Consumer medicine information

Vocabria Tablets

Cabotegravir

BRAND INFORMATION

Brand name

Vocabria

Active ingredient

Cabotegravir

Schedule

What is in this leaflet

This leaflet answers some common questions about VOCABRIA TABLETS. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking VOCABRIA TABLETS against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What VOCABRIA TABLETS are used for

VOCABRIA TABLETS are used to treat Human Immunodeficiency Virus (HIV) infection in adults.

VOCABRIA TABLETS contain the active ingredient cabotegravir, which belongs to a group of antiretroviral medicines called integrase inhibitors (INIs).

VOCABRIA TABLETS do not cure HIV infection; they keep the amount of virus in your body at a low level. This helps maintain the number of CD4+ cells in your blood. CD4+ cells are a type of white blood cell that are important in helping your body to fight infection.

VOCABRIA TABLETS are always given in combination with another antiretroviral medicine called rilpivirine to treat HIV infection. To control your HIV infection, and to stop your illness from getting worse, you must keep taking all your medicines, unless your doctor tells you to stop taking them.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

There is not enough information to recommend the use of this medicine for children and adolescents under the age of 18 years.

VOCABRIA TABLETS are not addictive.

This medicine is available only with a doctor's prescription

Before you take VOCABRIA TABLETS

When you must not take it

Do not take VOCABRIA TABLETS if you have an allergy to:

any medicine containing cabotegravir
any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

rash, itching or hives on the skin
high temperature (fever)
lack of energy (fatigue)
swelling of the face, lips, tongue or other parts of the body
wheezing or difficulty breathing
shortness of breath
muscle or joint aches

Do not take VOCABRIA TABLETS if you are taking any of these medicines:

rifampicin or rifapentine (to treat some bacterial infections such as tuberculosis)
phenytoin, phenobarbital, carbamazepine or oxcarbazepine (also known as anticonvulsants used to treat epilepsy and prevent seizures)

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Some other conditions may develop during HIV treatment.

Symptoms of infection and inflammation

People with advanced HIV infection (AIDS) have weak immune systems, and are more likely to develop serious infections (opportunistic infections). When they start treatment, the immune system becomes stronger, so the body starts to fight infections.

Symptoms of infection and inflammation may develop, caused by either:

old, hidden infections flaring up again as the body fights them
the immune system attacking healthy body tissue (autoimmune disorders).

The symptoms of autoimmune disorders may develop many months after you start taking medicine to treat your HIV infection.

Symptoms may include:

muscle weakness and/or muscle pain
joint pain or swelling
weakness beginning in the hands feet and moving towards the trunk of the body
palpitations or tremor
hyperactivity (excessive restlessness and movement).

If you get any symptoms of infection or if you notice any of the symptoms above tell your doctor immediately. Don’t take other medicines for the infection without your doctors' advice.

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

liver problems.

Signs of liver problems include yellowing of the skin and the whites of eyes, loss of appetite, itching tenderness of the stomach, light coloured stools or unusually dark urine

Your liver function will be monitored by your doctor during treatment with VOCABRIA TABLETS.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits, to you and your baby, of receiving VOCABRIA TABLETS while pregnant.

Where possible, women who are HIV-positive should not breast feed, because HIV infection can be passed on to the baby in breast milk.

It is not known whether the ingredients of VOCABRIA TABLETS can pass into breast milk and harm your baby.

If you have not told your doctor about any of the above, tell him/ her before you start taking VOCABRIA TABLETS.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and VOCABRIA TABLETS may interfere with each other. These include:

carbamazepine, oxcarbazepine, phenobarbital, or phenytoin (also known as anticonvulsants used to treat epilepsy and prevent seizures)
rifampicin or rifapentine (to treat some bacterial infections such as tuberculosis)
rifabutin (to treat some bacterial infections such as tuberculosis)
medicines call antacids to treat indigestion and heartburn.
medicines for the treatment of hepatitis C.

These medicines may be affected by VOCABRIA TABLETS or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take VOCABRIA TABLETS

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

As VOCABRIA TABLETS must always be taken with another HIV medicine (rilpivirine), you should also follow the instructions for rilpivirine carefully.

If you do not understand the instructions on the bottle, ask your doctor or pharmacist for help.

How much to take

The usual dose of VOCABRIA TABLETS is one tablet (30 mg cabotegravir) taken once a day for one month (or at least 28 days).

VOCABRIA TABLETS are always given with another HIV medicine called rilpivirine 25 mg tablets.

VOCABRIA TABLETS and rilpivirine tablets are taken for one month (oral lead-in) before you receive cabotegravir injection and rilpivirine injection, to allow your doctor to test how well you tolerate these medicines.

How to take it

VOCABRIA TABLETS should be swallowed whole with some liquid. VOCABRIA TABLETS can be taken with or without food, however, if you take VOCABRIA TABLETS at the same time as rilpivirine tablets, you must take them with a meal.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

If you need to take an antacid, take it at least 2 hours before or 4 hours after you take your VOCABRIA TABLET.

How long to take it

Initial treatment with VOCABRIA TABLETS
When you first start treatment, your doctor will advise you to take one VOCABRIA TABLET together with one rilpivirine tablet, once a day, for one month (lead-in period) before you start your first cabotegravir injection.

If you miss your monthly cabotegravir injection
If you are not able to receive your monthly cabotegravir injection, your doctor may recommend you instead take one VOCABRIA TABLET with one rilpivirine tablet, until you can receive the injections again.

Continue taking your medicine for as long as your doctor tells you. Don't stop unless your doctor advises you to.

If you forget to take it

If you miss a dose, take it as soon as you remember. Then continue your treatment as before.

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too many VOCABRIA TABLETS. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using VOCABRIA TABLETS

Things you must do

You will need regular blood tests
For as long as you're taking VOCABRIA TABLETS, your doctor will arrange regular blood tests to check for side effects.
Stay in regular contact with your doctor
VOCABRIA TABLETS help to control your condition, but it is not a cure for HIV infection. You need to keep taking it every day to stop your illness from getting worse. Because VOCABRIA TABLETS do not cure HIV infection, you may still develop other infections and illnesses linked to HIV infection.
Keep in contact with your doctor, and don't stop taking VOCABRIA TABLETS without your doctor's advice.
Protect other people
HIV infection is spread by sexual contact with someone who has the infection, or by transfer of infected blood (for example, by sharing injection needles). VOCABRIA TABLETS will not stop you passing HIV infection on to other people. To protect other people from becoming infected with HIV:
- Use a condom when you have oral or penetrative sex.
- Don't risk blood transfer - for example, don't share needles

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking VOCABRIA TABLETS.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not take VOCABRIA TABLETS to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

VOCABRIA TABLETS can make you dizzy and have other side effects that make you less alert.

Don't drive or operate machinery unless you are sure you are not affected.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking VOCABRIA TABLETS.

This medicine helps most people with HIV, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

When you're being treated for HIV, it can be hard to tell whether a symptom is a side effect of VOCABRIA TABLETS or other medicines you are taking, or an effect of the HIV disease itself. So it is very important to talk to your doctor about any changes in your health.

Some side effects may only be seen in your blood tests, and may not appear immediately after you start taking VOCABRIA TABLETS. If you get any of these effects, and if they are severe, your doctor may advise you to stop taking VOCABRIA TABLETS.

As well as the effects listed below for VOCABRIA TABLETS, other conditions can develop during combination therapy for HIV.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Very common side effects
These may affect more than 1 in 10 people:

headache
feeling hot (pyrexia)

Common side effects
These may affect up to 1 in 10 people:

depression (feelings of deep sadness and unworthiness)
anxiety
abnormal dreams
difficulty in sleeping (insomnia)
dizziness
feeling sick (nausea)
being sick (vomiting)
stomach (abdominal) pain or discomfort
wind (flatulence)
diarrhoea
rash
muscle pain (myalgia)
lack of energy (fatigue)
feeling weak (asthenia)
generally feeling unwell (malaise)

Uncommon side effects
These may affect up to 1 in 100 people:

feeling drowsy (somnolence)
liver damage
weight gain
changes in liver blood tests

Other side effects that may show up in blood tests
Other side effects have occurred in some people but their exact frequency is unknown:

increase in bilirubin (a substance produced by the liver) in the blood
an increase in lipase (an enzyme produced by the pancreas).
an increase in the level of enzymes produced in the muscles (creatine phosphokinase, creatinine)

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using VOCABRIA TABLETS

Storage

Keep your tablets in the bottle until it is time to take them. If you take the tablets out of the bottle they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store VOCABRIA TABLETS or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

VOCABRIA TABLETS are white, oval, film-coated tablets, debossed with 'SV CTV' on one side.

Ingredients

The active ingredient in VOCABRIA TABLETS is cabotegravir (as cabotegravir sodium). Each tablet contains 30 mg cabotegravir.

The other ingredients are:

lactose monohydrate
microcrystalline cellulose
hypromellose
sodium starch glycolate
magnesium stearate
hypromellose
titanium dioxide
macrogol

Supplier

VOCABRIA TABLETS is supplied in Australia by:

ViiV Healthcare Pty Ltd
Level 4, 436 Johnston Street
Abbotsford, VIC 3067
Australia

AUST R 323721.

Trade marks are owned by or licenced to the ViiV Healthcare group of companies.

This leaflet was prepared on 29 June 2021.

Version 2.0

Published by MIMS January 2022

BRAND INFORMATION

Brand name

Vocabria

Active ingredient

Cabotegravir

Schedule

1 Name of Medicine

Cabotegravir (as cabotegravir sodium).

2 Qualitative and Quantitative Composition

Vocabria tablet contains 30 mg cabotegravir (as cabotegravir sodium).
Cabotegravir is a white to almost white solid.

List of excipients with known effect.

Vocabria tablets contain lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Vocabria tablets are white, oval, film-coated, tablets, debossed with 'SV CTV' on one side.

4 Clinical Particulars

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) and have no known or suspected resistance to either cabotegravir or rilpivirine (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials) for:
oral lead in to assess tolerability of cabotegravir prior to administration of cabotegravir prolonged-release suspension for injection plus rilpivirine prolonged-release suspension for injection;
oral therapy for adults who will miss planned dosing with cabotegravir prolonged-release suspension for injection.

4.2 Dose and Method of Administration

Vocabria should be prescribed by a physician experienced in the management of HIV infection.
Vocabria is indicated for the treatment of HIV-1 in combination with rilpivirine, therefore, the product information for rilpivirine should be consulted for recommended dosing.
Prior to starting Vocabria tablets, healthcare professionals should carefully select patients who agree to the required injection schedule and counsel patients about the importance of adherence to scheduled dosing visits to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance with missed doses.

Adults.

The healthcare provider and patient may proceed directly to cabotegravir and rilpivirine prolonged-release suspension injections, Cabenuva. Alternatively, cabotegravir and rilpivirine oral tablets may be used as an optional oral lead-in prior to the initiation of cabotegravir and rilpivirine injections to assess tolerability to cabotegravir and rilpivirine (see Table 1).
Optional oral lead-in dosing. When used for oral lead-in, Vocabria tablets are recommended for approximately one month (at least 28 days) in virologically suppressed patients prior to the initiation of cabotegravir injections, a component of Cabenuva (cabotegravir and rilpivirine prolonged release suspensions for injection), to assess tolerability to cabotegravir. One Vocabria tablet (30 mg) should be taken together with one rilpivirine tablet (25 mg) once daily.

The final oral dose should be taken on the same day injections with Cabenuva are started.

Missed doses.

Missed Vocabria film-coated tablet. If a patient misses an oral dose of Vocabria, the patient should take the missed dose as soon as possible.
Oral dosing for missed injections of Cabenuva.

Missed monthly injection.

If a deviation of more than 7 days from a scheduled injection visit cannot be avoided, oral therapy (one Vocabria tablet [30 mg] and one rilpivirine tablet [25 mg] 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 dose of cabotegravir or rilpivirine. Injection dosing should be resumed on the day oral dosing completes. Refer to Cabenuva product information for injection dosing recommendations after missed injections or oral therapy for patients on monthly injection dosing.

Missed 2 month injection.

If a deviation of more than 7 days from a scheduled injection visit cannot be avoided, oral therapy (one Vocabria tablet [30 mg] and one rilpivirine tablet [25 mg] 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 two months (± 7 days) after the last injection dose of cabotegravir or rilpivirine. Injection dosing should be resumed on the day oral dosing completes. Refer to Cabenuva product information for injection dosing recommendations after missed injections or oral therapy for patients on every 2-month injection dosing.

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 Pharmacokinetic Properties, Special patient populations).

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 Pharmacokinetic Properties, Special patient populations).

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 Pharmacokinetic Properties, Special patient populations).

Paediatric and adolescent population.

The safety and efficacy of Vocabria in children and adolescents aged under 18 years has not been established.

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

Vocabria is contraindicated in patients:
with known hypersensitivity to cabotegravir or to any of the excipients listed in Section 6.1;
receiving rifampicin, rifapentine, phenytoin, phenobarbital carbamazepine and oxcarbazepine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Vocabria is only indicated for treatment of HIV-1 in combination with rilpivirine, therefore, the prescribing information for rilpivirine should also be consulted.

4.4 Special Warnings and Precautions for Use

Hypersensitivity reactions.

Hypersensitivity reactions have been reported in association with integrase inhibitors. These reactions were characterised by rash, constitutional findings and sometimes organ dysfunction, including liver injury. 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 (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 5.1 Pharmacodynamic Properties).

Hepatotoxicity.

Hepatotoxicity has been reported in a limited number of patients receiving cabotegravir with or without known pre-existing hepatic disease (see Section 4.8 Adverse Effects (Undesirable Effects)).
Monitoring of liver chemistries is recommended and treatment with Vocabria should be discontinued if hepatotoxicity is suspected.

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 cabotegravir and rilpivirine when dosed monthly and no later than two months after the final injection of cabotegravir and rilpivirine when dosed every 2 months.
If virologic failure is suspected, an alternative regimen should be adopted as soon as possible.

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 Pharmacodynamic Properties).

Interactions with medicinal products.

Caution should be given to prescribing Vocabria with medicinal products that may reduce its exposure (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Opportunistic infections.

Patients receiving Vocabria or any other antiretroviral therapy 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.

Transmission of infection.

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.

Concomitant treatment with rilpivirine.

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

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special patient populations.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special patient populations.

Use in the elderly.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special patient populations.

Paediatric use.

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

Effects on laboratory tests.

Small, non-progressive increases in total bilirubin (without clinical jaundice) were observed with treatment with cabotegravir 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 cabotegravir plus rilpivirine during the clinical studies. These elevations were primarily attributed to acute viral hepatitis. A few subjects had transaminase elevations attributed to suspected drug-related hepatotoxicity.
Elevated lipases were observed during clinical trials with cabotegravir + rilpivirine; Grade 3 and 4 lipase increases occurred at a higher incidence with cabotegravir + rilpivirine compared with the CAR group. These elevations were generally asymptomatic and did not lead to discontinuation.
Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise, have also been reported with cabotegravir plus rilpivirine treatment.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Vocabria, in combination with rilpivirine, is indicated for the treatment of HIV-1, therefore, the product information for rilpivirine 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 with some contribution from 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 Contraindications).
Simulations using physiologically based pharmacokinetic (PBPK) modelling show that no clinically significant interaction is expected following co-administration of cabotegravir with medicines that inhibit UGT enzymes.
In vitro, cabotegravir was not a substrate of organic anion transporting polypeptide (OATP) 1B1, OATP1B3, OATP2B1 or organic cation transporter (OCT1).
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. 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.
Cabotegravir inhibited the organic anion transporters (OAT) 1 (IC₅₀=0.81 microM) and OAT3 (IC₅₀=0.41 microM) in vitro, however, based on PBPK modelling no interaction with OAT substrates is expected at clinically relevant concentrations.
In vitro, cabotegravir did not induce CYP1A2, CYP2B6, or CYP3A4.
Based on these data and the results of drug interaction studies, cabotegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or transporters.
Based on the in vitro and clinical drug interaction profile, cabotegravir is not expected to alter concentrations of other antiretroviral 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 2 is obtained from studies with oral cabotegravir.

4.6 Fertility, Pregnancy and Lactation

Effects on 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.
Cabotegravir when administered orally to male and female rats at 1,000 mg/kg/day (> 30 times the exposure in humans at the Maximum Recommended Human Dose [MHRD] of 30 mg oral or 400 mg intramuscular (IM) dose) for up to 26 weeks did not cause adverse effects on male or female reproductive organs or spermatogenesis. No functional effects on male or female mating or fertility were observed in rats given cabotegravir at doses up to 1,000 mg/kg/day.
(Category B1)
There are no studies of cabotegravir in pregnant women. The effect of Vocabria on human pregnancy is unknown.
Vocabria should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.
Cabotegravir has been detected in systemic circulation for up to 12 months or longer after an injection, therefore, consideration should be given to the potential for fetal exposure during pregnancy (see Section 4.4 Special Warnings and Precautions for Use).
Cabotegravir crossed the placenta in pregnant rats and could be detected in fetal tissues. Cabotegravir was not teratogenic in rats at oral doses up to 1000 mg/kg/day (> 30 times the exposure in humans at the MRHD of 30 mg oral or 400 mg IM dose) but caused a delay in delivery that was associated with reduced survival and viability of rat offspring; there was no effect on survival at birth when fetuses were delivered by caesarean section. Exposures at the NOAEL were at least 11 times the exposure in humans at the MRHD of 30 mg oral or 400 mg IM dose. The relevance to human pregnancy is unknown.
To monitor maternal-fetal outcomes of pregnant women, an Antiretroviral Pregnancy Registry has been established (http://www.apregistry.com) for cabotegravir. This is a voluntary prospective, exposure-registration, observational study designed to collect and evaluate data on the outcomes of pregnancy exposures to antiretroviral products. For rilpivirine, sufficient first trimester exposures are available to allow detection of at least a two-fold increase in risk of overall birth defects.
Health experts recommend that where possible HIV 1 infected women should not breastfeed their infants in order to avoid transmission of HIV-1. In settings where formula feeding is not feasible, local official lactation and treatment guidelines should be followed when considering breast feeding during antiretroviral therapy.
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.

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of cabotegravir on driving performance or the ability to operate machinery. The clinical status of the patient and the adverse event profile of Vocabria should be borne in mind when considering the patient's ability to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The safety assessment of Vocabria in HIV-1-infected, virologically suppressed patients is based on pooled primary Week 48 analyses of data from two international, multicenter open-label studies, FLAIR and ATLAS and one Phase IIIb international, multicentre open-label study, ATLAS-2M.
In FLAIR and ATLAS, a total of 1,182 HIV-1 infected patients were randomized to receive either a cabotegravir plus rilpivirine regimen or remain on their baseline antiretroviral regimen. Patients randomized to receive the cabotegravir plus rilpivirine regimen, initiated treatment with daily oral lead-in dosing with one 30 mg cabotegravir tablet plus one 25 mg rilpivirine tablet (Edurant) for at least 4 weeks followed by treatment with cabotegravir injection plus rilpivirine injection for at least an additional 44 weeks.
In ATLAS-2M, 1045 HIV-1 infected, ART experienced, virologically suppressed subjects were randomised and received a cabotegravir plus rilpivirine injection regimen administered either every 2 months or monthly. Subjects initially on non-CAB/RPV treatment received oral lead-in treatment comprising one cabotegravir 30 mg tablet (Vocabria) plus one rilpivirine 25 mg tablet (Edurant), daily, for at least 4 weeks. Subjects randomised to monthly cabotegravir injections and rilpivirine injections received treatment for an additional 44 weeks. Subjects randomised to every 2 month cabotegravir injections and rilpivirine injections received treatment for an additional 44 weeks.

Adverse events.

The adverse events listed in Table 3 include subjects who received oral cabotegravir and rilpivirine and cabotegravir plus rilpivirine injections. For many of the adverse events listed in Table 3, it is unclear whether they are related to the active substance, route of administration (oral vs injection), the wide range of other medicinal products used in the management of HIV infection, or whether they are a result of the underlying disease process.
The most common adverse events reported in > 10% of subjects in the group that received Vocabria in the FLAIR and ATLAS studies were injection site pain, nasopharyngitis, upper respiratory tract infection, headache, diarrhoea, injection site nodule and injection site induration.

Adverse events leading to discontinuation and occurring in more than 1 subject were injection site reactions, hepatitis A, acute hepatitis B, headache, and diarrhea which occurred with an incidence of ≤ 1%. The incidence of serious adverse events was 5% in subjects receiving cabotegravir plus rilpivirine and 4% for subjects remaining on current antiretroviral therapy.

Adverse drug reactions.

ADRs are adverse events that are considered to be reasonably associated with the use of a drug based on the comprehensive assessment of the available adverse event information. A causal relationship cannot be reliably established in individual cases.
Adverse drug reactions for cabotegravir plus rilpivirine were identified from pivotal Phase III clinical studies (FLAIR and ATLAS) based on an analysis of pooled data (N=591) and ATLAS-2M at Week 48.
Cabotegravir plus rilpivirine were administered as a combination regimen (monthly and every 2 month dosing) and associated adverse reactions are listed in Table 4.
Adverse drug reactions listed include those attributable to both the oral and injectable formulations of cabotegravir and rilpivirine. When frequencies differed between phase III studies, the highest frequency category is quoted in Table 4.
The most frequently reported adverse drug reactions from monthly dosing studies were headache (up to 12%) and pyrexia³ (10%).
The most frequently reported adverse drug reactions from ATLAS-2M every 2 month dosing were headache (7%) and pyrexia³ (7%).
The adverse reactions considered at least possibly related to cabotegravir are listed in Table 4 and Table 5 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), including isolated reports.

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 prolonged-release suspension for injection plus RPV prolonged-release suspension for injection regimen with direct to injection did not identify any new safety concerns related to omitting the oral lead-in phase (see Section 5.1 Pharmacodynamic Properties).
The overall safety profile at Week 152 in the ATLAS-2M study was consistent with that observed at Week 48 and Week 96, with no new safety findings identified.

Description of selected adverse reactions.

Weight increased.

At the Week 48 time point, subjects in the FLAIR and ATLAS studies, who received cabotegravir plus rilpivirine gained a median of 1.5 kg in weight; those in the current antiretroviral therapy (CAR) group gained a median of 1.0 kg (pooled analysis). In the individual FLAIR and ATLAS studies, the median weight gains in the cabotegravir plus rilpivirine group were 1.3 kg and 1.8 kg respectively, compared to 1.5 kg and 0.3 kg in the CAR group. At the 48 week timepoint, in ATLAS-2M the median weight gain in both the monthly and 2-monthly cabotegravir plus rilpivirine dosing arms was 1.0 kg.

Post-marketing data.

See Table 5.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is currently no experience with overdosage of Vocabria.
There is no specific treatment for overdose with Vocabria. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
Cabotegravir is known to be highly protein bound in plasma; therefore, dialysis is unlikely to be helpful in removal of cabotegravir from the body. Management of overdose with cabotegravir injection should take into consideration the prolonged exposure to the medicine following an injection (see Section 4.4 Special Warnings and Precautions for Use).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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 nanoM in peripheral blood mononuclear cells (PBMCs), 0.74 nanoM in 293T cells and 0.57 nanoM 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 nanoM to 1.06 nanoM for HIV-1. Cabotegravir EC₅₀ values against three HIV-2 clinical isolates ranged from 0.10 nanoM to 0.14 nanoM. No clinical data is available in patients with HIV-2.

Antiviral activity in combination with other medicinal products.

In in vitro combination studies, cabotegravir had weak synergistic antiviral effects with nucleoside reverse transcriptase inhibitors (lamivudine, tenofovir disoproxil fumarate, emtricitabine) and additive effects with the non-nucleoside reverse transcriptase inhibitor, rilpivirine.

Effect of human serum and serum proteins.

In vitro studies suggested a 660 fold shift in IC₅₀ of cabotegravir in the presence of 100% human serum (by method of extrapolation), and the protein adjusted IC₅₀ (PA-IC₅₀) was estimated to be < 1.1 microM.

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 range 1.3-4.6), S153Y (fold-change range 2.8-8.4), and I162M (fold-change = 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 nanoM of cabotegravir through Day 56.
Among the known integrase resistant mutants tested, mild resistance (≥ 5-fold but < 10-fold resistance) was seen with E92Q/N155H, G118R, G140S/Q148H, Y143H/N155H, Q148K, Q148R, T66K/L74M and G140S/Q148K. High resistance (≥ 10-fold resistance) was seen with E138K/Q148K, V72I/E138K/Q148K, E138K/Q148R, E138K/G140S/Q148R, L74M/V75A/G140S/Q148H, G140C/Q148R, Q148R/N155H and G140S/Q148R.

Resistance in vivo.

The number of subjects who met Confirmed Virologic Failure (CVF) criteria was low across the pooled FLAIR and ATLAS studies. 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 3 CVFs on cabotegravir plus rilpivirine in FLAIR with resistance data had Subtype A1 with IN substitution L74I (which by itself does not cause resistance to any INI) detected at baseline and suspected virologic failure (SVF). In addition, 2 of the 3 CVFs had treatment-emergent integrase inhibitor resistance associated substitution Q148R while 1 of the 3 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 2 of the 3 showed reduced phenotypic susceptibility to rilpivirine. The 3 CVFs in ATLAS had subtype A, A1 and AG. The 2 CVFs with subtype A and A1 both carried IN substitution L74I in baseline PBMC HIV-1 DNA and at SVF in HIV-1 RNA. In addition, 1 of the 3 CVFs carried the INI resistance-associated substitution N155H at SVF. All 3 CVFs had treatment-emergent rilpivirine resistance-associated substitution: E138A, E138E/K or E138K, and showed reduced phenotypic susceptibility to rilpivirine while 1 of the 3 also showed reduced phenotypic susceptibility to cabotegravir. In 2 of these 3 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 studies 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 every 2 month dose arm and 2 subjects (0.4%) in the monthly dose arm. Eight subjects met CVF criteria at or before the Week 24 timepoint. At SVF, the 10 CVFs had HIV-1 subtype A (n=2), A1 (n=2), B (n=4), C (n=1) or Complex (n=1).
At baseline in the every 2 month dose arm, 5 subjects had RPV 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 RPV resistance-associated mutation). At the SVF timepoint in the every 2 month dose 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 fold-change (FC) was above the biological 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 (2); Q148R; Q148Q/R+N155N/H (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. Fold-changes 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 monthly dose arm, neither subject had any RPV 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 RPV. Both subjects also had INSTI resistance-associated mutations, either Q148R + E138E/K or N155N/H at SVF and 1 subject had reduced susceptibility to CAB. Neither subject had the INSTI substitution, L74I. Fold-changes 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.

Effects on electrocardiogram.

In a randomised, placebo-controlled, three-period cross-over trial, 42 healthy subjects were randomised into 6 random sequences and received three doses of oral administration of placebo, cabotegravir 150 mg every 12 hours (mean steady state C_max was approximately 2.8-fold, 5.4-fold and 5.6 fold above the 30 mg once-daily dose, the 400 mg cabotegravir injection monthly dose and the 600 mg cabotegravir injection every 2 month dose, respectively, and single dose of moxifloxacin 400 mg (active control). After baseline and placebo adjustment, the maximum time-matched mean QTc change based on Fridericia's correction method (QTcF) for cabotegravir was 2.62 msec (1-side 90% upper CI:5.26 msec). Cabotegravir did not prolong the QTc interval over 24 hours post-dose.

Clinical trials.

Monthly dosing. 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 (201584) and ATLAS (201585). The primary analysis was conducted after all subjects completed their Week 48 visit or discontinued the study prematurely.
In FLAIR, 629 HIV-1-infected, antiretroviral treatment (ART)-naïve 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 cabotegravir plus rilpivirine regimen or remain on the current antiretroviral (CAR) regimen. Subjects randomised to receive the cabotegravir plus rilpivirine regimen, initiated treatment with oral lead-in dosing with Vocabria 30 mg tablets plus rilpivirine 25 mg tablets, daily, for at least 4 weeks, followed by treatment 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 month, for an additional 44 weeks.
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 cabotegravir plus rilpivirine regimen or remained on the CAR regimen. Subjects randomised to receive the cabotegravir plus rilpivirine regimen, initiated treatment with oral lead-in dosing with Vocabria 30 mg tablets plus rilpivirine 25 mg tablets, daily, for at least 4 weeks, followed by treatment with cabotegravir injection (month 1: 600 mg, month 2 onwards: 400 mg injection) plus rilpivirine injection (month 1: 900 mg injection, month 2 onwards: 600 mg injection), 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.
At baseline, in the pooled analysis, for the cabotegravir plus rilpivirine arm, the median age of subjects was 38 years, 27% were female, 27% were non-white, 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, cabotegravir 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 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% CI below 4%). Furthermore, in the pooled analysis, cabotegravir plus rilpivirine was non-inferior to CAR on the proportion of subjects having plasma HIV-1 RNA < 50 c/mL (93.1% and 94.4%, respectively) at Week 48. The adjusted treatment difference between cabotegravir plus rilpivirine and CAR (-1.4; 95% CI: 4.1, 1.4) for the pooled analysis met the non-inferiority criteria (lower bound of the 95% CI greater than -10%. [See Table 6]).
The non-inferiority result established in FLAIR and ATLAS demonstrated that the length of HIV-1 RNA virologic suppression prior to initiation of cabotegravir plus rilpivirine (i.e. < 6 months or ≥ 6 months) did not impact overall response rates.
The primary endpoint and other week 48 outcomes, including outcomes by key baseline factors, for FLAIR and ATLAS are shown in Tables 6 and 7.

In both the FLAIR and ATLAS studies, treatment differences across baseline characteristics (CD4+ count, gender, age, race, BMI, baseline third agent treatment class) were comparable.
Subjects in both FLAIR and ATLAS were virologically suppressed prior to Day 1 or study entry, respectively, and a clinically relevant change from baseline in CD4+ cell counts was not observed.

Week 96 FLAIR.

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 cabotegravir plus rilpivirine (n=283) and CAR (n=283) was 3.2% and 3.2% respectively (adjusted treatment difference between cabotegravir 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 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.

In the FLAIR study, an evaluation of safety and efficacy was performed at Week 124 for patients electing to switch (at Week 100) from ABC/DTG/3TC to CAB + RPV in the Extension Phase, with and without an oral lead-in phase, creating an oral lead-in (OLI) group and a direct to injection (DTI) group.
At Week 124, rates of virologic suppression (HIV-1 RNA < 50 c/mL) were similar in both DTI (110/111 [99.1%]) and OLI groups (113/121 [93.4%]). Initiating the CAB LA + RPV LA regimen with DTI did not identify any new safety concerns related to omitting the OLI phase.
Every 2 month dosing. 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 or discontinued the study prematurely.
In ATLAS-2M, 1045 HIV-1 infected, ART experienced, virologically suppressed subjects were randomised (1:1) and received a cabotegravir plus rilpivirine injection regimen administered either every 2 months or monthly. Subjects initially on non-cabotegravir plus rilpivirine treatment received oral lead-in treatment comprising one cabotegravir 30 mg tablet plus one rilpivirine 25 mg tablet, daily, for at 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 2 onwards: 600 mg injection administered) received treatment for an additional 44 weeks. Subjects randomised to every 2 month cabotegravir 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) for an additional 44 weeks. Prior to randomisation, 63%, 13% and 24% of subjects received 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 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, cabotegravir + rilpivirine administered every 2 months was non-inferior to cabotegravir 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 cabotegravir + 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%). Furthermore, cabotegravir + rilpivirine dosed every 2 months was non-inferior to cabotegravir plus rilpivirine dosed every month on the proportion of subjects having plasma HIV-1 RNA < 50 c/mL (94% and 93%, respectively) at Week 48. The adjusted treatment difference between cabotegravir + rilpivirine dosed every 2 months and monthly (0.8; 95% CI: -2.1, 3.7) met the non-inferiority criteria (lower bound of the 95% CI greater than -10%. [See Table 8]).

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 (see Table 9).

Week 96 ATLAS-2M.

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 cabotegravir and rilpivirine administered every month. The proportion of subjects having plasma HIV-1 RNA ≥ 50 c/mL at Week 96 in cabotegravir plus rilpivirine every 2 months dosing (n=522) and cabotegravir plus rilpivirine monthly dosing (n=523) was 2.1% and 1.1% respectively (adjusted treatment difference between 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 cabotegravir plus rilpivirine every 2 months dosing and cabotegravir plus rilpivirine monthly dosing was 91% and 90.2% respectively (adjusted treatment difference between cabotegravir plus rilpivirine every 2 months dosing and monthly dosing [0.8; 95% CI: -2.8, 4.3]).

Week 152 ATLAS-2M.

The efficacy results at Week 152 are consistent with the results of the primary endpoint at Week 48 and at Week 96. Cabotegravir plus rilpivirine injections administered every 2 months is non-inferior to cabotegravir and rilpivirine administered every month. In an ITT analysis, the proportion of subjects having plasma HIV-1 RNA ≥ 50 c/mL at Week 152 in cabotegravir plus rilpivirine every 2 months dosing (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 months dosing and monthly dosing [1.7; 95% CI: 0.1, 3.3]). In an ITT analysis, the proportion of subjects having plasma HIV-1 RNA < 50 c/mL at Week 152 in cabotegravir plus rilpivirine every 2 months dosing and cabotegravir plus rilpivirine monthly dosing was 87% and 86% respectively (adjusted treatment 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 124 weeks 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 and dosing regimen and post-baseline predicted plasma drug concentrations on confirmed virologic failure (CVF) using regression modelling with a variable selection procedure. Following a total of 4291 person-years, the unadjusted CVF incidence rate was 0.54 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=0.014) was associated with CVF. Other variables including Q4W or Q8W dosing, female gender, or CAB/INSTI resistance mutations had no significant association with CVF. A combination of at least 2 of the following key baseline factors was associated with an increased risk of CVF: rilpivirine resistance mutations, HIV-1 subtype A6/A1, or BMI ≥ 30 mg/m² (see Table 10).

In the MVA five covariates were significantly associated (P < 0.05 for each adjusted incidence rate ratio) with increased risk of CVF: rilpivirine resistance mutations at baseline identified by proviral DNA genotypic assay, HIV-1 subtype A6/A1, predicted cabotegravir trough concentration 4 weeks following initial injection dose, and predicted cabotegravir/rilpivirine trough concentrations at injection week 44. Similar to the BFA results, a combination of these factors was associated with an increased risk of CVF.

Patient reported outcomes.

Patient reported outcomes were assessed by several distinct measures.
Treatment satisfaction significantly improved in the cabotegravir and rilpivirine injections group compared with daily oral antiretroviral therapy (CART) group (mean difference [95% CI] in HIV Treatment Satisfaction Questionnaire (HIVTSQs) at weeks 24 and 44 was 3.9 [3.0, 4.7] (p < 0.001) and 3.3 [2.5, 4.2] (p < 0.001) respectively, in the pooled ATLAS and FLAIR analysis). Key items driving this difference were "satisfaction to continue with treatment" as well as "flexibility" and "convenience".
Treatment acceptance also significantly improved in the cabotegravir and rilpivirine injections group compared with CART group (mean difference [95% CI] in ACCEPT General Dimension at weeks 24 and 44 was 4.9 [2.4, 7.5] (p < 0.01) and 6.8 [4.3, 9.4] (p < 0.001) respectively, in the pooled ATLAS and FLAIR analysis). Items were assessing acceptability based on advantages and disadvantages of treatment option.
Acceptability of injection site reactions (including pain) significantly improved from Week 5 (2.09 points) to weeks 24 (1.66 points; p < 0.001) and 48 (1.61 points; p < 0.001) in a pooled ATLAS and FLAIR analysis for participants in the cabotegravir and rilpivirine injections group according to "Acceptability of ISRs" dimension of Perception of Injection Questionnaire (PIN) (adapted from the Vaccinees' Perception of Injection (VAPI) Questionnaire) with 86% and 84% of participants in ATLAS and FLAIR finding pain following injections as "totally" or "very acceptable" at week 48.
According to the three dimensions of the HIV/AIDS Targeted Quality of Life (HAT-QoL) included in the study, "medication concerns" significantly improved in the cabotegravir and rilpivirine injections group compared with CART (mean difference [95% CI] at weeks 24 and 48 was 3.4 [1.9, 4.9] (p < 0.001) and 3.5 [1.8, 5.2] (p < 0.001), respectively, in the pooled ATLAS and FLAIR analysis) mostly driven by the improvement in "treatment burden" scores. "Life satisfaction" and HIV "disclosure worries" showed no significant difference between treatment groups, indicating no impact of either treatment options on those concepts.
SF-12 mental and physical component scores showed no significant difference in change from baseline between treatment groups at weeks 24 and 48, which indicates no improvement or worsening in mental or physical health status of participants in both groups.

5.2 Pharmacokinetic Properties

Cabotegravir pharmacokinetics is similar between healthy and HIV-infected subjects. The PK variability of cabotegravir is moderate. In Phase I studies in healthy subjects, between-subject CVb% for AUC, C_max, and C_tau 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-subject variability. See Table 11.

Absorption.

Cabotegravir is rapidly absorbed following oral administration, with median T_max at 3 hours post dose for the tablet formulation. The linearity of cabotegravir pharmacokinetics is dependent on dose and formulation. Following oral administration of tablet formulations, cabotegravir pharmacokinetics was dose-proportional to slightly less than proportional to dose from 5 mg to 60 mg. 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 of cabotegravir. Bioavailability of cabotegravir is independent of meal content: high fat meals increased cabotegravir AUC_(0-∞) by 14% and increased C_max by 14% relative to fasted conditions. These increases are not clinically significant.
The absolute bioavailability of cabotegravir has not been established.

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 (0.002 to 0.004), one week following a steady-state cabotegravir (monthly dose or every 2 month dose) 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.

Metabolism.

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).

Excretion.

Cabotegravir has a mean terminal half-life of 41 h and an apparent clearance (CL/F) of 0.21 L per hour observed following oral administration in healthy subjects.

Polymorphisms in drug metabolising enzymes.

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, C_max, and C_tau following injection administration compared with subjects with genotypes associated with normal metabolism via UGT1A1. 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.