Consumer medicine information

Apretude Prolonged-Release Suspension for Injection

Cabotegravir

BRAND INFORMATION

Brand name

Apretude

Active ingredient

Cabotegravir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Apretude Prolonged-Release Suspension for Injection.

SUMMARY CMI

APRETUDE prolonged-release suspension for injection

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. What is APRETUDE and what is it used for?

APRETUDE contains the active ingredient cabotegravir, which belongs to a group of antiretroviral medicines called integrase inhibitors (INIs). APRETUDE is used to reduce the risk of getting HIV infection in people weighing 35 kg or more. This is called pre-exposure prophylaxis (PrEP). For more information, see Section 1. What is APRETUDE and what is it used for? in the full CMI.

2. What should I know before I am given APRETUDE?

Do not use if you have ever had an allergic reaction to cabotegravir or any of the ingredients listed at the end of the CMI. Do not use unless you have had a recent HIV test to confirm you are HIV negative.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I am given APRETUDE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APRETUDE and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How APRETUDE is given to me?

  • APRETUDE will be given by a nurse or doctor through an injection in the muscle of your buttock (intramuscular injection (IM)) as a single injection once every 2 months.
  • You should be given APRETUDE for as long as your doctor recommends. Do not stop unless your doctor advises you to.

More instructions can be found in Section 4. How APRETUDE is given to me? in the full CMI.

5. What should I know while being given APRETUDE?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using APRETUDE.
  • Attend your planned appointments to receive your APRETUDE injection.
  • Get tested for HIV every 2-3 months
Things you should not do
  • Do not miss your planned appointments to receive your APRETUDE injection. Missing your dose may increase you risk of getting HIV infection.
Driving and using machines
  • APRETUDE can make you dizzy and have other side effects that make you less alert.
  • Do not drive or use machines unless you are sure you are not affected.
Looking after your medicine
  • APRETUDE injection will be given to you by a nurse or doctor who will be responsible for its storage.
  • APRETUDE injection should be kept in the pack until it is time to use it. It should be stored below 30°C.

For more information, see Section 5. What should I know while being given APRETUDE? in the full CMI.

6. Are there any side effects?

The following very common side effects may occur when using APRETUDE: headache, diarrhoea, injection site reactions, fever. Contact your doctor promptly if you develop an allergic reaction or if you have liver problems.

Whilst very rare, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious and life-threatening. Contact your doctor straight away if you develop painful red or purple skin, blisters on your skin, mouth, nose and genitals and red, painful, watery eyes.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

APRETUDE prolonged-release suspension for injection

Active ingredient: cabotegravir

Consumer Medicine Information (CMI)

This leaflet provides important information about being given APRETUDE injection. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using APRETUDE.

Where to find information in this leaflet:

1. What is APRETUDE and what it is used for?
2. What should I know before I am given APRETUDE?
3. What if I am taking other medicines?
4. How APRETUDE is given to me?
5. What should I know while using APRETUDE?
6. Are there any side effects?
7. Product details

1. What is APRETUDE and what is it used for?

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

APRETUDE is used to reduce the risk of getting HIV infection in people weighing 35 kg or more. This is called pre-exposure prophylaxis (PrEP).

2. What should I know before I am given APRETUDE?

Warnings

You must not be given APRETUDE:

  • if you are allergic to cabotegravir, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can be given this medicine.
  • if you are taking any of these medicines as they may affect the way APRETUDE works: 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).
  • unless you have had a recent HIV test to confirm you are HIV negative. APRETUDE can only help reduce your risk of getting HIV before you are infected so, you must get tested to make sure you don't already have HIV infection before taking APRETUDE.

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

If you are pregnant, or think you could be, or if you are planning to have a baby, don't receive APRETUDE injections without checking with your doctor. Your doctor will consider the benefit to you and the risk to your baby of receiving APRETUDE while you are pregnant.

If you are planning to have a baby, talk to your doctor in advance, as APRETUDE injection can stay in your system for up to 12 months or longer after the last injection of APRETUDE.

If you are thinking about breast-feeding, check with your doctor who will consider the benefit and risk to you and your baby.

It is not known whether the ingredients of APRETUDE can pass into breast milk and harm your baby. APRETUDE may still pass into breast milk for 12 months after the last injection of APRETUDE.

Allergic reaction

  • APRETUDE contains cabotegravir, which is an integrase inhibitor. Other integrase inhibitors can cause a serious allergic reaction known as a hypersensitivity reaction. You need to know about important signs and symptoms to look out for while you're receiving APRETUDE. See additional information under Section 6. Are there any side effects?

You must not be given APRETUDE injection after the expiry date shown on the pack.

3. What if I am taking other medicines?

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

Some medicines may interfere with APRETUDE and affect how it works or make it more likely that you will have side effects. APRETUDE can also affect how some other medicines work.

You must not be given APRETUDE with these medicines:

  • 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).

Tell your doctor if you are taking any of the medicines in the following list:

  • rifabutin (to treat some bacterial infections such as tuberculosis). You may need to receive APRETUDE injections more often.

Tell your doctor or pharmacist if you are taking any of these. Your doctor may decide you need extra check-ups.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect APRETUDE.

4. How APRETUDE is given to me?

How much is given

When you first start PrEP with APRETUDE, you and your doctor may decide to either:

  • start PrEP directly with APRETUDE injection.
    Or
  • start PrEP with APRETUDE tablets. If you start with APRETUDE tablets, the doctor will advise you to:
    - take one 30 mg APRETUDE tablet once a day, for approximately one month, then receive injections every 2 months.
    - Your first injection should preferably be on the same day as your last tablet or no later than 3 days after.

This first month of tablets is called the oral lead-in period. It allows your doctor to assess whether it's appropriate to proceed with injections.

When APRETUDE is given

  • You will be given APRETUDE as a single injection once every 2 months.

Injection Schedule for every 2 month dosing

Which medicineWhen
 First and second injections one month apartThird injection onwards, every two months.
APRETUDE3 mL (600 mg)3 mL (600 mg)

How APRETUDE is given

  • A nurse or doctor will give you APRETUDE through an injection in the muscle of your buttock (intramuscular injection [IM]).

If you miss an APRETUDE injection

Contact your doctor immediately to make a new appointment

It is important that you keep your regular planned appointments to receive your APRETUDE injection to reduce the risk of getting HIV. Talk to your doctor if you are thinking about stopping APRETUDE.

Talk to your doctor if you think you will not be able to receive your APRETUDE injection at the usual time. Your doctor may recommend you take APRETUDE tablets instead, until you are able to receive an APRETUDE injection again.

If you are given too much APRETUDE

A doctor or nurse will give this medicine to you, so it is unlikely that you will be given too much. If you are worried, tell the doctor or nurse.

Do not stop receiving APRETUDE injections without advice from your doctor.

You should be given APRETUDE for as long as your doctor recommends. Don't stop unless your doctor advises you to. If you miss an appointment to receive your injection, contact your doctor right away to make a new appointment.

5. What should I know while being given APRETUDE?

Things you should do

  • It is important that you attend your planned appointments to receive your APRETUDE injections. Talk to your doctor if you are thinking about stopping injections as this may increase your risk of getting HIV infection. If you do stop or are late receiving your APRETUDE injections, you will need to take other medicines or precautions to reduce your risk of getting HIV and possibly developing viral resistance.
  • Get tested for HIV every 2-3 months.

Call your doctor straight away if you:

  • think you were infected with HIV (you may get a flu-like illness). They may want to do more tests to make sure you are still HIV negative.

Remind any doctor, dentist or pharmacist you visit that you are using APRETUDE.

Things you should not do

  • Do not stop or be late receiving your APRETUDE injection. APRETUDE injection is a long-acting medication, so if you stop, cabotegravir will remain in your system for up to a year or more after your last injection. It is important that you attend your planned appointments to receive APRETUDE injection and talk to your doctor if you are thinking about stopping PrEP. You may need to take other medicines to reduce the risk of getting HIV infection or use other safe sex precautions if you stop APRETUDE injections.

Just receiving APRETUDE may not stop you getting HIV

You can still get HIV when taking this medicine, although APRETUDE lowers the risk. HIV infection is spread by sexual contact with someone who has the infection or by transfer of infected blood. To reduce your risk of getting HIV:

  • use a condom when you have oral or penetrative sex
  • Do no risk blood transfer, do not share needles.

Discuss with your doctor the additional precautions needed to further decrease the risk of getting HIV.

Liver problems

Let your doctor know if you have 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 may need to be closely monitored.

You may need regular blood tests

While you are using APRETUDE, your doctor may arrange regular blood tests to check for side effects. See additional information under Section 6. Are there any side effects?

Driving or using machines

Be careful before you drive or use any machines or tools until you know how APRETUDE affects you.

APRETUDE may cause dizziness in some people and have other side effects that make you less alert. Do not drive or use machines unless you are sure you are not affected.

Looking after your medicine

APRETUDE injection will be given to you by a doctor or a nurse who will be responsible for its storage.

APRETUDE injections should be kept in the pack until it is time to use it. It should be stored below 30°C.

Getting rid of any unwanted medicine

Your healthcare professional will be responsible for discarding APRETUDE injections..

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

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

Less serious side effects

Less serious side effectsWhat to do
Stomach or bowel problems:
Very common
  • Diarrhoea

Common

  • Feeling sick (nausea)
  • Vomiting
  • Stomach pain (abdominal pain)
  • Wind (flatulence)
General disorders:
Very common
  • Headache

Common

  • Depression
  • Abnormal dreams
  • Difficulty in sleeping (insomnia)
  • Dizziness
  • Lack of energy (fatigue)
  • Generally feeling unwell (malaise)
Skin problem:
Common
  • Rash
Injection site reactions:
Very common
  • Pain & tenderness, a hardened mass or lump

Common

  • Redness, itching, swelling, warmth, numbness or bruising (which may include discolouration or a collection of blood under the skin)

Uncommon

  • An abscess (collection of pus)
Other:
Very common
  • Feeling hot (fever)

Common

  • Muscle pain (myalgia)

Uncommon

  • Weight gain
  • Feeling lightheaded, during or following an injection. This may lead to fainting
Speak to your doctor if you have any of these less serious side effects and they worry you.
Tell your doctor or pharmacist if you experience severe or troublesome reactions at the site where you are given your injection

Very common: may affect more than 1 in 10 people

Common: may affect up to 1 in 10 people

Uncommon: may affect up to 1 in 100 people

Serious side effects

Serious side effectsWhat to do
Conditions you need to look out for
Some other conditions may develop while you are taking APRETUDE:
Allergic Reaction
  • Skin rash
  • A high temperature (fever)
  • Lack of energy (fatigue)
  • Swelling, sometimes of the face or mouth (angioedema), causing difficulty in breathing
  • Muscle or joint aches
Liver problems
Very common
  • changes in liver blood tests (increase in transaminases)

Uncommon

  • liver damage (signs may include yellowing of the skin and the whites of the eyes, loss of appetite, itching, tenderness of the stomach, light-coloured stools or unusually dark urine). (hepatotoxicity)
Psychological
Uncommon
  • suicidal thoughts*
  • Suicidal attempt*
* mainly in patients who have had depression or mental health problems before.
Skin and subcutaneous tissue disorders:
Very rare
  • Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious life-threatening conditions which usually start with flu-like symptoms. A few days later other symptoms appear including:
    - painful red or purple skin that looks burned and peels off
    - blisters on your skin, mouth, nose and genitals
  • red, painful, watery eyes
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Very common: may affect more than 1 in 10 people

Common: may affect up to 1 in 10 people

Uncommon: may affect up to 1 in 100 people

Very rare: may affect up to 1 in 10,000 people

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What APRETUDE contains

Active ingredient
(main ingredient)		Cabotegravir
Other ingredients
(inactive ingredients)		mannitol
polysorbate 20
macrogol 3350
water for injections

You must not be given this medicine if you are allergic to any of these ingredients.

What APRETUDE looks like

APRETUDE prolonged-release suspension for injection is a white to light pink suspension. Each 3 mL vial contains 600 mg cabotegravir.

AUST R 377474

Who distributes APRETUDE

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

Trademarks are owned by or licensed to the ViiV Healthcare group of companies.

© 2024 ViiV Healthcare group of companies or its licensor.

This leaflet was prepared in December 2024.

Version 3.0

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Apretude

Active ingredient

Cabotegravir

Schedule

S4

 

1 Name of Medicine

Film-coated tablets: Cabotegravir (as cabotegravir sodium).
Prolonged-release suspension for injection: Cabotegravir.

2 Qualitative and Quantitative Composition

Cabotegravir is a white to almost white solid.

Film-coated tablets.

Apretude tablet contains 30 mg cabotegravir (as cabotegravir sodium).

Prolonged-release suspension for injection.

Apretude injection contains 600 mg cabotegravir (as cabotegravir free acid) in 3 mL vial.

List of excipients with known effect.

Apretude tablets contain lactose monohydrate.
Apretude injection: none
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablets.

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

Prolonged-release suspension for injection.

Apretude injection is a white to light pink suspension.

4 Clinical Particulars

4.1 Therapeutic Indications

Apretude is indicated in at-risk adults and adolescents (at least 12 years of age) and weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection.
Apretude tablets may be used as an oral lead-in to assess tolerability of cabotegravir prior to administration of cabotegravir injections or as short-term oral PrEP in individuals who will miss planned dosing with cabotegravir injections.
Individuals must have a documented negative HIV-1 test prior to initiating Apretude for HIV1 PrEP.

4.2 Dose and Method of Administration

Individuals must have had a documented negative HIV-1 test, in accordance with applicable guidelines, prior to initiating Apretude.
Prior to starting Apretude, healthcare professionals should carefully select individuals who agree to the required injection dosing schedule and counsel individuals about the importance of adherence to scheduled dosing visits to help reduce the risk of acquiring HIV1 infection (see Section 4.4 Special Warnings and Precautions for Use).

Adults, adolescents weighing at least 35 kg.

Following discussion with the individual, the physician may proceed directly to Apretude injection, (see Table 2 for dosing recommendations).
Alternatively, Apretude tablets may be used as an oral lead in prior to the initiation of Apretude injection to assess tolerability to cabotegravir (see Table 1).
Oral lead-in (film-coated tablets). When used for oral lead-in, Apretude tablets are recommended for approximately one month (at least 28 days) prior to the initiation of Apretude injection to assess tolerability to cabotegravir.
Prolonged-release suspension for injection.

Initiation injections.

The recommended initial Apretude injection dose is a single 3 mL (600 mg) intramuscular injection. If oral lead-in has been used, the first injection should be planned for the last day of oral lead-in or within 3 days thereafter.
One month later, a second 3 mL (600 mg) intramuscular injection should be administered. Individuals may be given the second 3 mL (600 mg) initiation injection up to 7 days before or after the scheduled dosing date.

Continuation injections.

After the second initiation injection, the recommended Apretude continuation injection dose is a single 3 mL (600 mg) intramuscular injection administered every 2 months. Individuals may be given injections up to 7 days before or after the scheduled dosing date.
Missed dose.

Missed Apretude film-coated tablet.

If the individual misses a dose of Apretude tablets, they should take the missed dose as soon as possible.

Missed Apretude prolonged-release suspension for injection.

Adherence to the injection dosing schedule is strongly recommended.
Individuals who miss a scheduled injection visit should be clinically reassessed and a HIV test performed to ensure resumption of PrEP remains appropriate. See Table 3 for dosing recommendations after a missed injection.
If a delay of more than 7 days from a scheduled injection visit cannot be avoided, Apretude tablets (30 mg) may be used once daily to replace one scheduled injection visit.
For oral Apretude PrEP durations greater than two months, an alternative regimen is recommended.
The first dose of oral PrEP should be taken two months (+/- 7 days) after the last injection dose of Apretude. Injection dosing should be planned to resume on the last day of oral PrEP or within 3 days, thereafter, as recommended in Table 3.

Adolescents and children.

The safety and efficacy of Apretude in children < 12 years of age, and in adolescents weighing less than 35 kg have not been established.

Elderly.

No dose adjustment is required in elderly individuals. There are limited data available on the use of Apretude in individuals aged 65 years and over (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Renal impairment.

No dosage adjustment is required in individuals 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 who are not on dialysis (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Hepatic impairment.

No dosage adjustment is required in individuals with mild or moderate hepatic impairment (Child-Pugh score A or B). Apretude has not been studied in individuals with severe hepatic impairment (Child-Pugh score C) (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Method of administration.

Film-coated tablet.

Oral use. Apretude tablets may be taken with or without food.

Prolonged-release suspension for injection.

For gluteal intramuscular (IM) injection use only. Do not inject intravenously.
Apretude injection should be administered by a healthcare professional. For instructions on administration, see "Instructions for Use" attached. Carefully follow these instructions when preparing the suspension for injection to avoid leakage.
When administering Apretude injection, healthcare professionals should take into consideration the Body Mass Index (BMI) of the patient to ensure that the needle length is sufficient to reach the gluteus muscle.

4.3 Contraindications

Apretude is contraindicated in individuals: with an unknown or a positive HIV-1 status;
with known hypersensitivity to cabotegravir or to any of the excipients in the tablets or the injection formulation;
receiving rifampicin, rifapentine, phenytoin, phenobarbital, carbamazepine and oxcarbazepine.

4.4 Special Warnings and Precautions for Use

Overall HIV-1 infection prevention strategy.

Apretude is not always effective in preventing HIV-1 acquisition (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The time to onset of protection after commencing Apretude is unknown.
Apretude should be used for pre-exposure prophylaxis as part of an overall HIV-1 infection prevention strategy including the use of other HIV-1 prevention measures (e.g. knowledge of HIV-1 status, regular testing for other sexually transmitted infections, condom use).
Apretude should only be used to reduce the risk of acquiring HIV-1 in individuals confirmed to be HIV negative (see Section 4.3 Contraindications). Individuals should be reconfirmed to be HIV-negative at frequent intervals (e.g. in line with local guidelines, but at no more than 3 month intervals) while taking Apretude for pre-exposure prophylaxis.
Adolescents may benefit from more frequent visits and counselling to support adherence to the dosing and testing schedule.
If clinical symptoms consistent with acute viral infection are present and recent (< 1 month) exposures to HIV-1 are suspected, HIV-1 status should be reconfirmed.

Potential risk of resistance.

There is a potential risk of developing resistance to Apretude if an individual acquires HIV-1 either before or during administration of Apretude, or following discontinuation of Apretude, (see Prolonged-release properties of Apretude injection).
To minimise this risk, it is essential to clinically reassess individuals for risk of HIV acquisition and to frequently test to confirm HIV negative status. Individuals who are suspected or confirmed with HIV-1 should immediately begin antiretroviral treatment (ART).
Alternative forms of PrEP should be considered following discontinuation of Apretude for those individuals at continuing risk of HIV acquisition and initiated within 2 months of the final Apretude injection.

Prolonged-release properties of Apretude injection.

Residual concentrations of cabotegravir injection may remain in the systemic circulation of individuals for prolonged periods (up to 12 months or longer), therefore, physicians should take the prolonged release characteristics of Apretude into consideration when the medicinal product is discontinued (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.6 Fertility, Pregnancy and Lactation; Section 4.9 Overdose).

Importance of adherence.

Individuals should be counselled periodically to strictly adhere to the recommended Apretude dosing schedule in order to reduce the risk of HIV-1 acquisition and the potential development of resistance.

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 Apretude and other suspected agents 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 Dosage and Method of Administration; Section 4.3 Contraindications, Prolonged release properties of Apretude injection; Section 5.1 Pharmacodynamic Properties, Clinical trials.)

Hepatotoxicity.

Hepatotoxicity has been reported in a limited number of individuals receiving Apretude with or without known pre-existing hepatic disease (see Section 4.8 Adverse Effects (Undesirable Effects)).
Clinical and laboratory monitoring should be considered and Apretude should be discontinued if hepatotoxicity is confirmed and individuals managed as clinically indicated (see Prolonged-release properties of Apretude injection).

Interactions with medicinal products.

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

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 Apretude in children < 12 years of age, and in adolescents weighing less than 35 kg have not been established.

Effects on laboratory tests.

In both HPTN 083 and HPTN 084, a similar proportion of participants in the cabotegravir and tenofovir disoproxil fumarate (TDF)/ emtricitabine (FTC) groups were observed to have elevated hepatic transaminases (ALT/AST) levels and maximum post baseline increases were mostly Grades 1 and 2. In HPTN 083, the number of participants in the cabotegravir vs TDF/FTC groups who experienced maximum post baseline Grade 3 or 4 ALT levels were 40 (2%) vs 44 (2%) and Grade 3 or 4 AST levels were; 68 (3%) vs 79 (3%), respectively. In HPTN 084, the number of participants in the cabotegravir vs TDF/FTC groups who experienced maximum post baseline Grade 3 or 4 ALT levels were 12 (< 1%) vs 18 (1%) and Grade 3 and 4 AST levels were; 15 (< 1%) vs 14 (< 1%), respectively.
A few participants in both the cabotegravir and TDF/FTC groups had adverse events of AST or ALT increased which resulted in discontinuation of study product. In HPTN 083, the number of participants in the cabotegravir vs TDF/FTC groups who discontinued due to ALT increased were: 29 (1%) vs 31 (1%) and due to AST increased were 7 (< 1%) vs 8 (< 1%), respectively. In HPTN 084, the number of participants in the cabotegravir vs TDF/FTC groups who discontinued due to ALT increased were 12 (< 1%) vs 15 (< 1%) and there were no discontinuations due to AST increase.

4.5 Interactions with Other Medicines and Other Forms of 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 drugs 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 drugs 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, and ibalizumab.
No drug interaction studies have been performed with cabotegravir injection. The drug interaction data provided in Table 4 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 limited data for cabotegravir in pregnant women. The effect of Apretude on human pregnancy is unknown.
Apretude should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus.
Cabotegravir has been detected in systemic circulation for up to 12 months or longer after an injection, therefore, consideration should be given to the potential for foetal 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 foetal 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 foetuses 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.
 It is expected that cabotegravir will be secreted into human milk based on animal data, although this has not been confirmed in humans. Cabotegravir may be present in human milk for up to 12 months or longer after the last cabotegravir injection.
It is recommended that women breastfeed only if the expected benefit justifies the potential risk to the infant.

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 individual and the adverse event profile of Apretude should be borne in mind when considering the individual's ability to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The safety assessment of Apretude is based on two Phase III clinical studies; HPTN 083 and HPTN 084. In HPTN 083, the median time on blinded study product was 65 weeks and 2 days (1 day to 156 weeks and 1 day), with a total exposure on cabotegravir of 3270 person years. In HPTN 084, the median time on blinded study product was 64 weeks and 1 days (1 day to 153 weeks and 1 day), with a total exposure on cabotegravir of 1920 person years.

Adverse events.

The most common adverse events reported in greater than 10% of participants in any treatment group from HPTN 083 or HPTN 083 are presented in Table 5.

Adverse drug reactions (ADR).

ADRs listed include those attributable to the oral or injectable formulations of Apretude. When frequencies differed between HPTN 083 and 084, the highest frequency category is quoted.
The most frequently reported ADRs in HPTN 083 were: injection site reactions (ISR) (82%), headache (17%) and diarrhoea (14%).
The most frequently reported ADRs in HPTN 084 were: injection site reactions (38%), headache (23%) and transaminase increased (19%).
The ADRs identified in these studies are listed below by MedDRA system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000) and very rare (< 1/10,000), including isolated reports.

Local injection site reactions.

In HPTN 083, 2% of participants discontinued Apretude because of Injection site reactions (ISRs).
Out of 20286 injections, 8900 ISRs were reported.
A total of 2117 participants received at least one injection. Of the 1740 (82%) participants who experienced at least one ISR, the maximum severity of ISRs reported was mild (Grade 1, 34% of participants), moderate (Grade 2, 46% of participants) or severe (Grade 3, 3% of participants). No participants experienced Grade 4 ISRs. The median duration of overall ISR events was 4 days. The proportion of participants reporting ISRs at each visit and the severity of the ISRs decreased over time.
In HPTN 084, no participants discontinued Apretude because of ISRs.
Out of 13068 injections, 1171 ISRs were reported.
A total of 1519 participants received at least one injection. Of the 578 (38%) participants who experienced at last one ISR, the maximum severity of ISRs reported was mild (Grade 1, 25% of participants), moderate (Grade 2, 13% of participants) or severe (Grade 3, < 1% of participants). No participants experienced Grade 4 ISRs. The median duration of overall ISR events was 8 days. The proportion of participants reporting ISRs at each visit and the severity of the ISRs generally decreased over time.

Weight increased.

At the Week 41 and 97 timepoints in HPTN 083, participants who received Apretude gained a median of 1.2 kg (IQR -1.0, 3.5; n=1623) and 2.1 kg (IQR; -0.9, 5.9 n=601) in weight from baseline, respectively; those in the tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) group gained a median of 0.0 kg (IQR -2.1, 2.4, n=1611) and 1.0 kg (IQR -1.9, 4.0 n=598) in weight from baseline, respectively.
At the Week 41 and 97 timepoints in HPTN 084, participants who received Apretude gained a median of 2.0 kg (IQR 0.0, 5.0; n=1151) and 4.0 kg (IQR 0.0, 8.0, n=216) in weight from baseline, respectively; those in the tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) group gained a median of 1.0 kg (IQR -1.0, 4.0, n=1131) and 3.0 kg (IQR -1.0, 6.0 n=218) in weight from baseline, respectively.

Clinical trials experience in adolescents.

In adolescents receiving Apretude for HIV-1 PrEP, the safety data were comparable to the safety data reported in adults receiving Apretude for HIV-1 PrEP (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Post-marketing data.

See Table 7.

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

Symptoms and signs.

There is currently no experience of overdose with Apretude.

Treatment.

There is no specific treatment for overdose with Apretude. If overdose occurs, the individual 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.
Apretude is known to be highly protein bound in plasma; therefore, dialysis is unlikely to be helpful in removal of drug from the body. Management of overdose with Apretude injection should take into consideration the prolonged exposure to drug 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 antiviral agents. 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 408-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 102 nanoM in MT-4 cells.
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.

HPTN 083.

In the primary analysis of the HPTN 083 study, there were 13 incident infections on the cabotegravir arm and 39 incident infections on the tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) arm. In the cabotegravir arm, 5 incident infections occurred when receiving cabotegravir PrEP injections, of which 4 participants received on-time injections and 1 participant had one injection off-schedule. Five incident infections occurred ≥ 6 months after the last dose of cabotegravir PrEP. Three incident infections occurred during the oral lead-in period.
HIV genotyping and phenotyping were attempted at the first visit where HIV viral load was > 500 copies/mL. Of the 13 incident infections in the cabotegravir arm, 4 participants had INSTI resistance mutations. In the TDF/FTC arm, the 4 participants with NRTI resistance (including 3 who had multi-class resistance) included 3 with M184V/I and one with K65R.
None of the 5 participants who were infected after prolonged interruption from cabotegravir administration had INSTI resistance mutations. Neither genotype nor phenotype could be generated for one of the 5 participants, with just 770 copies/mL HIV-1 RNA. Integrase phenotype could not be generated for one of the remaining 4 participants. The remaining 3 participants retained susceptibility to all INSTIs.
Three participants became infected during the oral lead-in phase, prior to receiving cabotegravir injections. One participant with undetectable plasma cabotegravir levels had no INSTI resistance mutations and was susceptible to all INSTIs. Two participants with detectable plasma cabotegravir concentrations had INSTI resistance mutations. The first participant had INSTI resistant mutations E138E/K, G140G/S, Q148R and E157Q. Integrase phenotype could not be generated. The second participant had INSTI resistance mutations E138A and Q148R. This virus was resistant to cabotegravir (fold-change = 5.92) but susceptible to dolutegravir (fold-change=1.69).
Five participants acquired HIV-1, despite on time cabotegravir injections for 4 participants and one off-schedule injection for one participant. Two participants had viral loads too low to analyse. The third participant had no INSTI resistance mutations at the first viraemic visit (Week 17) but had R263K at 112 and 117 days later. While phenotype could not be determined 112 days later, day 117 phenotype showed this virus to be susceptible to both cabotegravir (fold-change = 2.32) and dolutegravir (fold-change=2.29). The fourth participant had INSTI resistance mutations G140A and Q148R. Phenotype showed resistance to cabotegravir (fold-change=13) but susceptibility to dolutegravir (fold-change=2.09). The fifth participant had no INSTI resistance mutations.
In addition to the 13 incident infections, one further participant was HIV-1 infected at enrolment and had no INSTI resistance mutations at that time, however, 60 days later, INSTI resistance mutation E138K and Q148K were detected. Phenotype could not be generated.
Following the primary analysis, extended retrospective virologic testing was performed to better characterise the timing of HIV infections. As a result, one of the 13 incident infections in a participant receiving on time cabotegravir injections was determined to be a prevalent infection.

HPTN 084.

In the primary analysis of the HPTN 084 study, there were 4 incident infections on the cabotegravir arm and 36 incident infections on the TDF/FTC arm.
In the cabotegravir arm, 2 incident infections occurred while receiving injections; one participant had 3 delayed cabotegravir injections and both had been non-adherent to oral cabotegravir.
Two incident infections occurred after the last dose of oral cabotegravir; both participants were non-adherent to oral cabotegravir. The first HIV positive visit occurred approx. 11 weeks after enrolment for one participant and 57 weeks after enrolment for the other.
HIV genotyping was attempted at the first visit where HIV viral load was > 500 c/mL (first viraemic visit). HIV genotyping results were available for 3 of the 4 cabotegravir arm participants. No major INSTI resistance mutations were detected.
HIV genotyping results were available for 33 of the 36 incident infections in the TDF/FTC group. One participant had a major NRTI mutation (M184V); this participant also had NNRTI resistance with the mutation K103N. Nine other participants had NNRTI resistance (7 had K103N, alone or with E138A or P225H; 1 had K101E alone; 1 had E138K alone).
Following the primary analysis, extended retrospective virologic testing was performed to better characterize the timing of HIV-1 infections. As a result, 1 of the 4 HIV-1 incident infections in participants receiving cabotegravir was determined to be a prevalent infection.

Effects on electrocardiogram.

In a randomised, placebo-controlled, three-period cross-over trial, 42 healthy subjects were randomized into 6 random sequences and received three doses of oral administration of placebo, cabotegravir 150 mg every 12 hours (mean steady-state Cmax was approximately 2.8-fold and 5.6-fold above the 30 mg oral once-daily dose and the 600 mg cabotegravir injection every 2 month dose, respectively), or 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 (1side 90% upper CI:5.26 msec). Cabotegravir did not prolong the QTc interval over 24 hours post-dose.

Clinical trials.

Clinical efficacy. The efficacy of Apretude to reduce the risk of acquiring HIV-1 infection has been evaluated in two randomised (1:1), double blind, multi-site, two-arm, controlled studies, HPTN 083 in HIV-1 uninfected men and transgender women who have sex with men and have evidence of high-risk behaviour for HIV-1 infection and HPTN 084 in HIV-1 uninfected cisgender women at risk of acquiring HIV-1. The efficacy of Apretude was compared with daily oral tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC).
Participants randomised to receive Apretude initiated oral lead-in dosing with one Apretude 30 mg tablet and a placebo daily, for up to 5 weeks, followed by Apretude intramuscular (IM) injection (single 600 mg [3 mL] injection, at months 1, 2 and every 2 months thereafter and a daily placebo tablet. Participants randomised to receive TDF/FTC initiated oral TDF 300 mg/FTC 200 mg and placebo for up to 5 weeks, followed by oral TDF 300 mg/FTC 200 mg daily and placebo (IM) injection (3 mL, 20% lipid injectable emulsion at months 1, 2 and every 2 months thereafter).

HPTN 083.

In HPTN 083, a non-inferiority study, 4566 cisgender men and transgender women who have sex with men, were randomised 1:1 and received either cabotegravir (n=2281) or TDF/FTC (n=2285) as blinded study medication up to Week 153.
At baseline, the median age of participants was 26 years, 12% were transgender women, 72% were non-white and 67% were < 30 years.
The primary endpoint was the rate of incident HIV infections among participants randomised to Apretude tablets and Apretude injections compared to oral TDF/FTC (corrected for early stopping). The primary analysis demonstrated the superiority of Apretude compared to TDF/FTC with a 66% reduction in the risk of acquiring incident HIV infection, hazard ratio (95% CI) 0.34 (0.18, 0.62); further testing revealed one of the infections on cabotegravir to be prevalent then yielding a 69% reduction in the risk of incident infection relative to TDF/FTC (see Table 8).
Results from all subgroup analyses were consistent with the overall protective effect, with a lower rate of incident HIV-1 infections observed for participants randomised to Apretude compared with participants randomised to TDF/FTC (see Table 9).

HPTN 084.

In HPTN 084, a superiority study, 3224 cisgender women were randomised 1:1 and received either cabotegravir (n=1614) or TDF/FTC (n=1610) as blinded study medication up to Week 153.
At baseline, the median age of participants was 25 years, > 99% were non-white, > 99% were cisgender women and 49% were < 25 years of age.
The primary endpoint was the rate of incident HIV infections among participants randomised to Apretude tablets and Apretude injections compared to oral TDF/FTC (corrected for early stopping). The primary analysis demonstrated the superiority of Apretude compared to TDF/FTC with an 88% reduction in the risk of acquiring incident HIV-1 infection hazard ratio (95% CI) 0.12 (0.05, 0.31); further testing revealed 1 of the infections on Apretude to be prevalent then yielding a 90% reduction in the risk of HIV-1 incident infection relative to TDF/FTC (see Table 10).
Results from pre-planned subgroup analyses were consistent with the overall protective effect, with a lower rate of incident HIV-1 infections observed for participants randomised to Apretude compared with participants randomised to TDF/FTC (see Table 11).

Adolescents.

The safety and effectiveness of Apretude for HIV-1 PrEP in at-risk adolescents aged 12 years and older and weighing at least 35 kg is supported by data from 2 adequate and wellcontrolled trials of Apretude for HIV-1 PrEP in adults with additional safety and pharmacokinetic data from studies in HIV-1 infected adults who were administered Cabenuva (cabotegravir and rilpivirine prolonged release suspensions for injection), and in HIV-1 infected paediatric subjects who were administered separate components of Cabenuva in addition to their current antiretroviral therapy (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)); Section 5.2 Pharmacokinetic Properties).

5.2 Pharmacokinetic Properties

Film-coated tablets.

Cabotegravir pharmacokinetics is similar between healthy and HIV-infected subjects. The PK variability of cabotegravir is moderate to high. In Phase I studies in healthy subjects, between-subject CVb% for AUC, Cmax, and Ctau ranged from 34 to 91% across healthy subject studies. Within-subject variability (CVw%) is lower than between-subject variability.

Prolonged-release suspension for injection.

Cabotegravir pharmacokinetics is similar between healthy and HIV-infected subjects. The PK variability of cabotegravir is moderate to high. In HIV-infected subjects participating in Phase III studies, between-subject CVb% for Ctau ranged from 39 to 48%. Higher between subject variability ranging from 65 to 76% was observed with single dose administration of long-acting cabotegravir injection. See Table 12.

Absorption.

Film-coated tablets.

Cabotegravir is rapidly absorbed following oral administration, with median Tmax at 3 hours post dose for 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 Cmax by 14% relative to fasted conditions. These increases are not clinically significant.
The absolute bioavailability of cabotegravir has not been established.

Prolonged-release suspension for injection.

Cabotegravir injection exhibits absorption-limited pharmacokinetics because cabotegravir is slowly absorbed into the systemic circulation from the gluteal muscle resulting in sustained plasma concentrations. Following a single 600 mg intramuscular dose, plasma cabotegravir concentrations are detectable on the first day with median cabotegravir concentrations at 4 hours post dose of 0.290 mg/mL, which is above in-vitro PA-IC90 of 0.166 mg/mL, and reach maximum plasma concentration with a median Tmax of 7 days. Target concentrations are achieved following the initial IM injection (see Table 11). Cabotegravir has been detected in plasma up to 52 weeks or longer after administration of a single injection.
Plasma CAB exposure increases in proportion or slightly less than in proportion to dose following single and repeat IM injection of doses ranging from 100 to 800 mg.

Distribution.

Cabotegravir is highly bound (approximately > 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 F, suggest some distribution of cabotegravir to the extracellular space.
Cabotegravir is present in the female and male genital tract, following a single 3 mL (600 mg) IM injection, as observed in a study in healthy participants (n=15). Median cabotegravir concentrations at Day 3 (the earliest tissue PK sample) were 0.49 mg/mL in cervical tissue, 0.29 mg/mL in cervicovaginal fluid, 0.37 mg/mL in vaginal tissue, 0.32 mg/mL in rectal tissue, and 0.69 mg/mL in rectal fluid, which are above the in vitro PA-IC90.

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 glucuronidate 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 glucuronic acid 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.

Film-coated tablets.

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.

Prolonged-release suspension for injection.

Cabotegravir mean apparent terminal phase half-life is absorption-rate limited and is estimated to be 5.6 to 11.5 weeks after a single dose IM injection. The significantly longer apparent half-life compared to oral administration reflects absorption from the injection site into the systemic circulation. The apparent CL/F was 0.151 L/h.

Special patient populations.

Gender.

Population pharmacokinetic analyses revealed no clinically relevant effect of gender on the exposure of cabotegravir. In addition, no clinically relevant differences in plasma cabotegravir concentrations were observed in the HPTN 083 study by gender, including in cisgender men and transgender women with or without cross-sex hormone therapy use. 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.

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.

Adolescents (aged > 12 years to < 18 years).

Population pharmacokinetic analyses revealed no clinically relevant differences in exposure between the HIV-1 infected adolescent and HIV-1 infected and uninfected adult participants from the cabotegravir development programme, therefore, no dosage adjustment is needed for adolescents weighing ≥ 35 kg.

Children.

The pharmacokinetics and dosing recommendations of cabotegravir in children less than 12 years of age or 35 kg or less have not been established.

Elderly.

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

Renal impairment.

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

Hepatic impairment.

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

HBV and HCV infected individuals.

There are no data for the use of cabotegravir in subjects with HBV and HCV infection in PrEP studies.

Polymorphisms in drug metabolising enzymes.

In a meta-analysis of healthy and HIV-infected subjects, HIV-infected subjects with UGT1A1 genotypes conferring poor cabotegravir metabolism had a 1.2-fold increase in mean steady-state cabotegravir AUC, Cmax, and Ctau following cabotegravir injection vs. 1.38-fold mean increase following oral cabotegravir administration. This was similar to 1.3- to 1.5-fold mean increase in steady-state cabotegravir, cabotegravir AUC, Cmax, and Ctau observed following oral cabotegravir in healthy and HIV infected subjects combined. These differences are not considered clinically relevant. Polymorphisms in UGT1A9 were not associated with differences in the pharmacokinetics of cabotegravir, therefore, no dose adjustment is required in subjects with either UGT1A1 or UGT1A9 polymorphisms.

5.3 Preclinical Safety Data

Genotoxicity.

Cabotegravir was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay.

Carcinogenicity.

Cabotegravir was not carcinogenic in long term oral studies in the mouse and rat at doses resulting in up to 7-8 and 26 times, respectively (75 mg/kg/day in male mice and rats and 35 mg/kg/day in female mice), the maximum AUC in patients.

6 Pharmaceutical Particulars

6.1 List of Excipients

Film-coated tablets.

Lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate type A, magnesium stearate, titanium dioxide, macrogol.

Cabotegravir prolonged-release suspension for injection.

Mannitol, polysorbate 20, macrogol 3350, water for injections.

6.2 Incompatibilities

In the absence of compatibility studies cabotegravir injection must not be mixed with other medicinal products.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

In use shelf life.

Once the suspension has been drawn into the syringe, the injection should be used as soon as possible, but may be stored for up to 2 hours at room temperature. If 2 hours are exceeded, the medication, syringe and needle must be discarded.

6.4 Special Precautions for Storage

Store below 30°C.
Do not freeze.

6.5 Nature and Contents of Container

Film-coated tablets.

Apretude tablets are supplied in HDPE (high density polyethylene) bottles with a polypropylene child-resistant closure and a polyethylene faced induction heat seal-liner.
Each bottle contains 30 tablets.

Prolonged-release suspension for injection.

Apretude injection is supplied in a type I clear glass vial, sealed with bromobutyl rubber stopper and an aluminum overseal with a removeable plastic cap. Supplied as a single 3 mL vial or 25 x 3 mL vials.
Not all pack sizes may be distributed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
Full instructions for use and handling of Apretude prolonged-release suspension for injection is provided in the Instructions for Use included as a package insert.

6.7 Physicochemical Properties

Cabotegravir sodium.

Chemical name: sodium (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido [1,2-d]pyrazine-8-carboxamide.
Molecular formula: C19H16F2N3NaO5.
Molecular weight: 427.33 g/mol.

Chemical structure.


CAS number.

1051375-13-3.

Cabotegravir.

Chemical name: (3S,11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide.
Molecular formula: C19H17F2N3O5.
Molecular weight: 405.35 g/mol.

Chemical structure.


CAS number.

1051375-10-0.
Cabotegravir is a white to almost white solid.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes