Consumer medicine information

Sublocade

Buprenorphine

BRAND INFORMATION

Brand name

Sublocade

Active ingredient

Buprenorphine

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sublocade.

SUMMARY CMI

SUBLOCADE®

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.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using SUBLOCADE?

SUBLOCADE contains the active ingredient buprenorphine. SUBLOCADE is used as part of medical, social and psychological treatment program for patients dependent on opioids. For more information, see Section 1. Why am I using SUBLOCADE? in the full CMI.

2. What should I know before I use SUBLOCADE?

Do not use if you have ever had an allergic reaction to SUBLOCADE or any of the ingredients listed at the end of the CMI.
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. Tell your doctor if you have or have had any of the following medical conditions: kidney disease, liver problems, breathing problems, problems with excess alcohol use or history of seizures.
For more information, see Section 2. What should I know before I use SUBLOCADE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with SUBLOCADE 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 do I use SUBLOCADE?

  • SUBLOCADE must be administered only by your doctor or healthcare professional.
  • The recommended first two doses following induction on a buprenorphine-containing product are 300 mg monthly. The subsequent dosing will be selected by your doctor based on clinical assessment of your condition

More instructions can be found in Section 4. How do I use SUBLOCADE? in the full CMI.

5. What should I know while using SUBLOCADE?

Things you should do

  • Remind any doctor, dentist, pharmacist or nurse you visit that you are using SUBLOCADE
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are using SUBLOCADE
  • Tell your family or friends that, in the event of emergency, they should inform the treating healthcare provider or Emergency Room staff that you are being treated with SUBLOCADE

Things you should not do

  • Do not rub or massage the injection site and be aware of placement of belts or clothing waistbands
  • Do not attempt to tamper with the medicine once given by your healthcare provider

Driving or using machines

  • SUBLOCADE may cause drowsiness which may be made worse if you drink alcohol or take sedatives or anti-anxiety medications
  • Be careful driving or operating machinery until you know how SUBLOCADE affects you

Drinking alcohol

  • Do not drink alcohol or take medicines that contain alcohol whilst being treated with SUBLOCADE
  • Alcohol and some medicines may increase the sedative effects of SUBLOCADE

Looking after your medicine

  • Store at 2°C - 8°C. Refrigerate. Do not freeze.
  • Once outside the refrigerator this product may be stored in its original packaging at room temperature (below 25°C) for up to 12 weeks prior to injecting.

For more information, see Section 5. What should I know while using SUBLOCADE? in the full CMI.

6. Are there any side effects?

Some common side effects include difficulty sleeping, anxiety, fatigue, weakness, numbness, flu-like symptoms, upset stomach, constipation and diarrhoea, abnormal liver function and injection site reactions. Cases of difficulty breathing and severe liver problems have been reported with SUBLOCADE.

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.

WARNINGS:

Risk of serious harm or death with intravenous administration

Serious harm or death could result if administered intravenously. SUBLOCADE forms a solid mass upon contact with body fluids and may cause occlusion, local tissue damage, and blood clotting events, including life threatening blood clots in the lungs, if administered intravenously.

Hazardous and harmful use

Although SUBLOCADE is indicated for the treatment of opioid dependence, it still poses risks of hazardous and harmful use which can lead to overdose and death. The doctor will monitor your ongoing risk during treatment with SUBLOCADE.

Life threatening respiratory depression

Serious, life-threatening difficulty breathing may occur with the use of SUBLOCADE. Talk to your doctor about situations which may increase the risk of severe difficulty breathing.

Concomitant use of medicines affecting the central nervous system, including alcohol

Use of SUBLOCADE with anti-anxiety medicines, sedatives, antihistamines, some antidepressants, antipsychotics, cannabis and alcohol may result in profound sedation, severe difficulty breathing, coma and death.



FULL CMI

SUBLOCADE®

Active ingredient: Buprenorphine

Consumer Medicine Information (CMI)

This leaflet provides important information about using SUBLOCADE. 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 SUBLOCADE.

Where to find information in this leaflet:

1. Why am I using SUBLOCADE?
2. What should I know before I use SUBLOCADE?
3. What if I am taking other medicines?
4. How do I use SUBLOCADE?
5. What should I know while using SUBLOCADE?
6. Are there any side effects?
7.Product details

1. Why am I using SUBLOCADE?

SUBLOCADE modified release injection contains the active ingredient buprenorphine. SUBLOCADE acts as a substitute for opioids like heroin, morphine, oxycodone or codeine and it helps withdrawal from opioids over a period of time.

SUBLOCADE is used as part of a medical, social and psychological treatment program for patients dependent on opioids.

SUBLOCADE must only be administered by your doctor or other healthcare professional.

2. What should I know before I use SUBLOCADE?

Warnings

Do not use SUBLOCADE if:

  • you are allergic to buprenorphine or any of the ingredients listed at the end of this leaflet.
  • always check the ingredients to make sure you can use this medicine.
  • you have serious problems with your liver, or if your doctor detects the development of a serious liver problem during treatment.
  • you are under the age of 18 years.
  • you have serious breathing problems.
  • you are intoxicated due to CNS depressant medicines (e.g. sedative/hypnotics, narcotic pain killers, anti-anxiety or antipsychotic medicines), alcohol or have delirium tremens (the ‘shakes’ and hallucinations).
  • the package is torn or shows signs of tampering.

Check with your doctor if you:

  • have any other medical conditions such as asthma or other breathing problems, thyroid problems, prostate problems, problems with excess alcohol use, problems with drowsiness, Addison's disease, Kyphoscoliosis (hunchback disease), low blood pressure, urination problems, kidney problems, liver problems, if you have head injuries or have a condition where you have increased pressure within your head, if you have problems related to the biliary tract, if you have a history of seizures or If you have severe mental problems or hallucinations (seeing or hearing things that are not really there).
  • take any medicines for any other condition

Some people have died from respiratory failure (inability to breathe) when using benzodiazepines (medicines used to treat anxiety or sleeping problems), or other depressants such as alcohol or other opioids at the same time as buprenorphine. For further information please discuss with your doctor.

Buprenorphine may cause fatal respiratory failure in children who accidentally ingest it.

SUBLOCADE can cause withdrawal symptoms (dependence). Withdrawal signs and symptoms were not observed in the month following discontinuation of SUBLOCADE. Considering the long-acting characteristic, any withdrawal signs and symptoms that may occur would be expected to be delayed.

If you stop receiving injections of SUBLOCADE, your doctor may want to monitor you for several months for signs and symptoms of withdrawal and treat appropriately due to the long-acting characteristic of this medicine.

Athletes should be aware that this medicine may cause a positive reaction to "anti-doping" tests.

The safety and effectiveness in patients over 65 years of age have not been established.

SUBLOCADE forms a depot following subcutaneous injection. Serious harm or death could result if injected intravenously.

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

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Use of SUBLOCADE or other opioids by the mother during pregnancy may result in withdrawal symptoms in the baby following birth, this is called Neonatal Abstinence Syndrome. Neonatal Abstinence Syndrome is a condition that includes disturbances to a newborn baby's nervous, gastro-intestinal and breathing systems. Not all babies who are exposed to SUBLOCADE in this way will have withdrawal symptoms. Talk to your doctor if you become pregnant or plan to become pregnant during treatment with SUBLOCADE. Your doctor will help you consider the risks and benefits of continued treatment and plan for monitoring your baby following birth. Due to the long duration of buprenorphine effect, your baby will be monitored for several days at the end of pregnancy for effects on breathing and for withdrawal symptoms.

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 SUBLOCADE and affect how it works.

  • medicines containing alcohol
  • certain medicines for treating HIV/AIDS
  • certain medicines for treating fungal and bacterial infections
  • strong pain killers
  • cough medicines containing opioid-related substances
  • certain antidepressants including monoamine oxidase inhibitors
  • certain medicines used to treat fits or epilepsy (anti-convulsants)
  • sedating antihistamines
  • sedatives
  • alcohol
  • anti-anxiety medicines
  • certain medicines for high blood pressure
  • antipsychotic medicines
  • naltrexone.

Tell your doctor if you are scheduled to have surgery using a general anaesthetic.

Some people have died when using sedatives (benzodiazepines) or other depressants, alcohol or other opioids at the same time as buprenorphine. You should not use benzodiazepines (medicines used to treat anxiety or sleep disorders) whilst you are taking SUBLOCADE unless they are prescribed by your doctor.

Alcohol and certain other medicines (as listed above) may increase the sedative effects of buprenorphine which can make driving and operating machinery hazardous.

Do not drink alcohol or take medicines that contain alcohol whilst you are being treated with SUBLOCADE.

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

4. How do I use SUBLOCADE?

How much to use

  • SUBLOCADE is injected under the skin in your abdomen by your doctor or other healthcare professional only. Your doctor will tell you when you need your next injection. It is important not to miss your scheduled dose.
  • SUBLOCADE must NOT be injected intravenously, intramuscularly or intradermally.
  • SUBLOCADE is only for adults.
  • The recommended first two doses following an induction on a buprenorphine-containing product is 300 mg monthly. The subsequent dosing will be selected by your doctor based on clinical assessment of your condition. Because SUBLOCADE lasts a long time, it should be given monthly and separated by a minimum of 26 days between doses.
  • Do not change the treatment in any way or stop treatment without the agreement of the doctor who is treating you.

When to use SUBLOCADE

SUBLOCADE will be administered once a month by your doctor or other healthcare professional.

If you forget to use SUBLOCADE

SUBLOCADE should be given monthly. It is important to remember to attend your next appointment to receive your next SUBLOCADE injection.

If you cannot keep your appointment for your next SUBLOCADE injection, call your healthcare professional right away so another appointment can be made as soon as possible.

Do not change the treatment in any way or stop treatment without the agreement of the doctor who is treating you.

Because SUBLOCADE lasts a long time, if you stop receiving injections of SUBLOCADE, you should be monitored for several months for symptoms (not sure you need signs and symptoms for the patient) of withdrawal so you can be treated appropriately.

If you use too much SUBLOCADE

Because SUBLOCADE will be administered to you under medical supervision, it is unlikely that you will be given too much.

If you think that you or anyone else may have received too much SUBLOCADE, you should immediately

  • phone the Poisons Information Centre by calling
    in Australia 13 11 26 or in New Zealand 0800 POISON or 0800 764 766, or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using SUBLOCADE?

Things you should do

If you are about to start on any new medicine, remind your doctor, nurse and pharmacist who treat you that you are using or will be starting SUBLOCADE.

If you are going to have surgery, tell the surgeon or anaesthetist that you are using SUBLOCADE.

It may affect other medicines used during surgery.

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

Call your doctor straight away if you:

  • experience hypersensitivity reactions such as swelling of the face, lips, mouth or throat, or severe difficulty in breathing, or
  • experience severe liver problems such as intense fatigue, no appetite, your skin and eyes look yellow, or you have light coloured bowel motions or dark coloured urine.

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

Things you should not do

  • do not attempt to tamper with the medicine once given by your healthcare provider.
  • do not rub or massage the injection site and be aware of the placement of any belts or clothing waistbands.
  • do not give your medicine to anyone else, even if they have the same condition as you.

Things to be careful of

  • SUBLOCADE may cause your blood pressure to drop suddenly, causing you to feel dizzy if you get up too quickly from sitting or lying down.
  • if you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.
  • if you stop using SUBLOCADE and if you start using opioids again, your sensitivity to opioids may change which could be dangerous. You should talk to your doctor before you start using opioids again.
  • SUBLOCADE contains a narcotic that can be a target for people who abuse prescription medicines or street drugs.

Treating pain, emergencies and anaesthesis

While on SUBLOCADE situations may arise where you need to be treated for pain or may require anaesthesia. SUBLOCADE can interfere with the action of some pain treatments. In the event of an emergency, it is important you and your family or friends inform your healthcare provider or Emergency Room staff that you are being treated with SUBLOCADE. For 6 months after stopping SUBLOCADE, you should continue to inform your healthcare providers you have been treated with SUBLOCADE because SUBLOCADE effect can last for a long time.

Driving or using machines

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

SUBLOCADE may cause drowsiness, which may be made worse if you also drink alcohol or take sedatives or anti-anxiety medicines. If you are drowsy, do not drive or operate machinery.

Drinking alcohol

Do not drink alcohol or take medicines that contain alcohol whilst you are being treated with SUBLOCADE.

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Store at 2°C - 8°C. Refrigerate. Do not freeze.
  • Once outside the refrigerator this product may be stored in its original packaging at room temperature (below 25°C) for up to 12 weeks prior to injecting.
  • Once the medicine is administered, the needle guard should be locked into place by pushing it against a hard surface such as a table.
  • All syringe components should be disposed of in a secure sharps disposal container.

Keep it where young children cannot reach it.

When to discard your medicine

SUBLOCADE should be discarded if not refrigerated for longer than 12 consecutive weeks.

Getting rid of any unwanted medicine

Do not use this medicine after the expiry date.

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.

Less serious side effects

Less serious side effects

What to do

Pain-related effects:

  • pain in abdomen, back, arms, legs, joints and muscles, leg cramps, muscle weakness
  • headache, migraine
  • chest pain

Gastrointestinal effects:

  • upset stomach and diarrhoea
  • nausea, vomiting, constipation, poor appetite
  • abnormal liver function

General effects:

  • difficulty sleeping, anxiety
  • fatigue, weakness, numbness
  • sleepiness, dizziness, fainting, vertigo
  • flushing, feeling of warmth
  • rash and itching
  • tooth disorders
  • abnormal vision
  • low sex drive, impotence
  • urinary tract infection

Injection site reactions:

  • redness, pain, itching, nodule just under the skin

Flu-like symptoms:

  • chills, fever, sore throat, coughing, runny nose and sweating

Breathing related

  • difficulty breathing
  • cough, respiratory infection

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Liver problems:

  • severe fatigue
  • you have no appetite
  • your skin and eyes look yellow
  • you have light coloured bowel motions or dark coloured urine

Hypersensitivity reactions:

  • swelling of the face, lips, mouth or throat
  • severe difficulty breathing

Severe injection site reactions:

  • signs of infection at the injection site such as pain, redness, swelling, itching and warmth.

Signs of overdose:

  • severe drowsiness, dizziness or difficulty thinking
  • severe drop in blood pressure
  • severe difficulty breathing

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.

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 in Australia to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems or in New Zealand online at nzphvc.otago.ac.nz/reporting.

For adverse event reporting please contact:

Indivior Pty Ltd

+800-270-81901

[email protected]

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 SUBLOCADE contains

Active ingredient

(main ingredient)

Buprenorphine

Other ingredients

(inactive ingredients)

Polyglactin
N-methyl-2-pyrrolidone

Potential allergens

None known

Do not take this medicine if you are allergic to any of these ingredients.

What SUBLOCADE looks like

SUBLOCADE 100 mg/0.5 mL modified release injection solution is supplied in a single use dose in a 1 mL plastic syringe with a plunger stopper, together with a 19 G 16mm pre-packaged safety needle (AUST R 303476).

SUBLOCADE 300 mg/1.5 mL modified release injection solution is supplied in a single use dose in a 2.25 mL plastic syringe with a plunger stopper, together with a 19 G 16mm pre-packaged safety needle (AUST R 303753).

Each assembled syringe with plastic plunger rod is supplied in an aluminium foil-laminate pouch containing an oxygen absorbing desiccant. The pouch is in a labelled paperboard carton along with a sterile safety needle and labelling.

SUBLOCADE 100mg/0.5mL and 300mg/1.5mL are supplied in a single use pack.

Who distributes SUBLOCADE

Indivior Pty Ltd
78 Waterloo Road
Macquarie Park NSW 2113
Australia

Pharmacy Retailing (NZ) Ltd
t/a Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks
Mangere
Auckland 2022

This leaflet was prepared in October 2023.

Published by MIMS December 2023

BRAND INFORMATION

Brand name

Sublocade

Active ingredient

Buprenorphine

Schedule

S8

 

1 Name of Medicine

Sublocade 100 mg/0.5 mL buprenorphine modified release solution for injection.
Sublocade 300 mg/1.5 mL buprenorphine modified release solution for injection.

2 Qualitative and Quantitative Composition

Buprenorphine is dissolved in Indivior's proprietary buprenorphine gel depot delivery system (Indivior's delivery system) at 18% by weight.
0.5 mL modified release injection solution in a prefilled syringe contains 100 mg buprenorphine (as buprenorphine base).
1.5 mL modified release injection solution in a prefilled syringe contains 300 mg buprenorphine (as buprenorphine base).
Buprenorphine is a white to cream, crystalline powder, very slightly soluble in water (< 1 mg/mL). Chemically, buprenorphine is (2S)-2-[17-(Cyclopropylmethyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol.
Buprenorphine has the molecular formula C29H41NO4 and the molecular weight is 467.6.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sublocade is a modified release solution for injection.
Sublocade is a clear colourless to yellow to amber sterile solution for subcutaneous injection only. It forms a depot upon administration which is designed to deliver buprenorphine at a controlled rate over a one-month period.

4 Clinical Particulars

4.1 Therapeutic Indications

Sublocade is indicated for maintenance treatment of opioid dependence, within a framework of medical, social and psychological treatment.

4.2 Dose and Method of Administration

Patients appropriate for Sublocade are adults who have undergone induction on a buprenorphine-containing product. Withdrawal signs and symptoms should be suppressed (COWS ≤ 12) before transitioning to Sublocade.
Dosing and induction of buprenorphine-containing products should be based on instructions in their product information.
For abdominal subcutaneous injection only. Do not administer Sublocade intravenously, intramuscularly or intradermally (see Section 4.4 Special Warnings and Precautions for Use).
Only healthcare providers should prepare and administer Sublocade.
Administer Sublocade monthly with a minimum of 26 days between doses.
Initiating treatment with Sublocade as the first buprenorphine product has not been studied. Initiate Sublocade treatment only following induction and dose adjustment with a buprenorphine containing product.
Administer each injection only using the syringe and safety needle included with the product.
Do not administer part of a dose.

Precautions to be taken before starting treatment.

Baseline liver function tests and documentation of viral hepatitis status are recommended prior to commencing therapy. Patients who are positive for viral hepatitis, on concomitant medicinal products (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) and/or who have existing liver dysfunction are at greater risk of liver injury. Regular monitoring of the liver function is recommended.

Recommended dosing.

Patients appropriate for Sublocade are adults who have initiated and stabilised treatment on a buprenorphine-containing product, delivering the equivalent of at least 8 mg/day of transmucosal buprenorphine for at least 7 days. Transferring patients stabilised on doses over 24 mg/day buprenorphine to Sublocade has not been studied in clinical trials. The patient may only be transitioned to Sublocade after stabilisation on a buprenorphine-containing product (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The recommended dose of Sublocade is 300 mg monthly for the first two months (treatment initiation). The recommended maintenance dose is 100 mg monthly. In clinical trials, randomisation to the 300 mg/month maintenance dose did not provide additional efficacy as compared to randomisation to the 100 mg/month maintenance dose and the 300 mg/month maintenance dose was associated with a higher incidence of adverse events and study discontinuations. However, patients who do not show a satisfactory clinical response following the second dose can receive a maintenance dose of 300 mg monthly.
Buprenorphine plasma levels in the month following the second 300 mg dose are maintained with 100 mg maintenance dosing. The 300 mg maintenance dose achieves higher levels and reaches steady state after the fourth monthly injection (see Section 5.2 Pharmacokinetic Properties).

Periodic assessment.

Periodic assessment is necessary to determine effectiveness of the treatment plan and overall patient progress. When evaluating the patient, examine the injection site for signs of infection or evidence of tampering or attempts to remove the depot.

Missed doses.

A patient who misses a dose should receive the next dose as soon as possible, with the following dose given no less than 26 days later. Occasional delays in dosing up to 2 weeks are not expected to have a clinically significant impact on treatment effect.

Termination of treatment.

Due to the chronic nature of opioid use disorder, the need for continuing medication-assisted treatment should be re-evaluated periodically. There is no maximum recommended duration of maintenance treatment. For some patients, treatment may continue indefinitely. If considering stopping treatment, the clinical status of the patient should be considered.
If Sublocade is discontinued, its modified-release characteristics should be considered and the patient should be monitored for several months for signs and symptoms of withdrawal or buprenorphine effects and treated appropriately.
After steady-state has been achieved (4-6 months), patients discontinuing Sublocade may have detectable plasma and urine levels of buprenorphine for twelve months or longer (see Section 5.2 Pharmacokinetic Properties).

Instructions for use.

Important information. For abdominal subcutaneous injection only. Do not inject intravenously, intramuscularly or intradermally.
To be administered by a healthcare professional only.
Please read the instructions carefully before handling the product.
Remove Sublocade from the refrigerator prior to administration. The product requires at least 15 minutes to reach room temperature. Do not open the foil pouch until the patient has arrived for his or her injection.
Product is for single use in one patient only. Discard any residue.
Discard Sublocade if left at room temperature (below 25°C) for longer than 12 weeks.
Do not attach the needle until time of administration.

Step 1: Getting ready.

Remove the foil pouch and safety needle from the carton. Open the pouch and remove the syringe (see Figure 1).
Discard the oxygen absorber pack. It is not needed.

Step 2: Check the liquid clarity.

Check that the medication for particulate matter and discolouration (see Figure 2). Sublocade can range from clear colourless to yellow to amber. Variations of colour within this range do not affect the potency of the product.
If the medication is discoloured or contains particulate matter it should not be used.

Step 3: Attach the safety needle.

Remove the cap from the syringe and the safety needle supplied in the carton from its sterile package.
Gently twist the needle clockwise until it is tight and firmly attached.
Do not remove the plastic cover from the needle (see Figure 3).

Step 4: Prepare the abdominal injection site.

Choose an injection site on the abdomen between the transpyloric and transtubercular planes with adequate subcutaneous tissue that is free of skin conditions (e.g. nodules, lesions, excessive pigment). It is suggested that the patient is in the supine position.
Do not inject into an area where the skin is irritated, reddened, bruised, infected or scarred in any way.
Clean the injection site well with an alcohol swab.
To avoid irritation, rotate injection sites following a pattern similar to the illustration in Figure 4. Record the location of the injection to ensure that a different site is used at the time of the next injection.

Step 5: Remove excess air from syringe.

Hold the syringe upright for several seconds to allow air bubbles to rise. Due to the viscous nature of the medication, bubbles will not rise as quickly as those in an aqueous solution.
Remove needle cover and slowly depress the plunger to push out the excess air from the syringe.
Small bubbles may remain in the medication. Large air gaps, however, can be minimised by pulling back on the plunger rod to pop air bubbles prior to expelling the air very slowly. Air should be expelled very carefully to avoid loss of medication.
If medication is seen at the needle tip, pull back slightly on the plunger to prevent medication spillage (see Figure 5).

Step 6: Pinch the injection site.

Pinch the skin around the injection area. Be sure to pinch enough skin to accommodate the size of the needle. Lift the adipose tissue from the underlying muscle to prevent accidental intramuscular injection (see Figure 6).

Step 7: Inject the medication.

Sublocade is for subcutaneous injection only. Do not inject intravenously, intramuscularly or intradermally (see Section 4.4 Special Warnings and Precautions for Use).
Insert needle fully into the abdominal subcutaneous tissue. The actual angle of injection will depend on the amount of subcutaneous tissue.
Use a slow, steady push to inject the medication. Continue pushing until all of the medication is given (see Figure 7).

Step 8: Withdraw the needle.

Withdraw the needle at the same angle used for insertion and release the pinched skin (see Figure 8).
Do not rub the injection area after the injection. There may be a small amount of blood or fluid at the injection site; wipe with a cotton ball or gauze before applying a gauze pad or bandage using minimal pressure.

Step 9: Lock the needle guard and discard the syringe.

Lock the needle guard into place by pushing it against a hard surface such as a table (see Figure 9).
Dispose of all syringe components in a secure sharps disposal container.

Step 10: Instruct the patient.

Advise the patient that they may have a lump for several weeks that will decrease in size over time. Instruct the patient not to rub or massage the injection site and to be aware of the placement of any belts or clothing waistbands.
Removal of the depot. In the event the depot must be removed, it can be surgically excised by a healthcare professional under local anaesthesia within 14 days of injection. The removed depot should be disposed of carefully. Patients who have the depot removed should be monitored for signs and symptoms of withdrawal and treated appropriately.

4.3 Contraindications

Hypersensitivity to buprenorphine or any other component of Indivior's delivery system.
Severe hepatic insufficiency (Child-Pugh C).
Subjects less than 18 years of age.
Severe respiratory insufficiency.
Acute intoxication with alcohol or other CNS depressants.

4.4 Special Warnings and Precautions for Use

Risk of serious harm or death with intravenous administration.

Intravenous injection presents significant risk of serious harm or death as Sublocade forms a solid mass upon contact with body fluids. Occlusion, local tissue damage, and thrombo-embolic events, including life threatening pulmonary emboli, could result if administered intravenously.

Incorrect administration.

Do not administer intravenously, intramuscularly or intradermally. Inadvertent intramuscular or intradermal administration may increase the likelihood of serious injection site reactions. In some post-marketing case reports injection site reactions have involved abscess, ulceration, and necrosis. Some cases resulted in surgical depot removal, debridement, antibiotic administration, and Sublocade discontinuation. Evaluate and treat serious injection site reactions as appropriate. Carefully review injection techniques (see Section 4.2 Dose and Method of Administration).

General.

Sublocade should be administered with caution in debilitated patients and those with severe impairment of hepatic, pulmonary or renal function; myxoedema or hypothyroidism, adrenal cortical insufficiency (e.g. Addison's disease); CNS depression or coma; toxic psychoses; acute alcoholism; or delirium tremens.
Buprenorphine increases intracholedochal pressure as do other opioids. Therefore, caution should be exercised when buprenorphine is to be administered to patients with dysfunction of the biliary tract.
As with other opioids, caution is advised in patients using buprenorphine and having hypotension, prostatic hypertrophy or urethral stenosis.
Opioids may produce orthostatic hypotension in ambulatory patients.
As with other mu-opioid receptor agonists, the administration of Sublocade may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Misuse, abuse and diversion.

Although Sublocade is indicated for the treatment of opioid dependence it still poses risks of hazardous and harmful use which can lead to overdose and death. Monitor the patient's ongoing risk of hazardous and harmful use regularly during opioid substitution therapy with Sublocade.
Buprenorphine can be misused or abused in a manner similar to other opioids, legal or illicit. Some risks of misuse and abuse include overdose, spread of blood borne viral infections, respiratory depression and hepatic injury. Sublocade misuse by someone other than the intended patient poses the additional risk of new opioid dependent individuals using buprenorphine as the primary opioid of abuse and may occur if the medicine is distributed for illicit use directly by the intended patient or if the medicine is not safeguarded against theft. Sub-optimal treatment with buprenorphine may prompt medication misuse by the patient, leading to overdose or treatment dropout. A patient who is under-dosed with buprenorphine may continue responding to uncontrolled withdrawal symptoms by self-medicating with opioids, alcohol or other sedative-hypnotics such as benzodiazepines. To minimise the risk of misuse, abuse and diversion, appropriate precautions should be taken when prescribing and patient follow-up visits with clinical monitoring appropriate to the patient's level of stability should be conducted.
Sublocade is injected as a liquid and the subsequent precipitation of the poly (D,L-lactide-co-glycolide) polymer creates a depot which contains buprenorphine. The entire contents of the prefilled syringe should be administered. After administration, a small amount (approximately 0.1 mL) of Sublocade will remain in the needle and syringe and should be properly disposed of.
After initial formation of the depot, buprenorphine is released via diffusion from, and the biodegradation of, the depot. Clinical monitoring for evidence at the injection site of tampering or attempting to remove the depot should be ongoing throughout treatment. No accounts of subjects removing or attempting to remove the depot after Sublocade administration were reported in clinical studies.
Intravenous injection presents significant risk of serious harm or death as Sublocade forms a mass upon contact with body fluids. Intramuscular injection presents risk of tissue damage.

Abuse deterrence studies.

Sublocade has physicochemical properties designed for modified-release after subcutaneous injection. These properties make both Sublocade and excised depot difficult to misuse and abuse. To evaluate the ability of these physicochemical properties to reduce the potential for abuse of Sublocade, a series of in vitro laboratory studies were conducted.

In vitro testing.

Results of in vitro testing suggest that it would be difficult to prepare a powder from either Sublocade or the excised depot.
Attempts to abuse either Sublocade or the excised depots via intravenous injection would result in serious harm.

Risk of respiratory and central nervous system (CNS) depression.

Serious, life-threatening or fatal respiratory depression may occur with the use of Sublocade. Be aware of situations which increase the risk of respiratory depression and monitor patients closely, especially on initiation or following a dose increase.
Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressants including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants at the same time as receiving Sublocade.
In the event of depression of respiratory or cardiac function, see Section 4.9 Overdose.
Sublocade may cause severe, possibly fatal, respiratory depression in children. Protect children against exposure.
Sublocade should be used with caution in patients with compromised respiratory function (e.g. chronic obstructive pulmonary disease, sleep apnoea, asthma, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression or kyphoscoliosis).
Due to its modified-release characteristics, if Sublocade is discontinued as a result of compromised respiratory function monitor patients for ongoing buprenorphine effects for several months.
Concomitant use of opioids with benzodiazepines, gabapentinoids, antihistamines, tricyclic antidepressants, antipsychotics, cannabis or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Patients and their caregivers should be made aware of the symptoms of respiratory depression. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while receiving Sublocade.

Head injury and increased intracranial pressure.

Buprenorphine, like other potent opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions and other circumstances where cerebrospinal pressure may be increased, or history of seizure. Buprenorphine can produce miosis and changes in the level of consciousness, or changes in the perception of pain as a symptom of disease may interfere with patient evaluation or obscure the diagnosis or clinical course of concomitant disease.

Dependence and risk of opioid withdrawal.

Buprenorphine is a partial agonist at the mu-opioid receptor and studies in animals, as well as clinical experience, have shown that buprenorphine may produce dependence but at a lower level than a full agonist (e.g. morphine).
Withdrawal signs and symptoms were not observed in the month following discontinuation of Sublocade. Considering the long half-life, any withdrawal signs and symptoms that may occur would be expected to be delayed. Model simulations indicate that steady-state buprenorphine plasma concentrations decreased slowly over time following the last injection and remained at therapeutic levels for 2 to 5 months on average, depending on the dosage administered (100 mg or 300 mg, respectively).
Patients who elect to discontinue treatment with Sublocade should be monitored for withdrawal signs and symptoms. Consider transmucosal buprenorphine if needed to treat withdrawal after discontinuing Sublocade.

Neonatal abstinence syndrome.

Chronic use of buprenorphine by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). Due to the long half-life of buprenorphine, neonatal monitoring for several days should be considered at the end of pregnancy to prevent the risk of respiratory depression or withdrawal syndrome in neonates.

Allergic reactions.

Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic oedema, and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a contraindication to Sublocade.

Use in opioid naïve patients.

There have been reported deaths of opioid naive individuals who received doses as low as 2 mg of buprenorphine sublingual tablet for analgesia. Sublocade is not appropriate as an analgesic.

Hepatitis, hepatic events.

Cases of acute hepatic injury have been reported in opioid-dependent patients, both in clinical trials and post-marketing adverse reaction reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of cytolytic hepatitis, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy and death. Serious cases of acute hepatic injury have also been reported in a context of misuse, especially by the intravenous route. These hepatic injuries were dose-related and could be due to mitochondrial toxicity. Pre-existing or acquired mitochondrial impairment (genetic diseases, viral infections particularly chronic hepatitis C, liver enzyme abnormalities, alcohol abuse, anorexia, associated mitochondrial toxins, e.g. aspirin, isoniazid, valproate, amiodarone, antiviral nucleoside analogues, or drug misuse by injection) could promote the occurrence of such hepatic injuries.
These co-factors must be taken into account before prescribing Sublocade and during treatment monitoring. Baseline liver function tests and documentation of viral hepatitis status are recommended prior to commencing therapy. Patients who are positive for viral hepatitis, on concomitant medicines (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) and/or have existing liver dysfunction are at greater risk of liver injury. Regular monitoring of liver function is recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending upon the findings, the medicine may be discontinued. If treatment is continued, hepatic function should be monitored closely.

Use in hepatic impairment.

Buprenorphine is extensively metabolised by the liver. The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a post-marketing study, in which a buprenorphine/naloxone 2.0 mg/0.5 mg sublingual tablet was administered to healthy subjects and subjects with varying degrees of hepatic impairment. Plasma levels were found to be elevated for buprenorphine in patients with moderate to severe hepatic impairment (Table 1). Buprenorphine plasma exposure increased approximately 3-fold in patients with severely impaired hepatic function.
In the same study, changes in Cmax and AUClast in subjects with HCV infection without hepatic impairment were not clinically significant in comparison to the healthy subjects.
The effect of hepatic impairment on the pharmacokinetics of Sublocade has not been studied.
Because of the long-acting nature of the product, adjustments to dosages of Sublocade are not rapidly reflected in plasma buprenorphine levels. Because buprenorphine levels cannot be rapidly decreased, patients with pre-existing severe hepatic impairment are not candidates for treatment with Sublocade.
Patients who develop moderate to severe hepatic impairment while being treated with Sublocade should be monitored for several months for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.

Use in renal impairment.

Renal elimination plays a relatively small role (~30%) in the overall clearance of buprenorphine and metabolites. Therefore, no dose modification based on renal function is generally required. Metabolites of buprenorphine accumulate in patients with renal failure. Caution is recommended when dosing patients with severe renal impairment (CLcr < 30 mL/min), which may require dose adjustment.
Clinical studies of Sublocade did not include subjects with renal impairment.

Use in patients at risk for arrhythmia.

Serial ECGs were collected following a single dose and at steady-state to evaluate the effect of Sublocade on the QT interval in five clinical studies including the Phase 3 study. In a Phase 3 study, seven patients had an increase from baseline QTc greater than 60 msec at any time [2/203 patients (1.0%) in the 300 mg/100 mg group and 5/201 patients (2.0%) in the 300 mg/300 mg group] and one patient in the 300 mg/300 mg group was found to have a QTc greater than 500 msec. These QTc findings were all sporadic and transient and none led to aberrant ventricular rhythm. Review of ECG and adverse event data provided no evidence for syncope, seizure, or ventricular tachycardia or fibrillation.
Consider these observations in clinical decisions when prescribing buprenorphine to patients with hypokalemia, hypomagnesemia, or clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia. Periodic electrocardiographic (ECG) monitoring is recommended in these patients. Avoid the use of buprenorphine in patients with a history of Long QT Syndrome or an immediate family member with this condition or those taking Class IA antiarrhythmic medications (e.g. quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g. sotalol, amiodarone, dofetilide), or other medications that prolong the QT interval.

Use in the elderly.

The safety and efficacy of buprenorphine in elderly patients over 65 years have not been established.

Risks associated with treatment of emergent acute pain.

While on Sublocade, situations may arise where patients need acute pain management, or may require anaesthesia. Treat patients receiving Sublocade with a non-opioid analgesic whenever possible. Patients requiring opioid therapy for analgesia may be treated with a high-affinity full opioid analgesic under the supervision of a physician, with particular attention to respiratory function. Higher doses may be required for analgesic effect. Therefore, a higher potential for toxicity exists with opioid administration.
If sedation or opioid therapy is required, e.g. as part of anaesthesia, patients should be continuously monitored in an anaesthesia care setting by persons not involved in the conduct of the surgical or diagnostic procedure. The sedation or opioid therapy should be provided by individuals specifically trained in the use of anaesthetic drugs and the management of the respiratory effects of potent opioids, specifically the establishment and maintenance of a patent airway and assisted ventilation.
Advise patients of the importance of instructing their family members, in the event of emergency, to inform the treating healthcare provider or emergency room staff that the patient is being treated with Sublocade.
The above guidance should also be considered for any patient who has been treated with Sublocade within the last 6 months.

Paediatric use.

Sublocade is not recommended for use in children. The safety and effectiveness of Sublocade in subjects below the age of 18 has not been established.

Effects on laboratory tests.

Athletes should be aware that this medicine may cause a positive reaction to "anti-doping" tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Table 2 includes clinically significant drug interactions with Sublocade.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In a fertility study in rats, female mating, fertility, and fecundity indices were unaffected by the subcutaneous (SC) administration of Sublocade up to approximately 38 times the maximum recommended human dose (MRHD) of 300 mg on an AUC basis. However, higher mean post implantation loss was observed with Sublocade at 38 times the maximum recommended human dose of buprenorphine and at an equivalent level of Indivior's delivery system alone, which correlated with higher mean number of resorptions and reduced mean number of viable fetuses/litter size. Mean gravid uterine weight and mean final body weight were lower and correlated with higher mean number of resorptions and lower fetal body weights. The NOAEL (No Observed Adverse Effect Level) for female fertility was approximately 25 times the MRHD for buprenorphine (AUC).
Male fertility and reproduction indices were lower as evidenced by abnormal sperm parameters (low motility, low mean number of sperm and higher percentage of abnormal sperm) with Sublocade at 600 mg/kg and with an equivalent level of Indivior's delivery system. The NOAEL for male fertility parameters, including sperm analysis, and male-mediated developmental parameters was approximately 32 times the MRHD on an AUC basis.
In a fertility study in male and female rats, there were no adverse effects on mating, fertility, and fecundity indices when N-methyl-2-pyrrolidone (NMP) an excipient in Sublocade, was administered SC at up to 288 mg/kg/day. NMP was administered daily in this study (compared with the proposed clinical monthly dosing) to ensure reproductive tissue exposure throughout the critical periods of development. The NOAEL for NMP corresponded to 91-fold the once monthly maximum human NMP exposure (AUC) in Sublocade.
(Category C)
In an embryofetal development study in rats, Sublocade administered subcutaneously to pregnant animals before mating and again on GD 7 during the period of organogenesis resulted in increased post implantation loss, which correlated with higher mean number of resorptions and decreased number of viable fetuses per litter, and decreased mean fetal body weights at 900 mg/kg (approximately 38 times the MRHD of 300 mg of Sublocade on an AUC basis); however, similar effects were observed with an equivalent level of Indivior's delivery system alone, indicating they may be attributable to the vehicle. Dose-related increases in incidences of skeletal malformations of the head and visceral malformations were observed with Sublocade with significant changes at 900 mg/kg (approximately 38 times the MRHD on an AUC basis). Similar effects were observed with equivalent levels of Indivior's delivery system. Based on these results, the NOAEL for developmental toxicity was 300 mg/kg, or approximately 15 times the MRHD for buprenorphine (on an AUC basis) and approximately 267 times the NMP exposure (AUC) at the MRHD.
In a separate embryofetal study, daily subcutaneous administration of NMP to pregnant rats during the period of organogenesis at doses greater than 86 mg/kg/day (corresponding approximately 15 times the NMP exposure (AUC) at the MRHD) was associated with reduced fetal body weight, but there were no teratogenic effects observed at NMP doses of up to 370 mg/kg/day, nor was any maternal toxicity observed. NMP was administered daily in this study (compared with the proposed clinical monthly dosing) to ensure reproductive tissue exposure throughout the critical periods of development. The NOAEL for fetal developmental effects corresponded to approximately 15 times the NMP exposure (AUC) at the MRHD.
In an embryofetal development study in rabbits, administration of a single subcutaneous injection of Sublocade to pregnant animals on Gestation Day 7 during the period of organogenesis resulted in an increased litter incidence of skeletal malformations at 155 mg/kg (approximately 6 times the MRHD on an AUC basis). There was also an increased litter incidence of external malformations, visceral, and skeletal malformations and variations at 390 mg/kg Sublocade (approximately 15 times the MRHD for buprenorphine [AUC]) with similar effects observed with an equivalent level of the Indivior's delivery system, indicating they may be attributable to the vehicle. Moreover, increased post-implantation loss, which correlated with increased mean number of resorptions and decreased mean number of viable fetuses, and decreased fetal body weights were observed at the same dose. The NOAEL for developmental toxicity for Sublocade was 78 mg/kg buprenorphine or approximately 2 times the maximum human buprenorphine exposure and approximately 52 times the maximum human NMP exposure (AUC).
In a separate embryofetal study, an increased incidence of brachydactyly of the forelimbs and reduced gallbladder size was seen in fetal rabbits following daily subcutaneous administration of NMP to their dams during the period of organogenesis at doses of 356 mg/kg/day (corresponding to exposures of 89 times MRHD NMP exposure (AUC) following daily SC NMP injections). The NOAEL for these effects (133 mg/kg/day), which was also the NOAEL for maternal toxicity, corresponded to daily administration of Sublocade at exposures of 15 times the MRHD NMP exposure (AUC). NMP was administered daily in this study (compared with the proposed clinical monthly dosing) to ensure reproductive tissue exposure throughout the critical periods of development.
Mean pup bodyweights were generally significantly lower than saline and Indivior's delivery system groups in both sexes in a rat pre-/postnatal development study with maternal SC administration at 150 mg/kg (administered once on GD 7 and LD7) from birth through weaning and to PND 28; however body weights returned to saline control levels during the F1 growth phase. Dosing with Indivior's delivery system or Sublocade had little or no effect on the physical development, sensory response, reflex performance, and subsequent reproductive performance of F1 pups. These results suggested that lowest dose of 50 mg/kg (exposure ratio 1.5 based on body surface area) is the NOAEL for rat pre-/postnatal development.
In a separate pre/postnatal development study, daily subcutaneous administration of NMP to female rats from GD 6 through to the end of lactation (PND 20) at 288 mg/kg/day (approximately 91 times the once monthly MRHD NMP exposure (AUC)) was associated with decreased offspring body weights at birth and throughout lactation and post weaning, and reduced fertility and fecundity in both male and female offspring, in the absence of maternal toxicity. Maternal doses of 144 mg/kg (approximately 38 times the once monthly MRHD NMP exposure (AUC)) throughout the same period had no adverse effects on pregnancy or on the physical development, sensory response, reflex performance and subsequent reproductive performance of F1 pups. NMP was administered daily in this study (compared with the proposed clinical monthly dosing) to ensure reproductive tissue exposure throughout the critical periods of development.
Continued use of heroin during pregnancy is associated with significant risk to the mother and the fetus and neonate.
Buprenorphine readily crosses the placental barrier and may cause respiratory depression in neonates. During the last three months of pregnancy, chronic use of buprenorphine may be responsible for a withdrawal syndrome in neonates (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, or convulsions). The syndrome is generally delayed for several hours to several days after birth. Due to the long half-life of buprenorphine, neonatal monitoring for several days should be considered at the end of pregnancy to prevent the risk of respiratory depression or withdrawal syndrome in neonates.
Data on the use of buprenorphine in pregnancy, and its impact on the mother and fetus, are limited. Data from randomised, controlled trials and observational studies do not indicate an increased risk of maternal or fetal adverse outcomes compared to methadone.
Buprenorphine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
 Animal studies indicate buprenorphine has the potential to inhibit lactation or milk production. Decreases in postnatal survival, growth and development were also observed in animals treated with buprenorphine during lactation. In two studies of thirteen women, buprenorphine was found in low levels in human breast milk. In both studies the estimated infant dose was < 1% of the maternal dose. Because buprenorphine passes into the mother's milk, the development and health benefits of breastfeeding should be considered along with the mother's clinical need for Sublocade and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

4.7 Effects on Ability to Drive and Use Machines

Buprenorphine may influence the ability to drive and use machines when administered to opioid dependent patients. This product may cause drowsiness, dizziness or impaired thinking especially during the first few days following treatment and dose adjustment. If used with alcohol or central nervous system depressants the effect is likely to be more pronounced (see Section 4.4 Special Warnings and Precautions for Use). Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that Sublocade does not adversely affect their ability to engage in such activities.
There is an increased level of buprenorphine for 3 days after each injection. Buprenorphine levels increase during the first two months and are maintained with the 100 mg dose; further accumulation occurs with the 300 mg maintenance dose, which achieves steady-state after the fourth monthly injection.

4.8 Adverse Effects (Undesirable Effects)

The clinical safety of Sublocade was evaluated in a total of 1083 opioid-dependent subjects who received at least 1 dose of Sublocade (948 of whom received at least 1 dose of 300 mg) during the clinical development program, with 848 subjects in the pivotal Phase 3 studies and 235 in the Phase 1 and 2 studies. In these studies, there were a total of 570 subjects who received at least 6 injections of Sublocade and 395 subjects who received 12 injections.
The most commonly reported treatment related adverse reactions reported during the pivotal clinical studies (≥ 5% of subjects) were constipation, nausea, vomiting, headache, fatigue, hepatic enzymes increased, and injection site pain and pruritus.
Adverse events reported for the groups receiving Sublocade and placebo following administration in the 6-month, double-blind, placebo-controlled study are shown in Table 3. Both dosing regimens of Sublocade included treatment with 300 mg for 2 months then either 100 mg or 300 mg for 4 months. The frequency of possible side effects listed is defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10).

Less common clinical trial adverse reactions.

Treatment-emergent adverse reactions reported as less common (< 1%) during the pivotal Phase 3 studies of the Sublocade clinical development program included:

Eye disorders.

Vision blurred.

General disorders and administration site conditions.

Injection site discomfort, injection site reaction.

Hepatobiliary disorders.

Hepatic function abnormal.

Infections and infestations.

Injection site cellulitis, injection site infection.

Nervous system disorders.

Dizziness postural, syncope.

Psychiatric disorders.

Euphoric mood, libido decreased.

Reproductive system and breast disorders.

Erectile dysfunction.

Vascular disorders.

Hypotension.

Post-marketing experience with buprenorphine.

Post-marketing experience with buprenorphine containing products for treatment of opioid dependence has been associated with the following side effects: respiratory depression (see Section 4.4 Special Warnings and Precautions for Use) and coma, hallucinations, neonatal withdrawal syndrome, neonatal tremor, neonatal feeding disorder, fetal disorders, convulsions, confusion, miosis, weight decrease, asphyxia, hypoventilation, urinary retention, vertigo, drug dependence, headache, nausea, vomiting, drug withdrawal syndrome, peripheral oedema, orthostatic hypotension, heart rate and rhythm disorders, and deaths.
Cases of hepatitis, jaundice, hepatic failure, hepatic necrosis, hepatorenal syndrome, hepatic encephalopathy, hepatic necrosis and elevations in hepatic transaminases have been reported (see Section 4.4 Special Warnings and Precautions for Use).
Cases of acute or chronic hypersensitivity to buprenorphine have been reported with symptoms including rashes, urticaria, pruritus and reported cases of bronchospasm, angioedema, and anaphylactic shock (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. As with other opioids, buprenorphine could cause serotonin syndrome with concomitant administration of serotonergic drugs (e.g. antidepressants, migraine medications). Treatment with the serotoninergic drug should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated.

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

Manifestations of acute overdose include miosis, sedation, hypotension, respiratory depression and death. Nausea and vomiting may be observed.
The major symptom requiring intervention is respiratory depression, which could lead to respiratory arrest and death. If the patient vomits, care must be taken to prevent aspiration of the vomitus.

Treatment.

In the event of depression of respiratory or cardiac function, primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation following standard intensive care measures. The patient should be transferred to an environment within which full resuscitation facilities are available. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. High doses of naloxone hydrochloride 10-35 mg/70 kg may be of limited value in the management of buprenorphine overdose.
The long duration of action of buprenorphine should be taken into consideration when determining the length of treatment needed to reverse the effects of an overdose. Naloxone can be cleared more rapidly than buprenorphine, allowing for a return of previously controlled buprenorphine overdose symptoms, so a continuing infusion may be necessary. Ongoing IV infusion rates should be titrated to patient response. If infusion is not possible, repeated dosing with naloxone may be required.
Clinical data are limited with regards to the possible surgical removal of the depot as only two cases of surgical removal were reported in premarketing clinical studies.
For further information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia) or National Poisons Centre on 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Buprenorphine is a mu-opioid receptor partial agonist, kappa-opioid receptor antagonist. Its activity in opioid maintenance treatment is attributed to its slow dissociation from the mu-receptors in the brain which reduces craving for opioids and opioid withdrawal symptoms. This minimises the need of the opioid dependent patient for illicit opioid medicines.
During clinical pharmacology studies in opioid-dependent subjects, buprenorphine demonstrated a ceiling effect on a number of parameters, including positive mood, "good effect", and respiratory depression.
An intent of buprenorphine treatment is to suppress withdrawal symptoms, cravings and opioid drug liking. These effects are achieved through sufficient receptor occupancy (receptor blockade) as described below.

Plasma concentration and clinical response.

In Opioid blockade study (13-0002) overall the relationship of the buprenorphine plasma concentration versus the VAS scores for the subjective measures (Drug Liking, Any Drug Effect, Good Drug Effect, Bad Drug Effect, Sedation, and High), indicate there was a reduction in VAS scores with increased buprenorphine plasma concentration.
In a Positron Emission Tomography (PET) study with Sublocade in 2 subjects (one subject receiving 200 mg SC injections and one subject receiving 300 mg SC injections) with opioid use disorder, 79 to 92% occupancy of the mu-opioid receptors in the brain at day 7 following the last dose under steady-state conditions was maintained for 28 days to 75 and 81%.
The Sublocade opioid blockade study evaluated the blockade of subjective opioid effects, pharmacokinetics (PK) and safety of SC injections of Sublocade and the results are presented in the Clinical trials section.
Exposure-response relationships were assessed for illicit opioid use, based on urine samples negative for illicit opioids combined with self-reports negative for illicit opioid use, craving and withdrawal symptoms using data obtained from 489 opioid dependent patients in the double-blind Phase 3 Study (13-0001).
The observed plateau for maximal response was reached at buprenorphine plasma concentrations of approximately 2-3 nanogram/mL for illicit opioid use and 4 nanogram/mL for opioid withdrawal symptoms.
Withdrawal symptoms [Clinical Opiate Withdrawal Scale (COWS)] were clinically controlled (defined as ≤ 12 on a 48-point scale) in most subjects consistent with a concentration of ≥ 2 nanogram/mL, however, observed maximal response (COWS 0) was reached at approximately 4 nanogram/mL.
Opioid craving was clinically controlled (defined as craving ≤ 20 on a 100-point Opioid Craving VAS) in most subjects consistent with a concentration of ≥ 2 nanogram/mL, however, the observed plateau for maximal response (0 craving) was reached at approximately 3 nanogram/mL.

Clinical trials.

The pivotal studies from the Sublocade clinical development program are a Phase 3 double-blind efficacy and safety study (13-0001) and an opioid blockade study (13-0002).

Opioid blockade study (13-0002).

The study evaluated the blockade of subjective opioid effects, PK and safety of SC injections of Sublocade in 39 subjects with OUD (not treatment-seeking).
The primary objective of this study was to demonstrate that the "Drug Liking" visual analog scale (VAS) measured after challenge with intramuscular injections of 6 mg (Dose 1) and 18 mg (Dose 2) hydromorphone is noninferior to the "Drug Liking" visual analog scale (VAS) measured after challenge with placebo at weeks 1 through 4 following the first injection of 300 mg Sublocade.
After Sublocade injections at weeks 0 and 4, on average, subjective effects of both 6 and 18 mg doses of hydromorphone were blocked; however, wide variability was seen across subjects. Complete blockade continued throughout the 8 weeks of observation that followed the second Sublocade injection.
For comparison, stabilisation doses of SL buprenorphine in Week 0 failed to provide full blockade of subjective effects of 18 mg of hydromorphone.

Efficacy study (13-0001).

The efficacy of Sublocade in the treatment of opioid use disorder was evaluated in a Phase 3, 24-week, randomised, double-blind, placebo-controlled, multicentre trial in treatment-seeking patients who met the DSM-5 criteria for moderate or severe opioid use disorder. Patients were randomised to one of following dosing regimens: 6 once-monthly 300 mg doses, 2 once-monthly 300 mg doses followed by 4 once-monthly 100 mg doses, or 6 once-monthly SC injections of placebo. All doses were administered by a physician or suitably-qualified designee and were separated by 28 ± 2 days. In addition to study medication, all subjects received protocol specified psychosocial support at least once a week (Individual Drug Counselling = IDC).
Prior to the first dose, subjects were inducted and dose stabilised on 8/2 to 24/6 mg per day of Suboxone (buprenorphine/naloxone) sublingual film (Suboxone SL Film) for a minimum of 7 days. Subjects were considered dose stabilised when cravings and withdrawal symptoms were clinically controlled (≤ 12 on a 48-point COWS scale and ≤ 20 on a 100-point Opioid Craving VAS) for a minimum of 24 hours. After randomisation, supplemental dosing with Suboxone SL Film was not permitted during the study.
Efficacy was evaluated over Weeks 5 to 24 based on weekly urine drug screens combined with self-reported use of illicit opioid use. A "grace period" was applied for Weeks 1 through 4 to allow patients to stabilise in treatment. During this period, opioid use, if it occurred, was not considered in the analysis. Missing urine drug screen samples and/or self-reports during weeks 5-24 were counted as positive for illicit opioids. The key secondary endpoint was treatment success (responder), defined as any subject with ≥ 80% of urine samples negative for opioids combined with self-reports negative for illicit opioid use (opioid-free weeks) from Week 5 through Week 24.
A total of 504 patients were randomised 4:4:1:1 [203 subjects in the 300 mg/100 mg group, 201 patients in the 300 mg/300 mg group and 100 patients in the placebo group (2 groups of volume-matched placebo)].
Based on the cumulative distribution function (CDF) of the percentage of urine samples negative for illicit opioids combined with self-reports of negative for illicit opioid is collected from week 5 through week 24 (Table 4), regardless of dose, Sublocade was superior to the placebo group with statistical significance. The proportion of patients achieving treatment success (defined as patients with ≥ 80% opioid-free weeks) was statistically significantly higher in both groups receiving Sublocade compared to the placebo group. See Table 5.
Analysis of the dropout pattern in Study 13-0001 indicated that opioid craving was a major predictor of dropout. An opioid craving score > 20 was associated with an increase in dropout rate of up to 3.0 and 3.6-fold in active treatment arms and placebo arm, respectively, compared to craving ≤ 5. See Figure 10.

Pharmacodynamic interaction with fentanyl.

An open‐label, cross‐over study was conducted in 8 opioid‐tolerant subjects to assess the ability of intravenous buprenorphine to prevent respiratory depression associated with high doses of fentanyl administered in a clinical setting. Opioid‐tolerant subjects were medically stable and taking oral morphine equivalents of ≥ 90 mg daily with no other CNS depressant use. Buprenorphine infusions at three dose levels and placebo infusions were administered, followed by up to four doses of fentanyl. The three intravenous buprenorphine dose levels were designated as low (0.25 mg/70 kg bolus + 0.1 mg/70 kg/hr), mid (0.5 mg/70 kg bolus + 0.2 mg/70 kg/hr), and high (1.25 mg/70 kg bolus + 0.5 mg/70 kg/hr). The low, mid, and high buprenorphine dose levels produced average plasma concentrations (from 2 hours to 6 hours after infusion onset) of 1.06 nanogram/mL, 2.26 nanogram/mL, and 6.04 nanogram/mL, respectively. Buprenorphine concentrations of approximately 2 and 6 nanogram/mL are consistent with steady-state plasma levels achieved by 100 mg and 300 mg Sublocade monthly injections, respectively.
Escalating intravenous fentanyl boluses of 0.25, 0.35, 0.50 and 0.70 mg/70 kg (up to a maximum cumulative dose of 1.8 mg/70 kg) were administered over 90 seconds at +2 hr, +3 hr, +4 hr and +5 hr after the start of intravenous infusion of buprenorphine or placebo. Apnoea events after each fentanyl bolus are shown in Figure 11. Four of the 8 subjects in the placebo infusion groups discontinued prior to the fourth fentanyl bolus because of apnoea (2 after the second bolus and 2 after the third bolus); 3 of the remaining 4 subjects experienced apnoea after the fourth fentanyl dose. All 8 subjects in the buprenorphine infusion groups completed the fentanyl boluses and 2 of the 8 experienced apnoea.

5.2 Pharmacokinetic Properties

Absorption.

The pharmacokinetics (PK) of buprenorphine following subcutaneous injection of Sublocade was evaluated in subjects with opioid use disorder after single doses (20 mg to 200 mg) and repeated doses (50 to 300 mg) separated by 28 days for up to 12 injections.
After Sublocade injection, an initial buprenorphine peak was observed and the median Tmax occurred at 24 hours after injection. After the initial buprenorphine peak, the plasma buprenorphine concentrations decreased slowly to a plateau. Steady-state was achieved at 4-6 months.
Buprenorphine average plasma concentration (Cavg) after one injection of 300 mg Sublocade following 24 mg Subutex stabilization was 2.19 nanogram/mL, with a peak concentration (Cmax) of 5.37 nanogram/mL and a trough concentration (Ctrough) of 1.86 nanogram/mL. Mean buprenorphine plasma concentrations levels for Cavg, Cmax and Ctrough at steady-state are presented in Figure 12 in comparison to transmucosal buprenorphine. At steady state, the plasma levels of buprenorphine reached with the maintenance dose of 100 mg are within the range obtained with transmucosal treatment: the peak concentration may be lower, while the average and trough concentration may be higher (see Figure 12).

Distribution.

Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.

Metabolism.

Buprenorphine is metabolised into its major metabolite, norbuprenorphine, primarily by CYP3A4. Norbuprenorphine can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in vitro; however, it has not been studied clinically for opioid-like activity. Norbuprenorphine steady-state plasma concentrations in humans after subcutaneous injection of Sublocade are low compared to buprenorphine (AUC norbuprenorphine/buprenorphine ratio of 0.20 to 0.40).

Excretion.

Buprenorphine is metabolised and eliminated in urine and faeces. The apparent terminal plasma half-life of buprenorphine following subcutaneous injection of Sublocade ranged from 43 to 60 days as a result of the slow release of buprenorphine from the subcutaneous depot.
Buprenorphine is essentially eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (70%), the rest being eliminated in urine.
A study assessing buprenorphine exposure 22 to 38 months following the last Sublocade injection indicated that buprenorphine could potentially be detected in plasma and urine over that time period. When detected, buprenorphine concentrations in plasma were below levels known to control disease symptoms. Concentrations in urine were more variable than in plasma and generally higher depending on the test used. Hence, it is expected that patients will be positive for a longer time in urine than in plasma.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence of clastogenic potential towards rat bone marrow cells by subcutaneous Sublocade was found in an in vivo micronucleus test.
The conclusion from various genotoxicity assays, including Ames tests and chromosome aberration studies is that buprenorphine and N-methyl-2-pyrrolidone (NMP) are not genotoxic.

Carcinogenicity.

Studies conducted in animals (rats and mice) show that buprenorphine is not carcinogenic at oral doses of up to 56 and 100 mg/kg/day, respectively, both of which equate to approximately 15-fold human exposure at the maximum recommended clinical dose of 32 mg based on body surface area. N-methyl-2-pyrrolidone (NMP), an excipient in Sublocade, produced an increase in hepatocellular adenomas and carcinomas in male and female mice at around 6 and 8 times, respectively, the maximum daily dose (MDD) of NMP delivered via Sublocade. The clinical significance of these findings is unclear. No tumours were noted at 1 and 1.3 times the MDD. Exposure of rats to NMP for 2 years via inhalation (at around 0.7 x MDD) or via diet (at around 3 x MDD) was shown to be non-carcinogenic. The possible carcinogenicity of NMP from subcutaneous Sublocade has not been tested.

6 Pharmaceutical Particulars

6.1 List of Excipients

Indivior's delivery system contains polyglactin, N-methyl-2-pyrrolidone.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product 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.

6.4 Special Precautions for Storage

Store at 2-8°C. Refrigerate. Do not freeze.
Once outside the refrigerator this product may be stored in its original packaging at room temperature (below 25°C) for up to 12 weeks prior to administration.
Discard Sublocade if left at room temperature for longer than 12 consecutive weeks.

6.5 Nature and Contents of Container

Sublocade is supplied in a single use pack.
Sublocade buprenorphine 100 mg/0.5 mL modified release injection solution for subcutaneous administration is supplied as a single use dose in a 1 mL plastic syringe with a plunger stopper (bromobutyl rubber), together with a pre-packaged sterile safety needle (19 G, 16 mm with polypropylene shield).
Sublocade buprenorphine 300 mg/1.5 mL modified release solution for injection for subcutaneous administration is supplied as a single-use dose in a 2.25 mL plastic syringe with a plunger stopper (bromobutyl rubber), together with a pre-packaged sterile safety needle (19 G, 16 mm with polypropylene shield).
Each assembled syringe with plastic plunger rod is supplied in an aluminium foil-laminate pouch containing an oxygen absorbing desiccant. The pouch is in a labelled paperboard carton along with a sterile safety needle and labelling.

6.6 Special Precautions for Disposal

Dispose of all syringe components in a secure sharps disposal container.

6.7 Physicochemical Properties

Chemical structure.

The chemical structure of buprenorphine is:

CAS number.

The CAS number is 52485-79-7.

7 Medicine Schedule (Poisons Standard)

Schedule 8.

Summary Table of Changes