VOCABRIA 30mg tablets medication leaflet

Vocabria 30 mg film-coated tablets

Each tablet contains cabotegravir sodium equivalent to 30 mg cabotegravir.

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 oneside.

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 and adolescents (at least 12 yearsof age and weighing at least 35 kg) who are virologically suppressed (HIV-1 RNA <50 copies/mL) ona stable 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) for:

* Oral lead-in to assess tolerability of Vocabria and rilpivirine prior to administration of longacting cabotegravir injection plus long acting rilpivirine injection.

* Oral therapy for adults and adolescents who will miss planned dosing with cabotegravirinjection 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 rilpivirinetablets, therefore, the prescribing information for rilpivirine tablets should be consulted forrecommended dosing.

Prior to starting Vocabria, healthcare professionals should carefully select patients who agree tothe required monthly or every 2 month injection schedules and counsel patients about theimportance of adherence to scheduled dosing visits to help maintain viral suppression andreduce the risk of viral rebound and potential development of resistance with missed doses (seesection 4.4).

The healthcare provider and patient may decide to use Vocabria tablets as an oral lead-in prior to theinitiation of cabotegravir injection to assess tolerability to cabotegravir (see Table 1) or may proceeddirectly to cabotegravir injections (see cabotegravir injection SmPC).

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

Oral lead-in

When used for oral lead-in, Vocabria tablets together with rilpivirine tablets should be taken forapproximately one month (at least 28 days) to assess tolerability to cabotegravir and rilpivirine (seesection 4.4). One Vocabria 30 mg tablet should be taken with one rilpivirine 25 mg tablet, once daily.

Table 1 Recommended Dosing Schedule

ORAL LEAD-IN

Medicinal Product During month 1

Vocabria 30 mg once daily

Rilpivirine 25 mg 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 Vocabria30 mg tablet and one rilpivirine 25 mg tablet once daily) may be used to replace up to 2 consecutivemonthly injection visits or one, every 2 month injection visit. Limited data is available on oral bridgingwith other fully suppressive antiretroviral therapy (ART) (mainly INI-based), see section 5.1. For oraltherapy 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 ofcabotegravir and rilpivirine for patients being given monthly injections. For patients being given every2-month injections, the first dose of oral therapy should be taken 2 months (+/- 7 days) after the lastinjection doses of cabotegravir and rilpivirine. Injection dosing should be resumed on the day oraldosing completes.

If the patient misses a dose of Vocabria tablets, the patient should take the missed dose as soon aspossible, 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 takeanother dose of Vocabria until the next regular scheduled dose.

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

No dosage adjustment is required in patients with mild (creatinine clearance ≥60 to <90 mL/min),moderate (creatinine clearance ≥30 to <60 mL/min) or severe renal impairment (creatinineclearance ≥15 to <30 mL/min and not on dialysis [see section 5.2]). Cabotegravir has not been studiedin patients with end-stage renal disease on renal replacement therapy. As cabotegravir is greater than99% protein bound, dialysis is not expected to alter exposures of cabotegravir. If administered in apatient on renal replacement therapy, cabotegravir should be used with caution.

No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pughscore 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.

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

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 orphenobarbital (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 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 patientsare treated according to the every 2 month dosing regimen as compared to the monthly dosingregimen. In patients with an incomplete or uncertain treatment history without pre-treatment resistanceanalyses, caution is warranted in the presence of either BMI 30 kg/m2 or HIV-1 A6/A1 subtype (seesection 5.1).

The severe cutaneous adverse reactions, Stevens-Johnson syndrome (SJS) and toxic epidermalnecrolysis (TEN), which can be life-threatening or fatal, have been reported very rarely in associationwith cabotegravir treatment.

At the time of prescription, patients should be advised of the signs and symptoms and monitoredclosely for skin reactions. If signs and symptoms suggestive of these reactions appear, cabotegravirshould be withdrawn immediately and an alternative treatment considered (as appropriate). If thepatient has developed a serious reaction such as SJS or TEN with the use of cabotegravir, treatmentwith cabotegravir must not be restarted in this patient at any time.

Hypersensitivity reactions have been reported in association with integrase inhibitors includingcabotegravir. These reactions were characterised by rash, constitutional findings and sometimes organdysfunction, including liver injury. Vocabria and other suspected medicinal products should bediscontinued immediately, should signs or symptoms of hypersensitivity develop (including, but notlimited 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). Clinicalstatus, including liver aminotransferases should be monitored and appropriate therapy initiated. (Seesections 4.2, pct. 4.8 and 5.1).

Hepatoxicity

Hepatotoxicity has been reported in a limited number of patients receiving Vocabria with or withoutknown pre-existing hepatic disease (see section 4.8). Administration of cabotegravir oral lead-in wasused in clinical studies to help identify patients who may be at risk of hepatotoxicity.

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

HBV/HCV co-infection

Patients with hepatitis B co-infection were excluded from studies with Vocabria. It is notrecommended to initiate Vocabria in patients with hepatitis B co-infection. 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. Monitoring of liver function isrecommended in patients with hepatitis C co-infection

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

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

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 Vocabria or any other antiretroviral therapy do not cure HIV infectionand 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 thetreatment of these associated HIV diseases.

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

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 associatedinteractions.

Effect of other agents on the pharmacokinetics of cabotegravir

Cabotegravir is primarily metabolised by uridine diphosphate glucuronosyl transferase (UGT) 1A1 andto a lesser extent by UGT1A9. Medicinal products which are strong inducers of UGT1A1 or UGT1A9are expected to decrease cabotegravir plasma concentrations leading to lack of efficacy (see section 4.3and table 2 below). In poor metabolizers of UGT1A1, representing a maximum clinical UGT1A1inhibition, the mean AUC, Cmax and Ctau of oral cabotegravir increased by up to 1.5-fold. The impact ofan UGT1A1 inhibitor may be slightly more pronounced, however, considering the safety margins ofcabotegravir, 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 OAT1/3substrate drugs (e.g. methotrexate).

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

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

Table 2 Drug Interactions

Medicinal products Interaction Recommendations concerningby therapeutic areas Geometric mean change co-administration(%)

HIV-1 Antiviral medicinal products

Non-nucleoside Cabotegravir  Etravirine did not significantly change

Reverse Transcriptase AUC  1% cabotegravir plasma concentration. No dose

Inhibitor: C  4% adjustment of Vocabria tablets is necessary.max

Etravirine Cτ  0%

Non-nucleoside Cabotegravir  Rilpivirine did not significantly change

Reverse Transcriptase AUC  12% cabotegravir plasma concentration. No dose

Inhibitor: C  5% adjustment of Vocabria tablets is necessary whenmax

Rilpivirine Cτ  14% co-administered with rilpivirine.

Rilpivirine 

AUC  1%

Cmax  4%

Cτ  8%

Anticonvulsants

Carbamazepine Cabotegravir  Metabolic inducers may significantly decrease

Oxcarbazepine cabotegravir plasma concentrations, concomitant

Phenytoin use is contraindicated (see section 4.3).

Phenobarbital

Antacids

Antacids (e.g. Cabotegravir  Co-administration of antacid supplements has themagnesium, potential to decrease oral cabotegravir absorptionaluminium, or and has not been studied.

calcium) Antacid products containing polyvalent cations arerecommended to be administered at least 2 hoursbefore or 4 hours after oral Vocabria (see section4.4).

Antimycobacterials

Rifampicin Cabotegravir  Rifampicin significantly decreased cabotegravir

AUC  59% plasma concentration which is likely to result in

C  6% loss of therapeutic effect. Dosing recommendationsmaxfor co-administration of Vocabria with rifampicinhave not been established and co-administration of

Vocabria with rifampicin is contraindicated (seesection 4.3).

Rifapentine Cabotegravir  Rifapentine may significantly decreasecabotegravir plasma concentrations, concomitantuse is contraindicated (see section 4.3).

Rifabutin Cabotegravir  Rifabutin did not significantly change cabotegravir

AUC  21% plasma concentration. No dose adjustment is

C  17% required.max

Cτ  26% Prior to initiation of oral cabotegravir therapy, theprescribing information for cabotegravir injectionshould be consulted regarding concomitant usewith rifabutin.

Oral Contraceptives

Ethinyl estradiol (EE) EE  Cabotegravir did not significantly change ethinyland Levonorgestrel AUC  2% estradiol and levonorgestrel plasma concentrations(LNG) C  8% to a clinically relevant extent. No dose adjustmentmax

Cτ  0% of oral contraceptives is necessary when co-administered with Vocabria tablets.

LNG 

AUC  12%

Cmax  5%

Cτ  7%

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 thanthe therapeutic dose showed reproductive toxicity in animals (see section 5.3). The relevance to humanpregnancy is unknown.

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

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

It is recommended that women living with HIV do not breast-feed their infants in order to avoidtransmission of HIV.

There are no data on the effects of cabotegravir on human male or female fertility. Animal studiesindicate 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 treatmentwith Vocabria. The clinical status of the patient and the adverse reaction profile of Vocabria should beborne in mind when considering the patient’s ability to drive or operate machinery.

The most frequently reported adverse reaction (ARs) from monthly dosing studies were headache (upto 12%) and pyrexia4 (10%).

The most frequently reported ARs, considered by the investigator as causally related, from ATLAS-2M every 2 month dosing were headache (7%) and pyrexia4 (7%).

The SCARs SJS and TEN have been reported in association with cabotegravir treatment (see section4.4).

The ARs identified for cabotegravir and rilpivirine are listed in Table 3 by body system organ classand 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).

Table 3 Tabulated summary of adverse reactions1

MedDRA System Organ Frequency ARs for Vocabria + rilpivirine regimen

Class (SOC) Category

Immune system disorders Uncommon Hypersensitivity*

Psychiatric disorders Common Depression

Anxiety

Abnormal dreams

Insomnia

Uncommon Suicide attempt; Suicidal ideation(particularly in patients with a pre-existinghistory of psychiatric illness)

Nervous system disorders Very common Headache

Common Dizziness

Uncommon Somnolence

Gastrointestinal disorders Common Nausea

Abdominal pain2

Flatulence

Hepatobiliary Disorders Uncommon Hepatotoxicity

Skin and subcutaneous tissue Common Rash3disorders

Uncommon Urticaria*

Angioedema*

Very rare Stevens-Johnson syndrome*, toxic epidermalnecrolysis*

Musculoskeletal and Common Myalgiaconnective tissue disorders

General disorders and Very common Pyrexia4administrative site conditions

Common Fatigue

Asthenia

Malaise

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 tothose considered at least possibly related by the investigator.2 Abdominal pain includes the following grouped MedDRA preferred term: upper abdominal pain.3 Rash includes the following grouped MedDRA preferred terms: rash, rash erythematous, rash generalised, rashmacular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic.4 Pyrexia includes the following grouped MedDRA preferred terms: feeling hot, body temperature increased.

* Please refer to section 4.4.

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 FLAIR study,initiating the CAB LA + RPV LA regimen with Direct to Injection did not identify any new safetyconcerns related to omitting the oral lead-in phase (see section 5.1).

Weight increased

At the Week 48 time point, subjects in studies FLAIR and ATLAS, who received Vocabria plusrilpivirine gained a median of 1.5 kg in weight; subjects continuing on their current antiretroviraltherapy (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 kgrespectively, 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.

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

Elevated transaminases (ALT/AST) were observed in subjects receiving Vocabria plus rilpivirineduring clinical studies. These elevations were primarily attributed to acute viral hepatitis. A fewsubjects on oral therapy had transaminase elevations attributed to suspected drug-relatedhepatotoxicity; 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 4lipase 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 rilpivirinediscontinuation. One case of fatal pancreatitis with Grade 4 lipase and confounding factors (includinghistory of pancreatitis) has been reported in study ATLAS-2M, for which causality to the injectionregimen could not be ruled out.

Based on data from the week 16 (Cohort 1C, n=30) and week 24 analysis (Cohort 2, n=144) 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 no specific treatment for Vocabria overdose. If overdose occurs, the patient should be treatedsupportively with appropriate monitoring as necessary.

Cabotegravir is known to be highly protein bound in plasma; therefore, dialysis is unlikely to behelpful in removal of medicinal product from the body.

Pharmacotherapeutic group: Antiviral for systemic use, integrase inhibitor, ATC code: J05AJ04

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

Cabotegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with meanconcentration of cabotegravir necessary to reduce viral replication by 50 percent (EC50) values of0.22 nM in peripheral blood mononuclear cells (PBMCs), 0.74 nM in 293T cells and 0.57 nM in MT-4cells. Cabotegravir demonstrated antiviral activity in cell culture against a panel of 24 HIV-1 clinicalisolates (three in each group of M clades A, B, C, D, E, F, and G, and 3 in group O) with EC50 valuesranging from 0.02 nM to 1.06 nM for HIV-1. Cabotegravir EC50 values against three HIV-2 clinicalisolates 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 antiviral medicines

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 andemtricitabine).

Isolation from wild-type HIV-1 and activity against resistant strains: Viruses with >10-fold increase incabotegravir EC50 were not observed during the 112-day passage of strain IIIB. The followingintegrase (IN) mutations emerged after passaging wild type HIV-1 (with T124A polymorphism) in thepresence of cabotegravir: Q146L (fold-change [FC] range 1.3-4.6), S153Y (FC range 2.8-8.4), and

I162M (FC = 2.8). As noted above, the detection of T124A is selection of a pre-existing minorityvariant that does not have differential susceptibility to cabotegravir. No amino acid substitutions in theintegrase region were selected when passaging the wild-type HIV-1 NL-432 in the presence of 6.4 nMof 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/Q148Rresulted in a 12-fold decrease in susceptibility and E138K/Q148K resulted in an 81-fold decrease insusceptibility to cabotegravir. G140C/Q148R and G140S/Q148R resulted in a 22- and 12-folddecrease in susceptibility to cabotegravir, respectively. While N155H did not alter susceptibility tocabotegravir, N155H/Q148R resulted in a 61-fold decrease in susceptibility to cabotegravir. Othermultiple 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).

The number of subjects who met Confirmed Virologic Failure (CVF) criteria was low across thepooled FLAIR and ATLAS trials. In the pooled analysis, there were 7 CVFs on cabotegravir plusrilpivirine (7/591, 1.2%) and 7 CVFs on current antiretroviral regimen (7/591, 1.2%). The three CVFson 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 oneof the three had G140R with reduced phenotypic susceptibility to cabotegravir. All 3 CVFs carried onerilpivirine resistance-associated substitution: K101E, E138E/A/K/T or E138K, and two of the threeshowed reduced phenotypic susceptibility to rilpivirine. The 3 CVFs in ATLAS had subtype A, A1and AG. One of the three CVFs carried the INI resistance-associated substitution N155H at failurewith reduced cabotegravir phenotype susceptibility. All three CVFs carried one rilpivirine resistance-associated substitution at failure: E138A, E138E/K or E138K, and showed reduced phenotypicsusceptibility to rilpivirine. In two of these three CVFs, the rilpivirine resistance-associatedsubstitutions 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 thepooled 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 Q8Warm and 2 subjects (0.4%) in the Q4W arm. Eight subjects met CVF criteria at or before the Week 24timepoint.

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 resistancemutation, 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 rilpivirineresistance-associated mutations with 2 subjects having an addition of K101E and 1 subject having anaddition of E138E/K from Baseline to SVF timepoint. Rilpivirine FC was above the biological cut-offfor 7 subjects and ranged from 2.4 to 15. Five of the 6 subjects with rilpivirine resistance-associatedsubstitution, 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 genotypeand 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 to1.7 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 NNRTIpolymorphism, V189I. At SVF timepoint, one subject had on-treatment rilpivirine resistance-associated mutations, K101E + M230L and the other retained the G190Q + V189I NNRTIsubstitutions with the addition of V179V/I. Both subjects showed reduced phenotypic susceptibility torilpivirine. 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 fordolutegravir and 1.1 and 1.5 for bictegravir.

The efficacy of cabotegravir 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 dolutegravirintegrase strand transfer inhibitor (INSTI) containing regimen for 20 weeks (eitherdolutegravir/abacavir/lamivudine or dolutegravir plus 2 other nucleoside reverse transcriptaseinhibitors 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 cabotegravir plusrilpivirine regimen or remain on the current antiretroviral (CAR) regimen. Subjects randomised toreceive the cabotegravir plus rilpivirine regimen, initiated treatment with oral lead-in dosing with one30 mg cabotegravir tablet plus one 25 mg rilpivirine tablet, daily, for at least 4 weeks, followed bytreatment with cabotegravir 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 monthfor 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 cabotegravirplus rilpivirine regimen or remained on the CAR regimen. Subjects randomised to receive thecabotegravir plus rilpivirine regimen, initiated treatment with oral lead-in dosing with one 30 mgcabotegravir tablet plus one 25 mg rilpivirine tablet, daily for at least 4 weeks, followed by treatmentwith cabotegravir injection (month 1: 600 mg injection, month 2 onwards: 400 mg injection) plusrilpivirine injection (month 1: 900 mg injection, month 2 onwards: 600 mg injection) every month foran 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 wassimilar between treatment arms.

Pooled data

At baseline, in the pooled analysis, for the cabotegravir plus rilpivirine 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 ≥50copies/mL at week 48 (snapshot algorithm for the ITT-E population).

In a pooled analysis of the two pivotal studies, cabotegravir plus rilpivirine was non-inferior to CARon 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 cabotegravir 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% CIbelow 4%).

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

FLAIR and ATLAS are shown in Tables 4 and 5.

Table 4 Virologic Outcomes of randomised treatment of FLAIR and ATLAS at 48 Weeks(Snapshot analysis)

FLAIR ATLAS Pooled Data

Cabotegravir CAR Cabotegravir CAR Cabotegravir CAR+ RPV N=283 + RPV N=308 +RPV N=591

N=283 N=308 N=591

HIV-1 RNA≥506 (2.1) 7 (2.5) 5 (1.6) 3 (1.0) 11 (1.9) 10 (1.7)copies/mL† (%)

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

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

Treatment 0.4 (-3.7, 4.5) -3.0 (-6.7, 0.7) -1.4 (-4.1, 1.4)

Difference %(95% CI)*

No virologic dataat Week 48 12 (4.2) 12 (4.2) 18 (5.8) 11 (3.6) 30 (5.1) 23 (3.9)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 drug4 (1.4) 10 (3.5) 7 (2.3) 6 (1.9) 11 (1.9) 16 (2.7)for other reasons(%)

Missing dataduring window 0 0 0 0 0 0but on study (%)

* 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.

Table 5 Proportion of subjects with plasma HIV-1 RNA ≥50 copies/mL at Week 48 forkey baseline factors (Snapshot Outcomes).

Pooled Data from FLAIR and ATLAS

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

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

BMI= body mass index

PI= Protease inhibitor

INI= Integrase inhibitor

NNRTI= non-nucleoside reverse transcriptase inhibitor

In both the FLAIR and ATLAS studies, treatment differences across baseline characteristics (CD4+count, gender, race, BMI, age, 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 cabotegravir plus rilpivirine (n=283)and CAR (n=283) was 3.2% and 3.2% respectively (adjusted treatment difference betweencabotegravir plus rilpivirine and CAR [0.0; 95% CI: -2.9, 2.9]). The proportion of subjects havingplasma HIV-1 RNA <50 c/mL in cabotegravir plus rilpivirine and CAR was 87% and 89%,respectively (adjusted treatment difference between cabotegravir plus rilpivirine and CAR[-2.8; 95% CI: -8.2, 2.5]).

Week 124 FLAIR Direct to Injection vs 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 cabotegravir plus rilpivirinein the Extension Phase. Subjects were given the option to switch with or without an oral lead-in phase,creating an oral lead-in (OLI) group (n=121) and a direct to injection (DTI) group (n=111).

At Week 124, the proportion of subjects with HIV-1 RNA ≥50 copies/mL was 0.8% and 0.9% for theoral lead-in and direct to injection groups, respectively. The rates of virologic suppression (HIV-1

RNA <50 c/mL) were similar in both OLI (93.4%) and DTI (99.1%) groups.

Every 2 month dosing

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

The efficacy and safety of cabotegravir 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 ordiscontinued the study prematurely.

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

Table 6 Virologic Outcomes of Randomised Treatment of ATLAS-2M at 48 Weeks(Snapshot analysis)2 month Dosing (Q8W) Monthly Dosing (Q4W)

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% CI)* 0.8 (-2.1, 3.7)

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

Reasons:

Discontinued study due to AE or 9 (1.7) 13 (2.5)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 antiviral regimen.

Table 7 Proportion of Subjects with Plasma HIV-1 RNA ≥50 copies/mL at Week 48 forkey baseline factors (Snapshot Outcomes).

Baseline factors Number of HIV-1 RNA ≥50 c/mL/Total Assessed(%)2 Month 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/African 4/101 (4.0) 0/ 90

American

Non- 5/421 (1.2) 5/421 (1.2)

Black/African

American

BMI <30 kg/m2 3/409 (0.7) 3/425 (0.7)

Baseline factors Number of HIV-1 RNA ≥50 c/mL/Total Assessed(%)2 Month Dosing Monthly dosing (Q4W)(Q8W)≥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/RPV1-24 weeks 3/69 (4.3) 0/68>24 weeks 1/126 (0.8) 0/128

BMI= body mass index

In the ATLAS-2M study, treatment differences on the primary endpoint across baselinecharacteristics (CD4+ lymphocyte count, gender, race, BMI, age and prior exposure tocabotegravir/rilpivirine) were not clinically meaningful.

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

Cabotegravir plus rilpivirine injections administered every 2 months is non-inferior to cabotegravirand rilpivirine administered every month. The proportion of subjects having plasma HIV-1 RNA ≥50c/mL at Week 96 in cabotegravir plus rilpivirine every 2 months dosing (n=522) and cabotegravir plusrilpivirine monthly dosing (n=523) was 2.1% and 1.1% respectively (adjusted treatment differencebetween cabotegravir plus rilpivirine 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 in cabotegravirplus rilpivirine every 2 months dosing and cabotegravir plus rilpivirine monthly dosing was 91% and90.2% respectively (adjusted treatment difference between cabotegravir plus rilpivirine every 2 monthsdosing 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 48and at Week 96. Cabotegravir plus rilpivirine injections administered every 2 months is non-inferior tocabotegravir and rilpivirine administered every month. In an ITT analysis, the proportion of subjectshaving plasma HIV-1 RNA ≥50 c/mL at Week 152 in cabotegravir plus rilpivirine every 2 monthsdosing (n=522) and cabotegravir plus rilpivirine monthly dosing (n=523) was 2.7% and 1.0%respectively (adjusted treatment difference between cabotegravir plus rilpivirine 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 cabotegravir plus rilpivirine every 2 monthsdosing and cabotegravir plus rilpivirine monthly dosing was 87% and 86% respectively (adjustedtreatment difference between cabotegravir plus rilpivirine 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 through 124weeks and 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 participant 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/INSTI resistance mutations had no significant associationwith CVF. A combination of at least 2 of the following key baseline factors was associated with anincreased risk of CVF: rilpivirine resistance mutations, HIV-1 subtype A6/A1, or BMI 30 kg/m2 (see

Table 8).

Table 8 Virologic outcomes by presence of key baseline factors of rilpivirine resistancemutations, Subtype A6/A11 and BMI ≥30 kg/m2

Baseline Factors (number) Virologic Successes (%)2 Confirmed Virologic Failure(%)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 Sequencedatabase (June 2020)2 Based on the FDA Snapshot algorithm of RNA <50 copies/mL at Week 48 for ATLAS, at Week 124 for

FLAIR, at Week 152 for ATLAS-2M.3 Defined as two consecutive measurements of HIV RNA ≥200 copies/mL.4 Positive Predictive Value (PPV) <2%; Negative Predictive Value (NPV) 98.5%; sensitivity 34.8%; specificity71.9%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 cabotegravir plus rilpivirine (alternativeoral bridging) during treatment with cabotegravir plus rilpivirine long-acting (LA) intramuscular (IM)injections. The median age of subjects was 32 years, 14% were female, 31% were non-white, 97%received an integrase inhibitor (INI)-based regimen for alternative oral bridging, 41% received an

NNRTI as part of their alternative oral bridging regimen (including rilpivirine in 11/12 cases), and62% received an NRTI. Three subjects withdrew during oral bridging or shortly following oralbridging 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 periodfollowing alternative oral bridging (up to 2 cabotegravir plus rilpivirine injections following oralbridging), no cases of CVF (plasma HIV-1 RNA ≥200 c/mL) were observed.

The safety, tolerability and pharmacokinetics (PK) of long-acting injectable cabotegravir incombination with long-acting injectable rilpivirine in adolescents has been evaluated in an ongoing

Phase I/II 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 cabotegravir 30 mg tablet and rilpivirine 25 mg tablet once daily for at least 4weeks followed by every 2 month cabotegravir intramuscular injections (months 1 and 2: 600 mg, andthen 600 mg every 2 months) and rilpivirine intramuscular injections (months 1 and 2: 900 mg, andthen 900 mg 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 % were non-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) with available data remaining virologically suppressed (plasma HIV-1 RNAvalue <50 c/mL) at Week 24.

The European Medicines Agency has deferred the obligation to submit the results of studies withcabotegravir film-coated tablets and prolonged-release suspension for injection in one or more subsetsof the paediatric population in the treatment of HIV-1 infection. See section 4.2 for information onpaediatric use.

Cabotegravir pharmacokinetics is similar between healthy and HIV-infected subjects. The PKvariability of cabotegravir is moderate. In Phase I studies in healthy subjects, between-subject CVb%for AUC, Cmax, and Ctau ranged from 26 to 34% across healthy subject studies and 28 to 56% across

HIV-1 infected subject studies. Within-subject variability (CVw%) is lower than between-subjectvariability.

Table 9 Pharmacokinetic parameters following cabotegravir orally once daily in Adultparticipants

Geometric Mean (5th, 95th Percentile)a

Dosage AUC b(0-tau) Cmax Ctau

Dosing Phase Regimen (µg*h/mL) (µg/mL) (µg/mL)30 mg 145 8.0 4.6

Oral lead-inconce daily (93.5, 224) (5.3, 11.9) (2.8, 7.5)a Pharmacokinetic parameter values based on pooled FLAIR and ATLAS individual post-hoc estimates fromcabotegravir population pharmacokinetic model (n = 581)b tau is dosing interval: 24 hours for oral administration.c Oral lead-in pharmacokinetic parameter values represent steady-state.

Cabotegravir is rapidly absorbed following oral administration, with median Tmax at 3 hours post dosefor tablet formulation. With once daily dosing, pharmacokinetic steady-state is achieved by 7 days.

Cabotegravir may be administered with or without food. Food increased the extent of absorption ofcabotegravir. Bioavailability of cabotegravir is independent of meal content: high fat meals increasedcabotegravir AUC(0-) by 14% and increased Cmax by 14% relative to fasted conditions. These increasesare not clinically significant.

The absolute bioavailability of cabotegravir has not been established.

Cabotegravir is highly bound (>99%) to human plasma proteins, based on in vitro data. Followingadministration of oral tablets, the mean apparent oral volume of distribution (Vz/F) in plasma was12.3 L. In humans, the estimate of plasma cabotegravir Vc/F was 5.27 L and Vp/F was 2.43 L. Thesevolume estimates, along with the assumption of high bioavailability, suggest some distribution ofcabotegravir to the extracellular space.

Cabotegravir is present in the female and male genital tract. Median cervical and vaginal tissue:plasmaratios ranged from 0.16 to 0.28 and median rectal tissue:plasma ratios were 0.08 following a single400 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 ofcabotegravir 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 longacting cabotegravir (Q4W or Q8W) injection. Consistent with therapeutic cabotegravir concentrationsin 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,

OATP2B1, OATP1B3 or organic cation transporter (OCT1).

Cabotegravir is primarily metabolised by UGT1A1 with a minor UGT1A9 component. Cabotegravir isthe 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 totaloral dose is excreted as unchanged cabotegravir in the faeces. It is unknown if all or part of this is dueto unabsorbed drug or biliary excretion of the glucuronide conjugate, which can be further degraded toform the parent compound in the gut lumen. Cabotegravir was observed to be present in duodenal bilesamples. 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 glucuronidemetabolite (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 saltexport pump (BSEP), OCT1, OCT2, OATP1B1, OATP1B3, multidrug and toxin extrusion transporter(MATE) 1, MATE 2-K, multidrug resistance protein (MRP) 2 or MRP4.

Cabotegravir has a mean terminal half-life of 41 h and an apparent clearance (CL/F) of 0.21 L perhour.

Polymorphisms

In a meta-analysis of healthy and HIV-infected subject trials, subjects with UGT1A1 genotypesconferring poor cabotegravir metabolism had a 1.3- to 1.5-fold mean increase in steady-statecabotegravir AUC, Cmax, and Ctau compared with subjects with genotypes associated with normalmetabolism via UGT1A1. These differences are not considered clinically relevant. No dose adjustmentis required in subjects with UGT1A1 polymorphisms.

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

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

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

No clinically important pharmacokinetic differences between subjects with severe renal impairment(creatinine clearance ≥15 to <30 mL/min and not on dialysis) and matching healthy subjects wereobserved. No dosage adjustment is necessary for patients with mild, moderate or severe renalimpairment (not on dialysis). Cabotegravir has not been studied in patients on dialysis.

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

Population pharmacokinetic simulations revealed no clinically relevant differences in exposurebetween adolescent (at least 12 years of age and weighing 35 kg or more) participants and HIV-1infected and uninfected adult participants from the cabotegravir development programme, therefore,no dosage adjustment is needed for adolescents weighing ≥ 35 kg.

Table 10 Pharmacokinetic parameters following cabotegravir orally once daily in

Adolescent participants aged 12 to less than 18 years (≥35 kg)

Geometric Mean (5th, 95th Percentile)a

Dosage AUC b(0-tau) Cmax Ctau

Dosing Phase Regimen (µg*h/mL) (µg/mL) (µg/mL)30 mg

Oral lead-inc 203 (136, 320) 11 (7.4, 16.6) 6.4 (4.2, 10.5)once dailya Pharmacokinetic (PK) parameter values were based on individual post-hoc estimates from population PKmodels in both a HIV-1 infected adolescent population (n=147) weighing 35.2-98.5 kg and a HIV-1 uninfectedadolescent population (n=62) weighing 39.9-167 kg.b tau is dosing interval: 24 hours for oral administration.c Oral lead-in pharmacokinetic parameter values represent steady-state.

Carcinogenesis and mutagenesis

Cabotegravir was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammaliancells, and an in vivo rodent micronucleus assay. Cabotegravir was not carcinogenic in long termstudies 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 to1000 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 oraladministration 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 bodyweights) were observed at 1,000 mg/kg/day. Studies in pregnant rats showed that cabotegravir crossesthe placenta and can be detected in foetal tissue.

In rat pre- and post-natal (PPN) studies cabotegravir reproducibly induced a delayed onset ofparturition, 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 10times the exposure in humans at the MRHD) cabotegravir was not associated with delayed parturitionor neonatal mortality. In rabbit and rat studies there was no effect on survival when foetuses weredelivered by caesarean section. Given the exposure ratio, the relevance to humans is unknown.

The effect of prolonged daily treatment with high doses of cabotegravir has been evaluated in repeatoral dose toxicity studies in rats (26 weeks) and in monkeys (39 weeks). There were no drug-relatedadverse effects in rats or monkeys given cabotegravir orally at doses up to 1,000 mg/kg/day or500 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 was the result of localdrug 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).

Lactose monohydrate

Microcrystalline cellulose (E460)

Hypromellose (E464)

Sodium starch glycolate

Magnesium stearate

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol (E1521)

Not applicable.

5 years

This medicinal product does not require any special storage conditions.

White HDPE (high density polyethylene) bottles closed with polypropylene child-resistant closures,with a polyethylene faced induction heat seal liner. Each bottle contains 30 film-coated tablets.

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

ViiV Healthcare BV

Van Asch van Wijckstraat 55H,3811 LP Amersfoort

Netherlands

EU/1/20/1481/001

Date of first authorisation: 17 December 2020

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

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