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 and adolescents (at least 12 years of age and weighing at least 35 kg) who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the non-nucleoside reverse transcriptase inhibitor (NNRTI) and integrase inhibitor (INI) class (see sections 4.2, 4.4 and 5.1) 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 and adolescents who will miss planned dosing with cabotegravir injection plus rilpivirine injection.

4.2. Posology and method of administration

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.

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

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

Posology

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 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.

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 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. Limited data is available on oral bridging with other fully suppressive antiretroviral therapy (ART) (mainly INI-based), see section 5.1. 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 (creatinine clearance ≥60 to 90 mL/min), moderate (creatinine clearance ≥30 to <60 mL/min) or severe renal impairment (creatinine clearance ≥15 to <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 aged less than 12 years or adolescents weighing less than 35 kg have not been established. No data are 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.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

Baseline factors associated with virological failure

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

Hypersensitivity reactions

Hypersensitivity reactions have been reported in association with integrase inhibitors including cabotegravir. These reactions were characterised by rash, constitutional findings and sometimes organ dysfunction, including liver injury. Vocabria and other suspected medicinal products should be discontinued 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. (See sections 4.2, 4.8 and 5.1).

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). Administration of cabotegravir oral lead-in was used 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 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).

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

Excipients

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

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

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

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 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 2 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. In vitro, 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 “C”).

Table 2 Drug Interactions

Medicinal products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co‑administration

HIV-1 Antiviral medicinal products

Non-nucleoside Reverse Transcriptase Inhibitor:Etravirine

Cabotegravir ↔

AUC ↑ 1%

Cmax ↑ 4%

C ↔ 0%

Etravirine did not significantly change cabotegravir plasma concentration. No dose adjustment of Vocabria tablets is necessary.

Non-nucleoside Reverse Transcriptase Inhibitor:Rilpivirine

Cabotegravir ↔AUC ↑ 12%Cmax ↑ 5%

C ↑ 14%

Rilpivirine ↔

AUC ↓ 1%

Cmax ↓ 4%

C ↓ 8%

Rilpivirine did not significantly change cabotegravir plasma concentration. No dose adjustment of Vocabria tablets is necessary when co-administered with rilpivirine.

Anticonvulsants

CarbamazepineOxcarbazepinePhenytoinPhenobarbital

Cabotegravir ↓

Metabolic inducers may significantly decrease cabotegravir plasma concentrations, concomitant use is contraindicated (see section 4.3).

Antacids

Antacids (e.g. magnesium, aluminium, or calcium)

Cabotegravir ↓

Co-administration of antacid supplements has the potential to decrease oral cabotegravir absorption and has not been studied.

Antacid products containing polyvalent cations are recommended to be administered at least 2 hours before or 4 hours after oral Vocabria (see section 4.4).

Antimycobacterials

Rifampicin

Cabotegravir ↓

AUC ↓ 59%

Cmax ↓ 6%

Rifampicin significantly decreased cabotegravir plasma concentration which is likely to result in loss of therapeutic effect. Dosing recommendations for co‑administration of Vocabria with rifampicin have not been established and co‑administration of Vocabria with rifampicin is contraindicated (see section 4.3).

Rifapentine

Cabotegravir ↓

Rifapentine may significantly decrease cabotegravir plasma concentrations, concomitant use is contraindicated (see section 4.3).

Rifabutin

Cabotegravir ↓

AUC ↓ 21%

Cmax ↓ 17%

C ↓ 26%

Rifabutin did not significantly change cabotegravir plasma concentration. No dose adjustment is required.

Prior to initiation of oral cabotegravir therapy, the prescribing information for cabotegravir injection should be consulted regarding concomitant use with rifabutin.

Oral Contraceptives

Ethinyl estradiol (EE) and Levonorgestrel (LNG)

EE ↔

AUC ↑ 2%

Cmax ↓ 8%

C ↔ 0%

LNG ↔

AUC ↑ 12%

Cmax ↑ 5%

C ↑ 7%

Cabotegravir did not significantly change ethinyl estradiol and levonorgestrel plasma concentrations to a clinically relevant extent. No dose adjustment of oral contraceptives is necessary when co‑administered with Vocabria tablets.

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 women living with HIV do not breast-feed their infants 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).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions (ARs) were headache and pyrexia6.

Tabulated list of adverse reactions

The ARs identified for cabotegravir and rilpivirine are listed in Table 3 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).

Table 3 Tabulated summary of adverse reactions1

MedDRA System Organ Class (SOC)

Frequency Category

ARs for Vocabria + rilpivirine regimen

Immune system disorders

Uncommon

Hypersensitivity*2

Psychiatric disorders

Common

Depression

Anxiety

Abnormal dreams

Insomnia

Uncommon

Suicide attempt2; Suicidal ideation2 (particularly in patients with a pre-existing history of psychiatric illness)

Nervous system disorders

Very common

Headache

Common

Dizziness

Uncommon

Somnolence

Gastrointestinal disorders

Common

Nausea

Vomiting

Abdominal pain3

Flatulence

Diarrhoea

Hepatobiliary Disorders

Uncommon

Hepatotoxicity

Skin and subcutaneous tissue disorders

Common

Rash4

Uncommon

Urticaria*2

Angioedema*2

Very rare

Stevens-Johnson syndrome*5, toxic epidermal necrolysis*5

Musculoskeletal and connective tissue disorders

Common

Myalgia

General disorders and administrative site conditions

Very common

Pyrexia6

Common

Fatigue

Asthenia

Malaise

Investigations

Common

Weight increased

Uncommon

Transaminase increased

Blood bilirubin increased

1 The frequency of the identified ARs are based on all reported occurrences of the events and are not limited to those considered at least possibly related by the investigator.

2 This adverse reaction was identified through post-marketing reporting. The frequency category is based on individuals exposed to cabotegravir in randomised clinical studies.

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

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

5 This adverse reaction was identified through post-marketing reporting. The frequency category is based on individuals exposed to cabotegravir in clinical studies.

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

* Please refer to section 4.4 'Hypersensitivity reactions'.

The overall safety profile at Week 96 and Week 124 in the FLAIR study was consistent with that observed at Week 48, with no new safety findings identified. In the extension phase of the FLAIR study, initiating the CAB LA + RPV LA regimen with Direct to Injection did not identify any new safety concerns related to omitting the oral lead-in phase (see section 5.1).

Description of selected adverse reactions

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 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.

Adolescents

Based on data from the Week 16 (Cohort 1) and Week 24 (Cohort 2) analyses of the MOCHA study, no new safety concerns were identified in adolescents (aged at least 12 years and weighing 35 kg or more) when compared with the safety profile established in adults (see section 5.1).

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is 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.