Consumer medicine information

Buvidal Weekly

Buprenorphine

BRAND INFORMATION

Brand name

Buvidal Weekly

Active ingredient

Buprenorphine

Schedule

SUMMARY CMI

Buvidal^® Weekly

Consumer Medicine Information (CMI) summary

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

WARNING
Risk of Serious Harm or Death with Intravenous Administration
Hazardous and harmful use
Life threatening respiratory depression
Concomitant use of benzodiazepines and other central nervous system (CNS) depressants, including alcohol.

1. Why am I being given Buvidal Weekly?

Buvidal Weekly contains the active ingredient buprenorphine. Buprenorphine acts as a substitute for opioids and helps opioid withdrawal. Buvidal Weekly is used is used for initiation and maintenance treatment of opioid dependence.

For more information, see Section 1. Why am I being given Buvidal Weekly? in the full CMI.

2. What should I know before I am given Buvidal Weekly?

Do not use if you have ever had an allergic reaction to Buvidal Weekly 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, problems with excess alcohol use, history of seizures or breathing problems.

For more information, see Section 2. What should I know before I am given Buvidal Weekly? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Buvidal Weekly 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 am I given Buvidal Weekly?

Your doctor will prescribe the correct starting dose of Buvidal Weekly for you. During treatment with Buvidal Weekly, your doctor may decrease or increase the dose of Buvidal Weekly according to your needs.

More instructions can be found in Section 4. How am I given Buvidal Weekly? in the full CMI.

5. What should I know while being given Buvidal Weekly?

Things you should do	Remind any doctor, dentist or pharmacist or other health professionals you visit that you are being given Buvidal Weekly.
Things you should not do	Do not stop treatment of this medicine suddenly, you should discuss stopping your treatment with your doctor. Stopping treatment may cause withdrawal symptoms.
Driving or using machines	Be careful driving or operating machinery until you know how Buvidal Weekly affects you. This medicine may cause dizziness and drowsiness in some people.
Drinking alcohol	If you drink alcohol with this medicine, the risk of breathing problems may be increased.

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

6. Are there any side effects?

Serious side effects that could occur while you are receiving Buvidal Weekly include wheezing, difficulty breathing, swelling of the eyelids, face, tongue, lips, throat or hands; rash or itching especially those covering your whole body. These may be signs of a life-threatening allergic reaction.

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.

WARNING: Risk of Serious Harm or Death with Intravenous Administration

Buvidal Weekly must not be injected into your veins as it could cause serious harm or death by stopping your blood flow and the possible formation of clots in your veins and lungs which could be life-threatening.

Hazardous and harmful use

Although Buvidal Weekly is indicated for the treatment of opioid dependence it still poses risks of hazardous and harmful use which can lead to overdose and death. You should be monitored for an ongoing risk of hazardous and harmful use regularly during opioid substitution therapy with Buvidal.

Life threatening respiratory depression

Serious, life-threatening or fatal respiratory depression may occur with the use of Buvidal Weekly. Be aware of situations which increase the risk of respiratory depression, and monitor patients closely, especially on initiation or following a dose increase.

Concomitant use of benzodiazepines and other central nervous system (CNS) depressants, including alcohol.

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. 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 taking Buvidal Weekly.

FULL CMI

Buvidal^® Weekly

Active ingredient(s): Buprenorphine

Consumer Medicine Information (CMI)

This leaflet provides important information about using Buvidal Weekly. 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 Buvidal Weekly.

Where to find information in this leaflet:

1. Why am I being given Buvidal Weekly?
2. What should I know before I am given Buvidal Weekly?
3. What if I am taking other medicines?
4. How am I given Buvidal Weekly?
5. What should I know while being given Buvidal Weekly?
6. Are there any side effects?
7. Product details

1. Why am I being given Buvidal Weekly?

Buvidal Weekly contains the active ingredient buprenorphine.

Buvidal Weekly is Schedule 8 medicine classification, it contains buprenorphine which acts as a substitute for opioids and it helps withdrawal from opioids over a period of time. This medicine is available only with a doctor's prescription.

Buvidal Weekly is used is used for initiation and maintenance treatment of opioid dependence, with or without prior stabilisation on sublingual buprenorphine or buprenorphine/naloxone, within a framework of medical, social and psychological support.

2. What should I know before I am given Buvidal Weekly?

Warnings

Do not receive Buvidal Weekly 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.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin
Do not receive Buvidal Weekly if you are under 16 years of age. Safety and effectiveness in children younger than 16 years has not been established.
Do not receive Buvidal Weekly if you have serious medical problems:
with your liver
with your breathing such as asthma
if you are intoxicated due to alcohol or have delirium tremens (the ‘shakes’ and hallucinations)

Check with your doctor if you:

Have any other medical conditions:
any kidney disease
liver problems such as hepatitis
low blood pressure
recently suffered a head injury or brain disease
a urinary disorder (especially linked to enlarged prostate in men)
thyroid problems
an adrenocortical disorder (eg Addison's disease)
gall bladder problems
problems with excess alcohol use
history of seizures.
take any medicines for any other condition

If you have not told your doctor about any of the above, tell him/her before you receive Buvidal Weekly.

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.

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

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 Buvidal Weekly and affect how it works.

Medicines that may increase the effect of Buvidal Weekly include:

certain medicines for treating anxiety and sleeping disorders such as benzodiazepines
gabapentinoids
alcohol
cannabis
medicines that may make you feel sleepy, which may be used for treating depression, convulsion, pain and high blood pressure. These may include methadone, anti-cough medications, anti-depressants, antihistamines, sedatives, barbiturates, some anxiolytics, neuroleptics, clonidine, and monoamine oxidase inhibitors
strong pain killers such as morphine, methadone and fentanyl
certain medicines for treating HIV/AIDS such as ritonavir, nelfinavir or indinavir
certain medicines for treating fungal and bacterial infections such as ketoconazole, itraconazole or macrolide antibiotics.

Medicines that may reduce the effect of Buvidal Weekly include:

naltrexone and nalmefene, which are used to treat dependence disorders
certain medicines used to treat epilepsy such as phenobarbital, carbamazepine and phenytoin
certain medicines used to treat tuberculosis such as rifampicin

Medicines that may be affected by Buvidal (Weekly)

Medicines that may increase serotonin levels, such as escitalopram, duloxetine, venlafaxine, tricyclic antidepressants, and phenelzine

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

4. How am I given Buvidal Weekly?

How much will I be given

Your doctor will determine the best dose for you. During your treatment, the doctor may adjust the dose, depending on how you respond to the medicine.
You will receive treatment with Buvidal Weekly in a hospital, clinic or pharmacy.
Buvidal Weekly is given by a healthcare professional as an injection under the skin (subcutaneously) in the buttock, thigh, abdomen or upper arm.

Starting treatment with Buvidal Weekly

Your doctor will prescribe the correct starting dose of Buvidal Weekly for you.

Maintenance treatment and dose adjustment

During maintenance treatment with Buvidal Weekly, your doctor may decrease or increase the dose of this medicine according to your needs. If required, you may receive one 8 mg dose on top of your regular weekly doses. The maximum weekly dose of Buvidal Weekly treatment that that you can receive is 32 mg with plus an additional 8 mg dose.

Changing between weekly treatment and monthly treatment

You may be changed from weekly dosing to monthly dosing or from monthly dosing to weekly dosing. Your doctor will prescribe the correct dose when you change between dosing intervals.

How long will it be given for

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition but does not cure it. It is important to keep taking your medicine even if you feel well.

After a period of successful treatment, your doctor may gradually reduce your dose. Depending on your condition, your dose may continue to be reduced under careful medical supervision.

If you forget your treatment with Buvidal Weekly

It is very important for you to keep all your appointments to receive Buvidal Weekly. If you miss an appointment, ask your doctor when to schedule your next dose.

If you are given too much Buvidal Weekly

As Buvidal Weekly is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. Buvidal Weekly comes in a syringe pre-filled with the dose your doctor has prescribed. However, if you feel you have been given too much of Buvidal Weekly you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), 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 being given Buvidal Weekly?

Important things to be aware of while you are being given this medicine

Breathing problems

Some people have died from the reduced ability to breathe (respiratory depression) because they took a similar medicine also containing buprenorphine, together with central nervous system depressants such as benzodiazepines, gabapentinoids, alcohol or other opioids.

Drowsiness

This medicine may cause drowsiness especially when taken with alcohol or other central nervous system depressants such as benzodiazepines, tranquilisers, sedatives, gabapentinoids or hypnotics.

Dependence

This medicine can cause dependence.

Liver damage

Liver damage has been reported after taking buprenorphine, especially when the medicine is misused. This could also be due to viral infections (chronic hepatitis C), alcohol abuse, anorexia or use of other medicines with the ability to harm your liver. Regular blood tests may be conducted by your doctor

Blood pressure

This product may cause your blood pressure to drop suddenly, causing you to feel dizzy, if you get up too quickly from sitting or lying down.

Athletes

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

Elderly

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

Diagnosis of unrelated medical conditions

This medicine may mask pain symptoms that could assist in the diagnosis of some diseases. Do not forget to advise your doctor if you are being given this medicine.

Things you should do

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

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

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

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

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

Your doctor may do some tests to check your liver function from time to time to make sure the medicine is working and to prevent unwanted side effects.

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

Things you should not do

Do not stop treatment with this medicine suddenly, you should discuss stopping your treatment with your doctor. Stopping treatment may cause withdrawal symptoms.

Driving or using machines

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

Buvidal Weekly may cause dizziness and drowsiness in some people. This is more likely to happen at the start of treatment and when your dose is being changed. This effect can be worse if you drink alcohol or take other sedative medicines. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may cause dizziness and risk of respiratory failure may be increased.

Looking after your medicine

The hospital, clinic. or pharmacy where you receive your treatment will store Buvidal Weekly under the required conditions.

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

Effects on the body - General:

flushing
tremor
decreased appetite
pain when urinating
swelling of the legs and arms

Effect on the body - Nervous system related:

difficulty sleeping
headache
sleepiness
dizziness, feeling off balance
malaise, yawning
dizziness or fainting when standing up
headache-migraine

Effect on the body - Stomach related:

upset stomach including, nausea, vomiting and diarrhoea or constipation
upset stomach including stomach pain, wind, indigestion
dry mouth

Effect on the body - Skin related:

redness, soreness, swelling or itching at the Buvidal Weekly injection site
hives, rash, itching

Effects on the body - Eye related:

abnormal vision

Effects on the body - Infection related:

flu like symptoms, such as chills, fever, sore throat, coughing, runny nose, watery eyes and sweating
respiratory infection

Effects on the body - Psychiatric related

depression, abnormal thinking, agitation, nervousness, anger, hallucinations
anxiety

Effect on the body - Pain related:

pain in the abdomen, back, and muscles, leg cramps, chest pain, neck pain, menstrual pain, muscle weakness
pain in joints,

Effect on the body - Breathing related:

shortness of breath, enlarged or sore lymph nodes

Effects on the body - heart related:

strong or irregular heartbeat

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

Effects on the body- breathing related:

sudden wheezing, difficulty breathing, swelling of the eyelids, face, tongue, lips, throat or hands; rash or itching especially those covering your whole body. These may be signs of a life-threatening allergic reaction.
if you start to breathe more slowly or weakly than expected (respiratory depression).

Effect on body- General:

severe fatigue (tiredness), have no appetite or if your skin or eyes look yellow. These may be symptoms of liver damage.
if you start to feel faint, as this may be a sign of low blood pressure.

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.

Some of these side effects such as liver problems can only be found when your doctor does tests from time to time to check your progress.

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 Buvidal Weekly contains

Active ingredient (main ingredient)	buprenorphine
Other ingredients (inactive ingredients)	phosphatidyl choline [soybean], glyceryl dioleate, ethanol absolute (alcohol), less than 100 mg per dose
Potential allergens	Contains soya bean products

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

What Buvidal Weekly looks like

Buvidal Weekly is a modified release solution for injection. Each pre-filled syringe contains a yellowish to yellow clear liquid.

Pre-filled syringe containing 8 mg buprenorphine in 0.16 ml solution - AUST R 294997.

Pre-filled syringe containing 16 mg buprenorphine in 0.32 ml solution - AUST R 295010

Pre-filled syringe containing 24 mg buprenorphine in 0.48 ml solution - AUST R 295013

Pre-filled syringe containing 32 mg buprenorphine in 0.64 ml solution - AUST R 295042

Who distributes Buvidal Weekly?

Camurus Pty Ltd
223 Liverpool St
Darlinghurst, NSW, 2010
Phone Toll Free: 1800 142 038

® = Registered Trademark

This leaflet was prepared in March 2023.

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Buvidal Weekly

Active ingredient

Buprenorphine

Schedule

1 Name of Medicine

Buvidal Weekly 8 mg/0.16 mL buprenorphine modified release solution for injection.
Buvidal Weekly 16 mg/0.32 mL buprenorphine modified release solution for injection.
Buvidal Weekly 24 mg/0.48 mL buprenorphine modified release solution for injection.
Buvidal Weekly 32 mg/0.64 mL buprenorphine modified release solution for injection.

2 Qualitative and Quantitative Composition

Buvidal Weekly modified release solutions for injection prefilled syringes contain either 8 mg/0.16 mL, 16 mg/0.32 mL, 24 mg/0.48 mL or 32 mg/0.64 mL buprenorphine as the active ingredient.
These strengths also contain small amounts of ethanol absolute.
For full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Modified release solution for injection.
Yellowish to yellow clear liquid in a pre-filled syringe.

4 Clinical Particulars

4.1 Therapeutic Indications

Buvidal Weekly is indicated for initiation and maintenance treatment of opioid dependence, with or without prior stabilisation on sublingual buprenorphine or buprenorphine/naloxone, within a framework of medical, social and psychological support.

4.2 Dose and Method of Administration

Administration of Buvidal Weekly is restricted to healthcare professionals. Buvidal Weekly is given by subcutaneous injection. Buvidal Weekly is indicated for initiation and maintenance treatment of patients with opioid dependence in patients who have been stabilised on treatment.

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.
To avoid precipitating symptoms of withdrawal, treatment with Buvidal should be started when objective and clear signs of mild to moderate withdrawal are evident (see Section 4.4 Special Warnings and Precautions for Use). Consideration should be given to the types of opioid used (that is long- or short-acting opioid), time since last opioid use and the degree of opioid dependence.
For patients using heroin or short-acting opioids, the initial dose of Buvidal must not be administered until at least 6 hours after the patient last used opioids.
For patients receiving methadone, the dose of methadone should be reduced to a maximum of 30 mg/day before starting treatment with Buvidal which should not be administered until at least 24 hours after the patient last received a methadone dose. Buvidal may trigger withdrawal symptoms in methadone-dependent patients.

Dosage.

Buvidal is indicated for individualised therapy across treatment phases from initiation and stabilisation to maintenance treatment.
The depot administration is used to support treatment adherence and avoid misuse and diversion.
The recommended starting dose is 16 mg of Buvidal Weekly, with one or two additional 8 mg doses at least 1 day apart, to a target dose of 24 mg or 32 mg during the first treatment week. The recommended dose for the second treatment week is the total dose administered during the week of initiation.
Treatment with Buvidal Monthly can be started after treatment initiation with Buvidal Weekly, in accordance with the dose conversion in Table 1 and once patients have been stabilised on weekly treatment.

Transitioning of patients from sublingual buprenorphine to Buvidal Weekly.

Patients stabilised on sublingual buprenorphine or buprenorphine/naloxone may be transitioned directly to Buvidal Weekly, starting on the day after the last daily sublingual treatment dose. Please see Table 1 for transition recommendations.

Maintenance treatment and dose adjustments.

Buvidal Weekly should be administered according to individual patient's needs as well as clinical judgement and at doses established after switching. A maximum of one supplemental Buvidal Weekly 8 mg dose may be administered at an unscheduled visit between the regular weekly doses. The maximum dose per week for patients who are on Buvidal Weekly treatment is 32 mg with an additional 8 mg dose.

Transitioning patients between Buvidal Weekly and Buvidal Monthly.

Patients may be switched from weekly to monthly dosing or from monthly to weekly dosing based on the recommendations in Table 2.

Switching from Buvidal Weekly to sublingual daily buprenorphine.

Treatment with sublingual buprenorphine should be initiated one week after the last dose of Buvidal Weekly according to the recommendations in Table 1.

Missed doses.

Dosing windows.

To avoid missed doses, the weekly dose may be administered up to 2 days before or after the weekly time point.

Missed doses.

If a dose is missed, the next dose should be administered as soon as practical.

Termination of treatment.

If Buvidal Weekly treatment is discontinued, its modified release characteristics must be considered.

Method of administration.

Buvidal Weekly is intended for subcutaneous use only. It should be injected slowly, into the subcutaneous tissue of the buttock, thigh, abdomen, or upper arm, provided there is sufficient subcutaneous tissue.
Each injection must be administered by a healthcare professional.
The administered dose should be in a single injection and not divided. Each pre-filled syringe of Buvidal Weekly is for single use in one patient only. Discard any residue.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Do not use Buvidal Weekly prefilled syringes exhibiting particulate matter or discolouration.
Injection sites should be rotated between injections. The dose must not be administered intravascularly or intradermally.

Special populations.

Elderly.

The efficacy and safety of buprenorphine in elderly patients > 65 years has not been established.
In general, recommended dosing of Buvidal Weekly for elderly patients with normal renal function is the same as for younger adult patients with normal renal function. However, because elderly patients may have diminished renal/hepatic function, dose adjustment may be necessary (see Renal impairment and Hepatic impairment below).

Hepatic impairment.

Buprenorphine should be used with caution in patients with moderate hepatic insufficiency (see Section 5.2 Pharmacokinetic Properties). In patients with severe hepatic insufficiency, the use of buprenorphine is contraindicated (see Section 4.3 Contraindications).

Renal impairment.

Modification of the buprenorphine dose is not generally required for patients with renal impairment. Caution is recommended when dosing patients with severe renal impairment, who may require dose adjustment (creatinine clearance < 30 mL/min) (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use).

Paediatric population.

The safety and efficacy of Buvidal Weekly in adolescents and children below 16 years of age has not been established. No data are available. (See Section 4.4 Special Warnings and Precautions for Use; Section 4.3 Contraindications).

4.3 Contraindications

Hypersensitivity to buprenorphine or to any of the excipients listed in Section 6.1.
Children less than 16 years of age.
Severe respiratory insufficiency.
Severe hepatic insufficiency (Child-Pugh C).
Acute alcoholism or delirium tremens.

4.4 Special Warnings and Precautions for Use

Administration.

Care must be taken to avoid inadvertent injection of Buvidal Weekly into a blood vessel or intradermally (into the skin).
Intravenous injection presents significant risk of serious harm or death as Buvidal Weekly forms a gel depot upon contact with body fluids. Occlusion, local tissue damage, and thrombo‐embolic events, including life threatening pulmonary emboli may occur if administered intravenously.

Concomitant use of benzodiazepines and other central nervous system (CNS) depressants, including alcohol.

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 taking Buvidal Weekly.

General.

Opioids may cause orthostatic hypotension in ambulatory patients.
Opioids may elevate cerebrospinal fluid pressure, which may cause seizures. Therefore, opioids should be used with caution in patients with head injury, intracranial lesions, other circumstances where cerebrospinal pressure may be increased, or history of seizure.
Opioids should be used with caution in patients with hypotension, prostatic hypertrophy or urethral stenosis.
Opioid-induced miosis, 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.
Opioids should be used with caution in patients with myxoedema, hypothyroidism, or adrenal cortical insufficiency (e.g. Addison's disease).
Opioids have been shown to increase intracholedochal pressure, and should be used with caution in patients with dysfunction of the biliary tract.
Opioids should be administered with caution to elderly or debilitated patients.

Misuse, abuse and diversion.

Buprenorphine is subject to misuse, abuse and diversion, similar to other opioids, legal or illicit. Buvidal Weekly must be administered directly to the patient by a healthcare professional. Buvidal Weekly should not be made available directly to patients. Although Buvidal Weekly 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 Buvidal Weekly.

Respiratory depression.

Serious, life‐threatening or fatal respiratory depression may occur with the use of Buvidal Weekly. Be aware of situations which increase the risk of respiratory depression, and monitor patients closely, especially on initiation or following a dose increase. A number of cases of death due to respiratory depression have been reported for patients being treated with buprenorphine, particularly when used in combination with benzodiazepines (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) or when buprenorphine was not used according to prescribing information. Deaths have also been reported in association with concomitant administration of buprenorphine and other depressants such as alcohol, gabapentinoids (see Section 4.5) or other opioids. If buprenorphine is administered to non-opioid dependent individuals who are not tolerant to the effects of opioids, potentially fatal respiratory depression may occur.
Buprenorphine should be used with care in patients with respiratory insufficiency (e.g. chronic obstructive pulmonary disease, asthma, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, pre-existing respiratory depression or kyphoscoliosis). The use of buprenorphine is contraindicated in patients with severe respiratory insufficiency (see Section 4.3 Contraindications).
Buprenorphine may cause severe, possibly fatal, respiratory depression in children and non-dependent persons who accidentally or deliberately ingest it.

Dependence.

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration can produce opioid dependence. Studies in animals, as well as clinical experience, have demonstrated that buprenorphine may cause dependence, albeit at a lower level than a full agonist (e.g. morphine).

Precipitation of opioid withdrawal syndrome.

When initiating treatment with buprenorphine, it is important to be aware of the partial agonist profile of buprenorphine. Buprenorphine products have caused precipitated withdrawal symptoms in opioid-dependent patients when administered before the agonist effects resulting from recent opioid use or misuse have subsided. To avoid precipitated withdrawal, induction must be undertaken when objective signs and symptoms of mild to moderate withdrawal are evident (see Section 4.2 Dose and Method of Administration).
Discontinuation of treatment may result in a withdrawal syndrome that may be delayed in onset.

Hepatitis and hepatic events.

Cases of acute hepatic injury have been reported in opioid-dependent patients both in clinical trials and in post-marketing adverse reaction reports with buprenorphine products. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of cytolytic hepatitis, hepatic failure, hepatic necrosis, hepatorenal syndrome, hepatic encephalopathy and death. In many cases, the presence of pre-existing liver enzyme abnormalities, genetic disease, infection with hepatitis B or hepatitis C virus, alcohol abuse, anorexia, concomitant use of other potentially hepatotoxic drugs and ongoing injecting drug use may have a causative or contributory role. These underlying factors must be taken into consideration before prescribing buprenorphine and during treatment. When a hepatic event is suspected, further biological and etiological evaluation is required. Depending on the findings, Buvidal Weekly may be discontinued. If treatment is continued, hepatic function should be monitored closely.

Use in hepatic impairment.

Buprenorphine is extensively metabolised in the liver. The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a post-marketing study on another marketed buprenorphine product. Plasma levels of buprenorphine were found to be higher in patients with moderate and severe hepatic impairment. Patients should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. Buprenorphine should be used with caution in patients with moderate hepatic impairment (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration). The use of buprenorphine is contraindicated in patients with severe hepatic insufficiency (see Section 4.3 Contraindications).

Use in renal impairment.

Renal elimination plays a relatively small role (approximately 30%) in the overall clearance of buprenorphine; 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 (creatinine clearance < 30 mL/min), (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Use in the elderly.

No data available.

Paediatric use.

The safety and efficacy of buprenorphine in children below the age of 16 years has not been established. Due to the limited amount of data in adolescents (from 16 up to 18 years), patients in this age group should be more closely monitored during treatment.

Neonatal abstinence syndrome.

Buprenorphine should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. 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, withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth (see Section 4.6, Use in pregnancy).

Allergic reactions.

Cases of acute and chronic hypersensitivity to buprenorphine have been reported. 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 Buvidal Weekly.

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

No interaction studies have been performed with Buvidal Weekly.
Buprenorphine should be used cautiously when co-administered with:

Benzodiazepines.

This combination may result in death due to respiratory depression of central origin. Therefore, dosages must be closely monitored, and this combination must be avoided in cases where there is a risk of misuse. Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines whilst taking this product and should also be cautioned to use benzodiazepines concurrently with this product only as directed by their doctor (see Section 4.4 Special Warnings and Precautions for Use).

Gabapentinoids.

This combination may result in death due to respiratory depression. Therefore, dosages must be closely monitored and this combination must be avoided in cases where there is a risk of misuse. Patients should be cautioned to use gabapentinoids concurrently with this product only as directed by their physician (see Section 4.4).

Alcoholic drinks or medications containing alcohol.

Alcohol increases the sedative effect of buprenorphine (see Section 4.4 Special Warnings and Precautions for Use).

Other central nervous system depressants.

Other opioid derivatives (e.g. methadone, analgesics and antitussives); certain antidepressants, antihistamines (e.g. sedating H₁-receptor antagonists), barbiturates, anxiolytics other than benzodiazepines, cannabis, neuroleptics, clonidine and related substances. These combinations increase central nervous system depression. The reduced level of alertness can make driving and using machinery hazardous (see Section 4.4 Special Warnings and Precautions for Use).

Opioid analgesics.

Adequate analgesia may be difficult to achieve when administering a full opioid agonist in patients receiving buprenorphine. The potential for overdose also exists with a full agonist, especially when attempting to overcome buprenorphine partial agonist effects, or when buprenorphine plasma levels are declining (see Section 4.4 Special Warnings and Precautions for Use).

Naltrexone and nalmefene.

These opioid antagonists can block the pharmacological effects of buprenorphine. For opioid-dependent patients currently receiving buprenorphine treatment, naltrexone may precipitate a sudden onset of prolonged and intense opioid withdrawal symptoms. For patients currently receiving naltrexone treatment, the intended therapeutic effects of buprenorphine administration may be blocked by naltrexone.

CYP3A4 inhibitors.

An interaction study of buprenorphine with ketoconazole (a potent inhibitor of CYP3A4) resulted in increased C_max (approximately 50%) and AUC (approximately 70%) of buprenorphine and, to a lesser extent, of the metabolite, norbuprenorphine. Patients receiving buprenorphine should be closely monitored and may require dose reduction if combined with potent CYP3A4 inhibitors (e.g. protease inhibitors like ritonavir, nelfinavir or indinavir, or azole antifungals such as ketoconazole or itraconazole, or macrolide antibiotics).

CYP3A4 inducers.

Concomitant use of CYP3A4 inducers with buprenorphine may decrease buprenorphine plasma concentrations, potentially resulting in sub-optimal treatment of opioid dependence with buprenorphine. It is recommended that patients receiving buprenorphine should be closely monitored if inducers (e.g. phenobarbital, carbamazepine, phenytoin or rifampicin) are co-administered. The dose of either buprenorphine or the CYP3A4 inducer may need to be adjusted accordingly.

Monoamine oxidase inhibitors (MAOI).

Possible exacerbation of the opioid effects, based on experience with morphine.

Serotonergic medicinal products, such as MAO inhibitors, selective serotonin re-uptake inhibitors, serotonin noradrenaline (norepinephrine) re-uptake inhibitors, or tricyclic antidepressants.

Risk of serotonin syndrome, a rare but potentially life-threatening condition, is increased.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no or limited data on effects of buprenorphine on human fertility.
An effect of buprenorphine on fertility in animals has not been seen.
There were no effects on mating performance or on fertility of male rats following short term treatment with buprenorphine at systemic exposures up to 38 times the maximum anticipated human exposure (based on plasma AUC).
(Category C)
There are no or limited data from the use of buprenorphine in pregnant women.
Buprenorphine readily crosses the placental barrier. Treatment with buprenorphine during pregnancy was associated with difficult parturition and fetotoxicity, including post-implantation loss and decreased postnatal survival, in rats and rabbits at systemic exposures higher than the maximum anticipated human exposure of buprenorphine by Buvidal Weekly. Teratology toxicity studies in rats by intramuscular administration concluded that buprenorphine is not embryotoxic or teratogenic and has no marked effects on weaning potential. Maternal oral administration at high doses (80 mg/kg/day) during gestation and lactation resulted in delayed postnatal development of some neurological functions (surface righting reflex and startle response) in neonatal rats with NOEL of 8 mg/kg/day PO.
Buprenorphine should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Towards the end of pregnancy, buprenorphine may induce respiratory depression in the newborn infant even after a short period of administration. Long-term administration during the last three months of pregnancy may cause a withdrawal syndrome in the neonate (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus or convulsions). The syndrome is generally delayed from several hours to several days after birth.
Due to the long half-life of buprenorphine, neonatal monitoring for several days after birth should be considered to prevent the risk of respiratory depression or withdrawal syndrome in neonates.
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.
Buprenorphine and its metabolites are excreted in human breast milk and Buvidal should be used with caution during breast-feeding.

4.7 Effects on Ability to Drive and Use Machines

Buprenorphine has moderate influence on the ability to drive and use machines when administered to opioid-dependent patients. Buprenorphine may cause drowsiness, dizziness or impaired thinking, especially during treatment induction and dose adjustment. If taken together with alcohol or central nervous system depressants, the effect is likely exaggerated (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Patients should be cautioned about operating hazardous machinery in case buprenorphine may affect their ability to engage in such activities.

4.8 Adverse Effects (Undesirable Effects)

The adverse events most frequently reported in the double-blind, pivotal phase 3 efficacy clinical trial were constipation, symptoms commonly associated with drug withdrawal, such as headache, nausea, insomnia and vomiting, injection site related events such as injection site pain, injection site pruritus and injection site erythema, urinary tract infection and upper respiratory tract infection.
Table 3 provides a summary of treatment-emergent adverse events (TEAEs) reported for at least 1% of patients in either treatment group by system organ class and preferred term (HS-11-421 safety population).
The pattern of TEAEs and serious adverse events (SAEs) was comparable between treatment groups and was consistent with the safety profile of SL BPN.
Overall in study HS-11-421, 247 subjects (57.7%) experienced at least 1 TEAE during the study (119 [55.3%], SL BPN/NX; 128 [60.1%], Buvidal), and 88 (20.6%) subjects had at least 1 injection site TEAE (48 [22.3%], SL BPN/NX; 40 [18.8%], Buvidal). Approximately 30% of all subjects had at least 1 study drug-related TEAE (18.0%, injection site TEAE; 18.0%, non-injection site TEAE).
Overall (across both treatment groups), the most common TEAEs (regardless of drug attribution) were injection site pain (8.4%), headache (7.7%), constipation (7.5%), nausea (7.5%), injection site pruritus (6.1%), and injection site erythema (5.6%). Other injection site TEAEs that occurred in > 1% of all subjects were injection site reaction (3.5%), injection site swelling (3.5%), injection site induration (2.3%), injection site inflammation (2.3%), injection site bruising (1.2%) and injection site ulcer (1.2%).
Incidences of injection site TEAEs were generally comparable between treatment groups, i.e. after injection of active Buvidal or placebo Buvidal. The incidence of injection site inflammation was slightly higher in the SL BPN/NX group (3.7%) than in the Buvidal group (0.9%). Injection site TEAEs, which were generally characterised as injection site pain, pruritus, and erythema, were all mild or moderate in intensity, with most being mild (see Tables 3 and 4).

Adverse reactions reported with buprenorphine.

The following adverse reactions have been reported with the use of buprenorphine products and may occur with Buvidal Weekly.
Very common: Insomnia, headache, nausea, hyperhidrosis, drug withdrawal syndrome, and pain.
Common: Bronchitis, infection, influenza, pharyngitis, rhinitis, lymphadenopathy, decreased appetite, agitation, anxiety, depression, hostility, nervousness, paranoia, thinking abnormal, dizziness, hypertonia, migraine, paraesthesia, somnolence, syncope, tremor, lacrimal disorder, mydriasis, palpitations, vasodilatation, cough, dyspnoea, yawning, abdominal pain, constipation, diarrhoea, dry mouth, dyspepsia, gastrointestinal disorder, flatulence, vomiting, rash, arthralgia, back pain, bone pain, muscle spasms, myalgia, neck pain, dysmenorrhoea, asthenia, chest pain, chills, malaise, oedema peripheral and pyrexia.
In addition, hallucination, urinary retention and vertigo have been reported with the use of buprenorphine products.

Post-marketing experience.

Injection site-related adverse reactions of abscess, ulceration and necrosis have been reported during post-marketing use with Buvidal (with frequency not known).

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.

Respiratory depression, as a result of central nervous system depression, is the primary symptom requiring intervention in the case of buprenorphine overdose because it may lead to respiratory arrest and death. Preliminary symptoms of overdose may also include excessive sweating, somnolence, amblyopia, miosis, hypotension, nausea, vomiting and/or speech disorders.

Treatment.

General supportive measures should be instituted, including close monitoring of respiratory and cardiac status of the patient. Symptomatic treatment of respiratory depression, following standard intensive care measures, should be instituted. A patent airway and assisted or controlled ventilation must be assured. The patient should be transferred to an environment within which full resuscitation facilities are available. If the patient vomits, precautions must be taken to prevent aspiration. Use of an opioid antagonist (i.e. naloxone) is recommended, despite the modest effect it may have in reversing the respiratory symptoms of buprenorphine compared with its effects on full agonist opioid agents.
The long duration of action of buprenorphine and the modified release from Buvidal Weekly, should be taken into consideration when determining 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.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia) for advice.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Buprenorphine is a high-affinity partial agonist at the human mu-opioid receptor and is a high-affinity antagonist at the δ (delta) and κ (kappa) opioid receptors, as well as being a moderate-affinity partial agonist for nociception opioid receptors.
Its activity in opioid maintenance treatment is attributed to its slowly reversible properties with the mu-opioid receptors which, over a prolonged period, might minimise the need of illicit opioids for patients with opioid dependence.
Opioid agonist ceiling effects were observed during clinical pharmacology studies in opioid-dependent persons.

Pharmacodynamic effects.

The blockade of subjective opioid effects of Buvidal Weekly was investigated in a multiple-dose, opioid challenge study in 47 patients with moderate to severe opioid dependence. After stabilisation on immediate-release morphine, all patients completed a 3-day qualification/baseline hydromorphone challenge session, which included intramuscular administration of 3 doses of hydromorphone (0 mg [placebo], 6 mg and 18 mg) once daily for 3 consecutive days in a randomised, double-blind, crossover manner. Following the qualification phase, eligible patients received 2 randomised doses of 24 mg or 32 mg Buvidal Weekly. Two hydromorphone challenge sessions (3 consecutive days each) were conducted after each dose of Buvidal Weekly.
The primary endpoint was maximum rating (E_max) on the visual analogue scale (VAS) for drug liking. During the qualification/baseline phase, patients could differentiate between hydromorphone 6 mg or 18 mg and placebo and showed an appropriate hydromorphone dose response (i.e. increase in drug liking E_max with increasing dose of hydromorphone). Minimal differences in E_max scores were observed between placebo and hydromorphone 6 mg or 18 mg during the hydromorphone challenge sessions performed after each administration of 24 mg or 32 mg Buvidal Weekly. The pre-defined upper bound of the 95% confidence interval (CI) for complete blockade of drug liking was 11 mm VAS E_max between hydromorphone doses and placebo. Complete blockade (i.e. VAS E_max ≤ 11 mm between hydromorphone and placebo injections) was observed at all challenge sessions with both doses of Buvidal Weekly.
Secondary VAS E_max measures (including high, good drug effects, any drug effects, and desire to use) were also blocked or suppressed by both weekly doses.

Clinical trials.

Clinical efficacy.

Study HS-11-421.

The efficacy and safety of Buvidal in the treatment of opioid dependence were established in a pivotal phase 3, randomised, double-blind, double-dummy, active-controlled, flexible-dose study in patients with moderate to severe opioid dependence who were not currently participating in opioid substitution treatment. In this study, 428 patients were randomised to one of two treatment groups. Patients in the Buvidal group (n = 213) received weekly injections (16 mg to 32 mg) at the clinic during the first 12 weeks, followed by monthly injections (64 mg to 160 mg) during the last 12 weeks, plus daily take-home doses of sublingual placebo tablets during the complete treatment period. Patients in the sublingual buprenorphine/naloxone group (n = 215) received weekly placebo injections at the clinic during the first 12 weeks, followed by monthly placebo injections during the last 12 weeks, plus daily take-home sublingual buprenorphine/naloxone tablets during the complete treatment period (8 mg to 24 mg during the first 12 weeks and 8 mg to 32 mg during the last 12 weeks). During the 12 weeks with monthly injections, patients in both groups could receive one additional 8 mg weekly dose of Buvidal Weekly per month, if needed. Patients attended 12 weekly visits during the first 12 weeks and 6 visits during the last 12 weeks (3 scheduled monthly visits and 3 random urine toxicology visits). At each visit, efficacy and safety outcome measures were assessed. The primary endpoint of the study was to demonstrate non-inferiority in mean percentage of urine samples negative for illicit opioids during treatment weeks 1 to 24 for the Buvidal group compared with the sublingual buprenorphine/naloxone group. Non-inferiority was to be concluded if the lower limit of the two-sided 95% confidence interval (CI) for the difference (Buvidal and sublingual buprenorphine/naloxone) in percent negative urine samples was above -11%.
The study met the primary endpoint of non-inferiority in mean percentage of urine samples negative for illicit opioids (p < 0.001). The Least Squares mean (95% CI) was 35.1% (30.3%, 40.0%) in the Buvidal group and 28.4% (23.5%, 33.3%) in the sublingual buprenorphine/naloxone group. The difference between treatment groups was 6.7% (Buvidal vs sublingual buprenorphine/naloxone) with a 95% CI of -0.1%, 13.6%. Figure 1 shows percentage of patients with urine samples negative for illicit opioids over the 24-week treatment period.

Superiority of Buvidal versus sublingual buprenorphine/naloxone was met for the secondary endpoint cumulative distribution function (CDF) for percentage of opioid-negative urine samples during treatment weeks 4 to 24. The median CDF was 26.7% for Buvidal and 6.7% for sublingual buprenorphine/naloxone (p = 0.008), Figure 2. A closed testing procedure controlling for overall type 1 error rate (5%, two-sided) with a pre-specified test order was applied, where testing for superiority only was applicable if the primary outcome demonstrated non-inferiority.

When the primary analysis was repeated in a post hoc analysis without imputation of missing urine samples, a significant difference between treatment groups of 8.7% (95% CI: 0.9%, 16.4%) was demonstrated for Buvidal compared to sublingual buprenorphine/naloxone (p = 0.028). Post hoc sensitivity analyses of CDF for urine samples negative for illicit opioids over the full treatment period (weeks 1 to 24) confirmed superiority of Buvidal (median 22.2%) compared to sublingual buprenorphine/naloxone (median 5.6%) (p = 0.011).
Of the 428 randomised patients, 69.0% (147/213) of the patients in the Buvidal treatment group and 72.6% (156/215) of the patients in the sublingual buprenorphine/naloxone treatment group completed the 24-week treatment period.
During the first 12 weeks of the study, excluding the first week of initiation, the median Buvidal Weekly dose was 24 mg (range 16 to 32 mg) and the median daily sublingual buprenorphine/naloxone dose was 16 mg (range 8 to 24 mg). During the last 12 weeks of the study, the median Buvidal Monthly dose was 96 mg (range 64 to 160 mg) and the median daily sublingual buprenorphine/naloxone dose was 16 mg (range 8 to 32 mg).

Study HS-14-499.

A long-term, open-label, phase 3 safety study with flexible dosing of weekly and monthly Buvidal for 48 weeks was conducted. The study enrolled a total of 227 patients with moderate to severe opioid dependence, of which 190 patients were transferred from sublingual buprenorphine (with or without naloxone), and 37 patients were new to buprenorphine treatment. During the 48-week treatment period, patients could switch between weekly and monthly injections with Buvidal and between doses (8 mg to 32 mg weekly Buvidal and 64 mg to 160 mg monthly Buvidal) according to the physician's clinical judgement. The mean duration of treatment with Buvidal Weekly was 162.5 days (median 112 days; range 7 to 336 days) and the mean duration of treatment with Buvidal Monthly was 239.6 days (median 280 days; range 28 to 336 days). The median doses that the patients were stabilised on were 24 mg Buvidal Weekly (range 16 to 32 mg) or 96 mg Buvidal Monthly (range 64 to 160 mg).
For patients who were transferred from sublingual buprenorphine, the percentage of patients with illicit opioid-negative urine samples was 78.8% at baseline and 84.0% at the end of the 48-week treatment period. For the new-to-treatment patients, the percentage of patients with illicit opioid-negative urine samples was 0.0% at baseline and 63.0% at the end of the 48-week treatment period. Overall, 156 patients (68.7%) completed the 48-week treatment period.
No illicit drug overdoses were reported for the 440 patients treated Buvidal in the two phase 3 studies.

HS-17-585.

A randomised, open-label, study comparing flexible dosing of weekly and monthly Buvidal versus buprenorphine standard of care for 24 weeks was conducted. The study enrolled a total of 120 patients with opioid dependence (60 patients per group) to treatment with either Buvidal or standard of care with daily SL BPN. Patients in the Buvidal group could be transitioned between weekly and monthly injections with Buvidal and between doses (8 mg to 32 mg weekly Buvidal and 64 mg to 160 mg monthly Buvidal) according to the physician's clinical judgement. Patients in the standard of care group were allowed dose changes according to the approved product labelling.
Buvidal was shown to result in a higher patient treatment satisfaction compared to buprenorphine standard of care, as measured using the Treatment Satisfaction Questionnaire for Medication (TSQM) global satisfaction score (82.5 versus 74.3 at Week 24).

5.2 Pharmacokinetic Properties

Absorption.

Buvidal Weekly is a modified release formulation of buprenorphine designed for administration by subcutaneous injection once a week. After injection, the buprenorphine plasma concentration increases with a median time to maximum plasma concentration (t_max) of about 24 hours. Buvidal Weekly has complete absolute bioavailability, and a 6 to 9-fold higher bioavailability compared to sublingual buprenorphine. Steady-state exposure is reached at the fourth weekly dose.
Dose-proportional increases in exposure and time-independent pharmacokinetics are observed for Buvidal Weekly (8 mg to 32 mg).

Distribution.

Buprenorphine is lipophilic and has a large volume of distribution. Buprenorphine is highly protein bound (96%), primarily to α-(alpha) and β-(beta) globulin.

Metabolism.

Buprenorphine is metabolised by N-dealkylation to norbuprenorphine via cytochrome P450 CYP3A4 and both parent molecule and metabolite then undergo glucuronidation. The norbuprenorphine metabolite can show high affinity for and biological activity at opioid receptors.
Subcutaneous administration of Buvidal Weekly results in significantly lower plasma concentrations of norbuprenorphine metabolite compared to administration of sublingual buprenorphine, due to avoidance of first-pass metabolism.

Excretion.

The rate of release of buprenorphine from Buvidal Weekly controls its elimination with a terminal half-life in plasma ranging from 3 to 5 days.
Buprenorphine is primarily eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (70%), the remainder being eliminated in the urine. Total clearance of buprenorphine is approximately 68 L/h.

Special populations.

Elderly.

No pharmacokinetic data in elderly patients (> 65 years) are available.

Renal impairment.

Renal elimination plays a relatively small role (~ 30%) in the overall clearance of buprenorphine. No dose modification based on renal function is required, but caution is recommended when dosing subjects with severe renal impairment (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone has been evaluated in a post-marketing study of sublingual buprenorphine. Results are provided in Table 5.

Overall, buprenorphine plasma exposure increased approximately 3-fold in patients with severely impaired hepatic function (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

General.

Chronic toxicity studies in rat and dog of the vehicle used for Buvidal Weekly revealed no specific special hazard for humans.

Genotoxicity.

Buprenorphine has been shown to give negative results in mutagenicity and clastogenicity assays. Similarly, the other components of Buvidal Weekly have either been shown to lack in vitro mutagenic and clastogenic activity (i.e. glyceryl dioleate, ethanol) or are generally recognised as safe (i.e. phosphatidyl choline).

Carcinogenicity.

Buprenorphine and the other components of Buvidal Weekly are considered to have low carcinogenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

Phosphatidyl choline [soybean], glyceryl dioleate, ethanol absolute.

6.2 Incompatibilities

This 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 below 25°C.
Do not refrigerate or freeze.

6.5 Nature and Contents of Container

Buvidal Weekly injection solution for subcutaneous administration is supplied as a single dose in a 1 mL pre-filled syringe (glass) with plunger stopper (fluoropolymer-coated bromobutyl rubber) with needle (½-inch, 23 gauge, 12 mm) and needle shield (styrene butadiene rubber). The filled syringe is assembled in a safety device for post-injection needlestick prevention.
Each pack contains a single (1) prefilled syringe in the following strengths:
Pre-filled syringe containing 8 mg buprenorphine in 0.16 mL solution.
Pre-filled syringe containing 16 mg buprenorphine in 0.32 mL solution.
Pre-filled syringe containing 24 mg buprenorphine in 0.48 mL solution.
Pre-filled syringe containing 32 mg buprenorphine in 0.64 mL solution.

6.6 Special Precautions for Disposal

In Australia, any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Other information.

Do not use if the safety syringe is broken or the packaging is damaged.
The needle cap of the safety syringe may contain rubber latex that may cause allergic reactions in latex sensitive individuals.
Handle the safety syringe carefully to avoid a needle stick injury. The safety syringe includes a needle protection safety device that will activate at the end of the injection. The needle protection will help to prevent needle stick injuries.
Do not uncap the safety syringe until you are ready to inject. Once uncapped never try to recap the needle.
Dispose of the used safety syringe immediately after use. Do not re-use the safety syringe.

Administration instructions for health care professionals.

Before administration.

Safety syringe parts (see Figure 3).

Please note that the smallest injection volume is barely visible in the viewing window as the spring of the safety device is "covering" part of the glass cylinder close to the needle.

Administration.

Take the syringe out of the cardboard box: pick up the syringe by the syringe guard body.
While holding the syringe by the needle cap, insert the plunger rod into the plunger stopper by gently rotating the plunger rod clockwise until secured (see Figure 4).

Inspect the safety syringe closely.
Do not use the safety syringe after the expiration date shown on the cardboard box or on the syringe label.
A small air bubble may be seen, which is normal.
The liquid should be clear. Do not use the safety syringe if the liquid contains visible particles or is cloudy.
Choose the injection site. Injections should be rotated and alternated between sites in the buttock, thigh, abdomen, or upper arm (see Figure 5). Injections on the waistline or within 5 cm of the navel should be avoided.

Put on gloves and clean the injection site with a circular motion using an alcohol wipe (not provided in the pack). Do not touch the cleaned area again before injecting.
While holding the safety syringe by the syringe guard body as shown (see Figure 6), carefully pull the needle cap straight off. Immediately dispose of the needle cap (never try to recap the needle). A drop of liquid may be seen at the end of the needle. This is normal.

Pinch the skin at the injection site between the thumb and finger as shown (see Figure 7).
Hold the safety syringe as shown and insert the needle at an angle of approximately 90° (see Figure 7). Push the needle all the way in.

While holding the syringe as shown (see Figure 8), slowly depress the plunger until the plunger head latches between the syringe guard wings and all the solution is injected.

Gently pull the needle out of the skin. It is recommended that the plunger is kept fully depressed while the needle is carefully lifted straight out from the injection site (see Figure 9).

As soon as the needle has been completely removed from the skin, slowly take the thumb off the plunger and allow the syringe guard to automatically cover the exposed needle (see Figure 10). There may be a small amount of blood at the injection site, if required wipe with a cotton ball or gauze.

Disposing of the syringe.

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

6.7 Physicochemical Properties

Chemical structure.

CAS number.

52485-79-7.

7 Medicine Schedule (Poisons Standard)

Schedule 8.

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