtype A1 or A6 classification based on Los Alamos National Library panel from HIV Sequence

database (June 2020)

2Based on the FDA Snapshot algorithm of RNA <50 copies/mL.

3  Defined as two consecutive measurements of HIV RNA >200 copies/mL.

4  Positive Predictive Value (PPV) <1%; Negative Predictive Value (NPV) 98%; sensitivity 8%; specificity 74%

5  PPV 26%; NPV 99.6%; sensitivity 69%; specificity 97.5%

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Vocabria injection in one or more subsets of the paediatric population in the treatment of HIV-1 infection.

Cabotegravir pharmacokinetics is similar between healthy and HIV-infected subjects. The PK variability of cabotegravir is moderate to high. In HIV-infected subjects participating in Phase III studies, between-subject CVb% for Ctau ranged from 39 to 48%. Higher between-subject variability ranging from 41% to 89% was observed with single dose administration of long-acting cabotegravir injection.

a Pharmacokinetic (PK) parameter values were based on individual post-hoc estimates from population PK models for patients in FLAIR and ATLAS for the monthly regimen and in ATLAS-2M for the every 2 month

regimen.

b   tau is dosing interval: 24 hours for oral administration; 1 month for IM injections of extended-release injectable suspension.

c    Oral lead-in pharmacokinetic parameter values represent steady-state.

d   Initial injection AUC(0-tau) and Cmax values primarily reflect values following oral dosing because the initial injection was administered on the same day as the last oral dose; however, the Ctau value at Week 4 reflects the

initial injection.

e    Monthly and every 2 month injection pharmacokinetic parameter values represent Week◦48 data.

Absorption

Cabotegravir injection exhibits absorption-limited (flip-flop) kinetics resulting from slow absorption from the gluteal muscle into the systemic circulation resulting in sustained plasma concentrations. Following a single intramuscular dose, plasma cabotegravir concentrations are detectable on the first day and gradually rise to reach maximum plasma concentration with a median Tmax of 7 days. Cabotegravir has been detected in plasma up to 52 weeks or longer after administration of a single injection. Pharmacokinetic steady-state is achieved by 44 weeks.

Plasma cabotegravir exposure increases in proportion or slightly less than in proportion to dose following single and repeat IM injection of doses ranging from 100 to 800 mg.

Distribution

Cabotegravir is highly bound (>99%) to human plasma proteins, based on in vitro data. Following administration of oral tablets, the mean apparent oral volume of distribution (Vz/F) in plasma was

12.3 L. In humans, the estimate of plasma cabotegravir Vc/F was 5.27 L and Vp/F was 2.43 L. These volume estimates, along with the assumption of high bioavailability, suggest some distribution of

cabotegravir to the extracellular space.

Cabotegravir is present in the female and male genital tract. Median cervical and vaginal tissue:plasma ratios ranged from 0.16 to 0.28 and median rectal tissue:plasma ratios were ≤0.08 following a single 400 mg intramuscular injection (IM) at 4, 8, and 12 weeks after dosing.

Cabotegravir is present in cerebrospinal fluid (CSF). In HIV-infected subjects receiving a regimen of cabotegravir injection plus rilpivirine injection, the cabotegravir CSF to plasma concentration ratio [median (range)] (n=16) was 0.003(range: 0.002 to 0.004) one week following a steady-state long acting cabotegravir (Q4W or Q8W) injection. Consistent with therapeutic cabotegravir concentrations in the CSF, CSF HIV-1 RNA (n=16) was <50 c/mL in 100% and <2 c/mL in 15/16 (94%) of subjects. At the same time point, plasma HIV-1 RNA (n=18) was <50 c/mL in 100% and <2 c/mL in 12/18 (66.7%) of subjects.

In vitro, cabotegravir was not a substrate of organic anion transporting polypeptide (OATP) 1B1, OATP1B3 or organic cation transporter (OCT1).

Biotransformation

Cabotegravir is primarily metabolised by UGT1A1 with a minor UGT1A9 component. Cabotegravir is the predominant circulating compound in plasma, representing > 90% of plasma total radiocarbon. Following oral administration in humans, cabotegravir is primarily eliminated through metabolism; renal elimination of unchanged cabotegravir is low (<1% of the dose). Forty-seven percent of the total oral dose is excreted as unchanged cabotegravir in the faeces. It is unknown if all or part of this is due to unabsorbed drug or biliary excretion of the glucuronide conjugate, which can be further degraded to form the parent compound in the gut lumen. Cabotegravir was observed to be present in duodenal bile samples. The glucuronide metabolite was also present in some, but not all, of the duodenal bile samples. Twenty-seven percent of the total oral dose is excreted in the urine, primarily as a  glucuronide metabolite (75% of urine radioactivity, 20% of total dose).

Cabotegravir is not a clinically relevant inhibitor of the following enzymes and transporters: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B15, and UGT2B17, P-gp, BCRP, Bile salt

export pump (BSEP), OCT1, OCT2, OATP1B1, OATP1B3, multidrug and toxin extrusion transporter (MATE) 1, MATE 2-K, multidrug resistance protein (MRP) 2 or MRP4.

Elimination

Cabotegravir mean apparent terminal phase half-life is absorption-rate limited and is estimated to be

5.6 to 11.5 weeks after a single dose IM injection. The significantly longer apparent half-life compared to oral reflects elimination from the injection site into the systemic circulation. The apparent CL/F was

0.151 L/h.

Linearity/non-linearity

Plasma CAB exposure increases in proportion or slightly less than in proportion to dose following single and repeat IM injection of doses ranging from 100 to 800 mg.

Polymorphisms

In a meta-analysis of healthy and HIV-infected subject trials, HIV-infected subjects with UGT1A1 genotypes conferring poor cabotegravir metabolism had a 1.2-fold mean increase in steady-state cabotegravir AUC, Cmax, and Ctau following long acting injection administration compared with

subjects with genotypes associated with normal metabolism via UGT1A1. These differences are not considered clinically relevant. No dose adjustment is required in subjects with UGT1A1 polymorphisms.

Special patient populations

Gender

Population pharmacokinetic analyses revealed no clinically relevant effect of gender on the exposure of cabotegravir, therefore no dose adjustment is required on the basis of gender.

Race

Population pharmacokinetic analyses revealed no clinically relevant effect of race on the exposure of cabotegravir, therefore no dosage adjustment is required on the basis of race.

Body Mass Index (BMI)

Population pharmacokinetic analyses revealed no clinically relevant effect of BMI on the exposure of cabotegravir, therefore no dose adjustment is required on the basis of BMI.

Elderly

Population pharmacokinetic analysis of cabotegravir revealed no clinically relevant effect of age on cabotegravir exposure. Pharmacokinetic data for cabotegravir in subjects of >65 years old are limited.

Renal impairment

No clinically important pharmacokinetic differences between subjects with severe renal impairment (CrCL <30 mL/min and not on dialysis) and matching healthy subjects were observed. No dosage

adjustment is necessary for patients with mild to severe renal impairment (not on dialysis).

Cabotegravir has not been studied in patients on dialysis.

Hepatic impairment

No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of cabotegravir has not been studied.

Carcinogenesis and mutagenesis

Cabotegravir was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay. Cabotegravir was not carcinogenic in long term studies in the mouse and rat.

Reproductive toxicology studies

No effect on male or female fertility was observed in rats treated with cabotegravir at oral doses up to 1,000 mg/kg/day (>20 times the exposure in humans at the maximum recommended dose).

In an embryo-foetal development study there were no adverse developmental outcomes following oral administration of cabotegravir to pregnant rabbits up to a maternal toxic dose of 2,000 mg/kg/day

(0.66 times the exposure in humans at the MRHD) or to pregnant rats at doses up to 1,000 mg/kg/day (>30 times the exposure in humans at the MRHD). In rats, alterations in foetal growth (decreased body

weights) were observed at 1,000 mg/kg/day. Studies in pregnant rats showed that cabotegravir crosses the placenta and can be detected in foetal tissue.

In rat pre- and post-natal (PPN) studies cabotegravir reproducibly induced a delayed onset of parturition, and an increase in the number of stillbirths and neonatal mortalities at 1,000 mg/kg/day

(>30 times the exposure in humans at the MRHD). A lower dose of 5 mg/kg/day (approximately 10 times the exposure in humans at the MRHD) cabotegravir was not associated with delayed parturition or neonatal mortality. In rabbit and rat studies there was no effect on survival when foetuses were delivered by caesarean section. Given the exposure ratio, the relevance to humans is unknown.

Repeated dose toxicity

The effect of prolonged daily treatment with high doses of cabotegravir has been evaluated in repeat oral dose toxicity studies in rats (26 weeks) and in monkeys (39 weeks). There were no drug-related adverse effects in rats or monkeys given cabotegravir orally at doses up to 1,000 mg/kg/day or

500 mg/kg/day, respectively.

In a 14 day and 28 day monkey toxicity study, gastro-intestinal (GI) effects (body weight loss, emesis, loose/watery faeces, and moderate to severe dehydration) were observed and were the result of local drug administration and not systemic toxicity.

In a 3 month study in rats, when cabotegravir was administered by monthly sub-cutaneous (SC) injection (up to 100 mg/kg/dose); monthly IM injection (up to 75 mg/kg/dose) or weekly SC injection (100 mg/kg/dose), there were no adverse effects noted and no new target organ toxicities (at exposures

>30 times the exposure in humans at the MRHD of 400 mg IM dose).

6.1         List of excipients

Mannitol (E421) Polysorbate 20 (E432) Macrogol (E1521) Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Unopened vial 3 years

Shelf life of suspension in syringe

Chemical and physical in-use stability has been demonstrated for 2 hours at 25°C.

Once the suspension has been drawn into the syringe, from a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions

prior to use are the responsibility of the user.

Unopened vial

This medicinal product does not require any special storage conditions. Do not freeze.

Suspension in syringe

For storage conditions after first opening of the product, see section 6.3.

400 mg (2 mL vial)

Brown 2 mL type I glass vial, with bromobutyl rubber stopper and a grey aluminium overseal with a dark grey plastic flip-cap.

Each pack contains: 1 vial (400 mg), 1 graduated syringe (sterile, single use with volumetric markings every 0.2 mL), 1 vial adaptor and 1 injection needle (0.65 mm, 38 mm [23 gauge, 1½ inch]).

600 mg (3mL vial)

Brown 3 mL type I glass vial, with bromobutyl rubber stopper and a grey aluminium overseal with an orange plastic flip-cap.

Each pack contains: 1 vial (600 mg), 1 graduated syringe (sterile, single use with volumetric markings every 0.2 mL), 1 vial adaptor and 1 injection needle (0.65 mm, 38 mm [23 gauge, 1½ inch]).

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

Full instructions for use and handling of Vocabria injection are provided in the package leaflet (see Instructions for Use).

ViiV Healthcare BV

Van Asch van Wijckstraat 55H, 3811 LP Amersfoort

Netherlands

EU/1/20/1481/002 EU/1/20/1481/003

Date of first authorisation: 17 December 2020

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Vocabria 30 mg film-coated tablets

Each tablet contains cabotegravir sodium equivalent to 30 mg cabotegravir. Excipient with known effect

Each film-coated tablet contains 155 mg lactose (as monohydrate). For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

White, oval, film-coated tablets (approximately 8.0 mm by 14.3 mm), debossed with ‘SV CTV’ on one side.

4.1         Therapeutic indications

Vocabria tablets are indicated in combination with rilpivirine tablets for the short-term treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults 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 NNRTI and INI class (see sections 4.2, 4.4 and 5.1) for:

•      oral lead in to assess tolerability of Vocabria and rilpivirine prior to administration of long acting cabotegravir injection plus long acting rilpivirine injection.

•      oral therapy for adults who will miss planned dosing with cabotegravir injection plus rilpivirine injection.

Vocabria should be prescribed by physicians experienced in the management of HIV infection. Vocabria tablets are indicated for the short-term treatment of HIV in combination with rilpivirine

tablets, therefore, the prescribing information for rilpivirine tablets should be consulted for recommended dosing.

Posology

Adults

Oral lead in

Prior to the initiation of cabotegravir injection, Vocabria tablets together with rilpivirine tablets should be taken for approximately one month (at least 28 days) to assess tolerability to cabotegravir and

rilpivirine (see section 4.4). One Vocabria 30 mg tablet should be taken with one rilpivirine 25 mg tablet, once daily.

Oral dosing for missed injections of cabotegravir

If a patient plans to miss a scheduled injection visit by more than 7 days, oral therapy (one Vocabria 30 mg tablet and one rilpivirine 25 mg tablet once daily) may be used to replace up to 2 consecutive monthly injection visits or one, every 2 month injection visit. For oral therapy durations greater than two months, an alternative oral regimen is recommended.

The first dose of oral therapy should be taken one month (+/- 7 days) after the last injection doses of cabotegravir and rilpivirine for patients being given monthly injections. For patients being given every 2-month injections, the first dose of oral therapy should be taken 2 months (+/- 7 days) after the last injection doses of cabotegravir and rilpivirine. Injection dosing should be resumed on the day oral dosing completes.

Missed doses

If the patient misses a dose of Vocabria tablets, the patient should take the missed dose as soon as possible, providing the next dose is not due within 12 hours. If the next dose is due within 12 hours,

the patient should not take the missed dose and simply resume the usual dosing schedule.

If a patient vomits within 4 hours of taking Vocabria tablets, another Vocabria tablet should be taken. If a patient vomits more than 4 hours after taking Vocabria tablets, the patient does not need to take another dose of Vocabria until the next regular scheduled dose.

Elderly

No dose adjustment is required in elderly patients. There are limited data available on the use of cabotegravir in patients aged 65 years and over (see section 5.2).

Renal impairment

No dosage adjustment is required in patients with mild to severe renal impairment (CrCL <30 mL/min and not on dialysis [see section 5.2]). Cabotegravir has not been studied in patients with end-stage  renal disease on renal replacement therapy. As cabotegravir is greater than 99% protein bound, dialysis is not expected to alter exposures of cabotegravir. If administered in a patient on renal replacement therapy, cabotegravir should be used with caution.

Hepatic impairment

No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). Cabotegravir has not been studied in patients with severe hepatic impairment (Child- Pugh score C [see section 5.2]).

If administered in a patient with severe hepatic impairment, cabotegravir should be used with caution.

Paediatric population

The safety and efficacy of Vocabria in children and adolescents aged under 18 years have not been established. No data is available.

Method of administration

Oral use.

Vocabria tablets may be taken with or without food. When taken at the same time as rilpivirine tablets, Vocabria tablets should be taken with a meal.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant use with rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenytoin or

phenobarbital (see section 4.5).

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. 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 A6/A1 subtype (see section 5.1).

Hypersensitivity reactions

Hypersensitivity reactions have been reported in association with other integrase inhibitors. These reactions were characterised by rash, constitutional findings and sometimes organ dysfunction, including liver injury. While no such reactions have been observed to date in association with Vocabria, physicians should remain vigilant and should discontinue Vocabria and other suspected medicinal products immediately, should signs or symptoms of hypersensitivity develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia or angioedema). Clinical status, including liver aminotransferases should be monitored and appropriate therapy  initiated. Administration of oral lead-in is recommended to help identify patients who may be at risk of a hypersensitivity reaction (see section 4.2).

Hepatoxicity

Hepatotoxicity has been reported in a limited number of patients receiving Vocabria with or without known pre-existing hepatic disease (see section 4.8).

Monitoring of liver chemistries is recommended and treatment with Vocabria should be discontinued if hepatotoxicity is suspected.

HBV/HCV co-infection

Patients with hepatitis B co-infection were excluded from studies with Vocabria. It is not recommended to initiate Vocabria in patients with hepatitis B co-infection. 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. Monitoring of liver function is recommended in patients with hepatitis C co-infection

Interactions with medicinal products

Caution should be given to prescribing Vocabria tablets with medicinal products that may reduce its exposure (see section 4.5).

Polyvalent cation containing antacids are recommended to be taken at least 2 hours before and 4 hours after taking Vocabria tablets (see section 4.5).

Transmission of HIV

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

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 Vocabria or any other antiretroviral therapy do 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.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption should not take this medicine.

Excipients

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

Vocabria tablets, in combination with rilpivirine tablets, are indicated for the treatment of HIV-1, therefore, the prescribing information for rilpivirine tablets should be consulted for associated interactions.

Effect of other agents on the pharmacokinetics of cabotegravir

Cabotegravir is primarily metabolised by uridine diphosphate glucuronosyl transferase (UGT) 1A1 and to a lesser extent by UGT1A9. Medicinal products which are strong inducers of UGT1A1 or UGT1A9 are expected to decrease cabotegravir plasma concentrations leading to lack of efficacy (see section 4.3 and table 5 below). In poor metabolizers of UGT1A1, representing a maximum clinical UGT1A1 inhibition, the mean AUC, Cmax and Ctau of oral cabotegravir increased by up to 1.5-fold. The impact of an UGT1A1 inhibitor may be slightly more pronounced, however, considering the safety margins of

cabotegravir, this increase is not expected to be clinically relevant. No dosing adjustments for Vocabria are, therefore, recommended in the presence of UGT1A1 inhibitors (e.g. atazanavir, erlotinib, sorafenib).

Cabotegravir is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), however, because of its high permeability, no alteration in absorption is expected when co- administered with either P-gp or BCRP inhibitors.

Effect of cabotegravir on the pharmacokinetics of other medicinal products

In vivo, cabotegravir did not have an effect on midazolam, a cytochrome P450 (CYP) 3A4 probe. Invitro, cabotegravir did not induce CYP1A2, CYP2B6, or CYP3A4.

In vitro, cabotegravir inhibited the organic anion transporters (OAT) 1 (IC50=0.81 µM) and OAT3 (IC50=0.41 µM). Therefore, caution is advised when co-dosing with narrow therapeutic index OAT1/3 substrate drugs (e.g. methotrexate).

Based on the in vitro and clinical drug interaction profile, cabotegravir is not expected to alter concentrations of other anti-retroviral medications including protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, entry inhibitors and ibalizumab.

The drug interaction data provided in Table 2 is obtained from studies with oral cabotegravir (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus time curve as “AUC”, maximum observed concentration as “Cmax”, concentration at end of dosing interval as “Cτ”).

4.6         Fertility, pregnancy and lactation

Pregnancy

There are a limited amount of data from the use of cabotegravir in pregnant women. The effect of Vocabria on human pregnancy is unknown.

Cabotegravir was not teratogenic when studied in pregnant rats and rabbits but, exposures higher than the therapeutic dose showed reproductive toxicity in animals (see section 5.3). The relevance to human pregnancy is unknown.

Vocabria tablets are not recommended during pregnancy unless the expected benefit justifies the potential risk to the foetus.

Breast-feeding

It is expected that cabotegravir will be secreted into human milk based on animal data, although this has not been confirmed in humans.

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

Fertility