Consumer medicine information

Temgesic Sublingual Tablets

Buprenorphine

BRAND INFORMATION

Brand name

Temgesic

Active ingredient

Buprenorphine

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Temgesic Sublingual Tablets.

What is in this leaflet

This leaflet answers some common questions about TEMGESIC. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

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

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

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

What TEMGESIC is used for

TEMGESIC is a "pain killer". It is used for the short term relief of severe pain.

TEMGESIC belongs to a group of medicines called opioid (narcotic) analgesics.

Opioid analgesics act directly on the brain and spinal cord to block the sensation of pain.

Your doctor may have prescribed TEMGESIC for another reason.

Ask your doctor if you have any questions about why TEMGESIC has been prescribed for you.

TEMGESIC contains the active ingredient, buprenorphine (as hydrochloride). People who take buprenorphine to relieve short term pain do not usually become addicted to it.

It is important that you discuss this issue with your doctor.

Before you are given TEMGESIC.

When you must not use it

You should not take TEMGESIC if you are:

  • allergic to buprenorphine or to any of the other ingredients in this medicine (see Product Description at the end of this leaflet).
  • allergic to opioid (narcotic) medicines.
  • pregnant.
  • breast-feeding.
  • a child
  • suffering from severe or acute respiratory disease

Do not take TEMGESIC after the Expiry Date printed on the pack. If you take this medicine after the Expiry Date has passed it may not work as well.

Do not take TEMGESIC if the package is torn, shows signs of tampering or the tablets do not look quite right.

Before you are given TEMGESIC

You must tell your doctor if:

  1. you have been given TEMGESIC (buprenorphine) before and had any problems with it
  2. you have any allergies to
  • any ingredients in this medicine (see Product Description at the end of this leaflet).
  • other strong analgesics (pain killers) eg. morphine
  • any other substances such as foods, preservatives, or dyes.
  1. you have any of these medical conditions:
  • asthma or other breathing problems
  • thyroid problems
  • prostate problems
  • problems with excess alcohol use
  • Addison's disease
  • Kyphoscoliosis (hunchback disease)
  • Low blood pressure problems
  • liver problems
  • kidney problems
  • if you are pregnant
  • biliary tract problems
  • head injuries or a condition where you have increased pressure within your head
  • stomach (abdominal) pains
  • severe mental problems or hallucinations (seeing or hearing things that are not really there)

It may not be safe for you to be given TEMGESIC if you have any of these conditions.

Tell your doctor if you are currently taking or have been taking other opioid medicines or drugs. Some people who are taking or using opioid medicines or drugs may experience opioid withdrawal effects when they are given TEMGESIC.

Taking Other Medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop, before you begin treatment with TEMGESIC.

You should not use benzodiazepines (medicines used to treat anxiety or sleeping problems) whilst you are taking TEMGESIC tablets unless they are prescribed by your doctor.

A number of medicines may change the effects of TEMGESIC. These include:

  • other strong pain killers (eg morphine)
  • cough medicines containing opioid-related substances
  • certain medicines for treating HIV/AIDS
  • certain medicines for treating fungal and bacterial infections
  • certain drugs for treating high blood pressure
  • certain antidepressants including monoamine oxidase inhibitors
  • certain medicines for treating epilepsy (fits)
  • sedatives
  • sedating anti-histamines
  • certain anti-anxiety/anti-psychotic medicines
  • certain medicines for treating nerve and muscle pain, including fibromyalgia
  • certain medicines for treating nausea/vomiting
  • general anaesthetics
  • naltrexone
  • cannabis

The above medicines may be affected by TEMGESIC, or may affect how well it works.

Do not drink alcohol or take medicines that contain alcohol while you are being treated with TEMGESIC. Alcohol and certain other medicines (as listed above) may increase the sedative effects of TEMGESIC, which can make driving and operating machinery hazardous.

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking TEMGESIC.

How to take TEMGESIC

TEMGESIC tablets must be placed under the tongue (sublingually). The tablets should be kept under the tongue for about 10 minutes. The tablets will not work if you chew or swallow them whole, or are split or broken before you take them.

The usual recommended dose is 1 to 2 tablets dissolved under the tongue every 6 to 8 hours, or as required.

If you have any questions about the dose given to you, ask your doctor.

How long to take it

When used for the relief of pain, TEMGESIC tablets are usually taken for short periods of time.

If you forget to take it

If you forget to take a dose of TEMGESIC take it as soon as you remember.

If it is almost time for your next dose, skip the dose you have missed and take your next dose when you are meant to.

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

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

Overdose

If you or someone else receive too much TEMGESIC (overdose), call triple zero (000) for an ambulance. Keep the person awake by talking to them or gently shaking them every now and then. You should follow the above steps even if someone other than you have accidentally used TEMGESIC that was prescribed for you. If someone takes an overdose they may experience one or more of the following symptoms:

  • slow, unusual or difficult breathing
  • drowsiness, dizziness or unconsciousness
  • slow or weak heartbeat
  • nausea or vomiting
  • convulsions or fits.

If you think you or someone else may have used too much TEMGESIC, you should immediately:

  • phone the Poisons Information Centre (in Australia telephone 13 11 26 or in New Zealand telephone 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.

When seeking medical attention, take this leaflet and remaining medicine with you to show the doctor. Also tell them about any other medicines or alcohol which have been taken.

While you are taking TEMGESIC

Things to be careful of

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

You should not drive or operate machinery until you know how TEMGESIC affects you.

TEMGESIC can cause drowsiness, which may be made worse if you also drink alcohol or take certain other medicines. If you are drowsy, do not drive or operate machinery.

TEMGESIC 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 lightheaded or dizzy or faint, get up slowly when getting out of bed or standing up.

Things you must not do

Do not take TEMGESIC to treat any condition other than the one prescribed for by your doctor.

Do not give TEMGESIC to anyone else, even if their symptoms seem the same as yours. It may harm them.

Addiction

You can become addicted to TEMGESIC even if you take it exactly as prescribed. TEMGESIC may become habit forming causing mental and physical dependence. If abused it may become less able to reduce pain.

Dependence

As with all other opioid containing products, your body may become used to you taking TEMGESIC. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking TEMGESIC suddenly, so it important to take it exactly as directed by your doctor.

Tolerance

Tolerance to TEMGESIC may develop, which means that the effect of the medicine may decrease. If this happens, more may be needed to maintain the same effect.

Withdrawal

Continue taking you medicine for as long your doctor tells you. If you stop having this medicine suddenly, your pain may worsen and you may experience some or all of the following withdrawal symptoms:

  • nervousness, restlessness, agitation, trouble sleeping or anxiety
  • body aches, weakness or stomach cramps
  • loss of appetite, nausea, vomiting or diarrhoea
  • increased heart rate, breathing rate or pupil size
  • watery eyes, runny nose, chills or yawning
  • increased sweating

TEMGESIC given to the mother during labour can cause breathing problems and signs of withdrawal in the newborn.

Side effects.

TEMGESIC, like all medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

Drowsiness or sleep from which you can be easily awoken is very common, particularly if TEMGESIC is used to relieve pain following surgery. Other very common side effects include vertigo, dizziness and nausea.

Less common side effects include:

  • vomiting
  • sweating
  • blood pressure changes causing dizziness or fainting
  • blurred vision
  • headache
  • difficulty breathing or slowed breathing

Uncommon side effects include:

  • changes in heart rate or blood pressure
  • difficulty urinating
  • dry mouth
  • weakness/fatigue
  • malaise
  • mood changes
  • slurred speech
  • tremor
  • paleness of skin
  • feeling of "pins and needles"
  • confusion
  • nervousness or uneasiness
  • depression
  • hallucinating
  • dreaming
  • skin rash/itchiness
  • flushing/warmth
  • chills/cold
  • tinnitus (ringing in the ears)
  • constipation
  • heartburn
  • flatulence
  • conjunctivitis
  • coma

Rare side effects include:

  • loss of appetite
  • diarrhoea
  • hives
  • convulsions (fits)
  • lack of body co-ordination
  • agitation

Cases of hypersensitivity reactions have been reported. Signs and symptoms include, rashes, hives, and skin itchiness. Serious, life threatening allergic reactions have occurred, including, difficulty breathing, swelling, and anaphylactic shock.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on the list. Other side effects not listed above may also occur in some patients.

After taking TEMGESIC.

Safe Storage

Keep your tablets in the original pack (blister) until it is time to take them. If you take the tablets out of the box or the blister pack they may not keep well.

Keep it in a cool, dark and dry place where the temperature stays below 30°C.

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

Disposal

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use the medicine after the expiry date.

Product Description

TEMGESIC Sublingual Tablets are available in blister packs of 20 tablets and 50 tablets.

Each tablet contains 216 micrograms of buprenorphine hydrochloride (equivalent to 200 micrograms of buprenorphine) as the active ingredient. The other ingredients in the tablet are: lactose monohydrate, mannitol, maize starch, povidone, magnesium stearate, citric acid and sodium citrate dihydrate.

Each blister pack of TEMGESIC Sublingual Tablets is marked with Australian Registration Number AUST R 34091.

Sponsor

Indivior Pty Ltd
78 Waterloo Road
Macquarie Park NSW 2113
Australia

For adverse event reporting please contact:

Indivior Pty Ltd
+800-270-81901
[email protected]

Date of most recent amendment:
8 May 2020

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Temgesic

Active ingredient

Buprenorphine

Schedule

S8

 

1 Name of Medicine

Temgesic injection and Temgesic sublingual tablets contain buprenorphine (as hydrochloride).

2 Qualitative and Quantitative Composition

Each 1 mL of Temgesic injection contains 300 micrograms of buprenorphine (as hydrochloride).
Each Temgesic sublingual tablet contains 200 micrograms of buprenorphine (as hydrochloride).

Excipients with known effect.

Temgesic injection contains glucose.
Temgesic sublingual tablets contain lactose monohydrate and mannitol.
Chemically, buprenorphine is 21-cyclopropyl -7α-[(S)-1-hydroxy -1,2,2-trimethylpropyl] -6,14-endo-ethano -6,7,8,14-tetrahydrooripavine hydrochloride. Buprenorphine hydrochloride has the molecular formula C29H41NO4.HCl and the molecular weight is 504.09.
Buprenorphine hydrochloride is a white powder, weakly acidic with limited solubility in water (19.5 mg/mL at 37°C, pH 4.1).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Temgesic injection.

Colourless liquid in clear glass snap-ampoules.

Temgesic sublingual tablets.

White, circular, biconvex tablets debossed with a "L".

4 Clinical Particulars

4.1 Therapeutic Indications

Temgesic sublingual tablets and injection are indicated for the short-term (not more than one week) management of severe pain for which other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain.
Temgesic injection should be employed when sublingual administration is not practical, e.g. pre- or peri-operatively.
Temgesic is not recommended for use in children.
Temgesic does not have an approved role in opioid dependence rehabilitation programmes.

4.2 Dose and Method of Administration

Temgesic injection.

The ampoule should be inspected visually for particulate matter and discolouration prior to administration.
The recommended dosage is 300-600 micrograms by intramuscular or slow intravenous injection, repeated every 6-8 hours, or as required.

Temgesic sublingual tablets.

The sublingual formulation is not designed to be split or broken. The tablets should not be chewed or swallowed as this will reduce their efficacy. The usual recommended dose is 1 to 2 tablets 200-400 micrograms of buprenorphine dissolved under the tongue every 6-8 hours, or as required. Tablets should be kept in place for 10 minutes without swallowing.

4.3 Contraindications

Pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation).
Temgesic should not be administered to patients who have been shown to be hypersensitive to buprenorphine or other opioids. Hypersensitivity to any of the ingredients.
Temgesic is contraindicated for use in patients with severe respiratory disease, acute respiratory disease and respiratory depression.

4.4 Special Warnings and Precautions for Use

Naloxone may not be effective in reversing the respiratory depression produced by Temgesic. Therefore, the primary management of overdose should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required.

General.

Temgesic should be administered with caution in debilitated patients and those with myxoedema or hypothyroidism, adrenal cortical insufficiency (e.g. Addison's disease); toxic psychoses; orthostatic hypotension; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis.

Hazardous and harmful use.

Temgesic contains the opioid buprenorphine and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Temgesic at recommended doses.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed Temgesic.
All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Patients should be advised not to share Temgesic with anyone else.
Temgesic, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Temgesic should therefore be prescribed and handled with a high degree of caution appropriate to the use of a drug with strong abuse potential. Abuse of opioids poses a risk of overdose and death. This risk is increased with concurrent abuse of opioids with alcohol and other substances including other opioids and benzodiazepines.

Use in the elderly.

The safety and efficacy of buprenorphine in elderly patients over 65 years have not been established (see Respiratory depression).

Cardiovascular effects.

Buprenorphine may cause a slight reduction in pulse rate and blood pressure in some patients.
Like other opioids, buprenorphine may produce orthostatic hypotension in ambulatory patients.

Respiratory depression.

Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of Temgesic but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times.
The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients and in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease, sleep apnoea, asthma, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia), hepatic impairment (see Use in hepatic impairment) and severe renal impairment (see Use in renal impairment). Opioids should be used with caution and with close monitoring in these patients (see Section 4.2 Dose and Method of Administration). The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
The risk of respiratory depression is greater with the use of high doses of opioids, especially high potency and modified release formulations, and in opioid naïve patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations, together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variations in response.
Should respiratory depression occur to a clinically undesirable degree, supportive measures should be used to maintain adequate ventilation and oxygenation. The effects of buprenorphine are only partially reversed by standard narcotic reversal agents, such as naloxone.

Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.

Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of Temgesic with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible. If a decision is made to prescribe Temgesic concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers should be made aware of these symptoms. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while taking Temgesic.

Use of opioids in chronic (long-term) non-cancer pain (CNCP).

Opioid analgesics have an established role in the treatment of acute pain, cancer pain and palliative and end-of-life care. Current evidence does not generally support opioid analgesics in improving pain and function for most patients with chronic non-cancer pain. The development of tolerance and physical dependence and risks of adverse effects, including hazardous and harmful use, increase with the length of time a patient takes an opioid. The use of opioids for long-term treatment of CNCP is not recommended.
The use of an opioid to treat CNCP should only be considered after maximised non-pharmacological and non-opioid treatments have been tried and found ineffective, not tolerated or otherwise inadequate to provide sufficient management of pain. Opioids should only be prescribed as a component of comprehensive multidisciplinary and multimodal pain management.
Opioid therapy for CNCP should be initiated as a trial in accordance with clinical guidelines and after a comprehensive biopsychosocial assessment has established a cause for the pain and the appropriateness of opioid therapy for the patient (see Hazardous and harmful use). The expected outcome of therapy (pain reduction rather than complete abolition of pain, improved function and quality of life) should be discussed with the patient before commencing opioid treatment, with agreement to discontinue treatment if these objectives are not met.
Owing to the varied response to opioids between individuals, it is recommended that all patients be started at the lowest appropriate dose and titrated to achieve an adequate level of analgesia and functional improvement with minimum adverse reactions. Immediate-release products should not be used to treat chronic pain, but may be used for a short period in opioid-naïve patients to develop a level of tolerance before switching to a modified-release formulation. Careful and regular assessment and monitoring is required to establish the clinical need for ongoing treatment. Discontinue opioid therapy if there is no improvement of pain and/or function during the trial period or if there is any evidence of misuse or abuse. Treatment should only continue if the trial has demonstrated that the pain is opioid responsive and there has been functional improvement. The patient's condition should be reviewed regularly and the dose tapered off slowly if opioid treatment is no longer appropriate (see Ceasing opioids).

Tolerance, dependence and withdrawal.

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine). Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate.
The current opioid dependence level of patients with a history of opioid abuse or misuse should be assessed prior to treatment with analgesic buprenorphine products.
When discontinuing Temgesic in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids; see Section 4.2 Dose and Method of Administration).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Temgesic, especially by children, can result in a fatal overdose of buprenorphine. Patients and their caregivers should be given information on safe storage and disposal of unused Temgesic (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).

Hyperalgesia.

Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Tolerance, dependence and withdrawal). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.

Ceasing opioids.

Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Tolerance, dependence and withdrawal). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to pain management should be in place before initiating an opioid analgesic taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
There are no standard tapering schedules suitable for all patients and an individualised plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks (see Section 4.2 Dose and Method of Administration). If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.

Head injury and increased intracranial pressure.

Temgesic, like other potent opioids may itself 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. Temgesic can produce miosis and changes in the level of consciousness that may interfere with patient evaluation. The miosis is more marked than with morphine and persists for more than 24 hours.

Use in hepatic impairment.

The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a post-marketing study, in which a buprenorphine/naloxone 2 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 which may require dose adjustment. Since hepatic elimination plays a relatively large role (~70%) in the overall clearance of Temgesic, the intensity and duration of its action may be altered in those individuals with impaired hepatic function. Buprenorphine should be used with caution in patients with moderate to severe hepatic impairment. Patients should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. Lower initial doses and cautious titration of dosage may be required in patients with hepatic dysfunction.
Buprenorphine increases intracholedochal pressure as do other opioids. Therefore, caution should be exercised when Temgesic is to be administered to patients with dysfunction of the biliary tract.

Use in renal impairment.

Renal elimination plays a relatively small role (~ 30%) in the overall clearance of Temgesic. 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).

Acute abdominal conditions.

As with other mu-opioid receptor agonists, the administration of Temgesic may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

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 Temgesic.

Paediatric use.

Temgesic is not recommended for use in children.

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

Benzodiazepines.

A number of deaths and cases of coma have occurred when buprenorphine and benzodiazepines were concomitantly intravenously misused. There have been reports of respiratory and cardiovascular collapse in patients who received therapeutic doses of diazepam and analgesic doses of buprenorphine; therefore, dosages must be limited and this combination must especially be avoided in cases where there is a risk of misuse. Patients should be warned of the potential danger of the intravenous self-administration of benzodiazepines or other CNS depressants at the same time as receiving Temgesic (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).

Alcohol.

Buprenorphine should not be taken together with alcoholic drinks or medications containing alcohol. Alcohol increases the sedative effect of buprenorphine.

Other central nervous system depressants.

Combining central nervous system depressants with buprenorphine increases central nervous system depressant effects. Examples of central nervous system depressants include: other opioid analgesics or antitussives, general anaesthetics, tricyclic antidepressants, sedative H1-receptor antagonists, barbiturates, anxiolytics, centrally-active anti-emetics, gabapentinoids, antipsychotics, neuroleptics, clonidine, cannabis and other CNS depressants. When such combined therapy is contemplated, it is particularly important that the dose of one or both agents be reduced (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).

Naltrexone and other opioid antagonists.

Opioid antagonists such as naltrexone, may antagonize the pharmacologic effect of buprenorphine. Patients treated with naltrexone may not receive the intended analgesic effects of buprenorphine. Patients who have developed physical dependence to the effects of buprenorphine may experience a sudden onset of opioid withdrawal effect.

Other opioid analgesics.

The analgesic effects of full agonist opioids may be competitively diminished by the partial agonist buprenorphine. For patients who have developed a physiological dependence to full opioid agonists, administration of the partial agonist buprenorphine may elicit withdrawal symptoms (see Section 4.4 Special Warnings and Precautions for Use).

CYP3A4 inhibitors.

Since the metabolism of buprenorphine to norbuprenorphine is mediated by the CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance and hence increased levels of buprenorphine. Thus patients receiving buprenorphine coadministered with inhibitors of CYP3A4 such as macrolide antibiotics (e.g. erythromycin), azole antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g. ritonavir) should be carefully monitored. Caution is advised when administering buprenorphine to patients receiving these medications and if necessary, dose adjustments should be considered.

CYP3A4 inducers.

Cytochrome P450 inducers, such as rifampicin, carbamazepine and phenytoin induce metabolism and as such may cause increased clearance of buprenorphine. It is recommended that patients receiving Temgesic should be closely monitored if inducers are co-administered and the dose of buprenorphine or CYP3A4 inducer may need to be adjusted accordingly.

Narcotic antagonist activity.

Buprenorphine demonstrates narcotic antagonistic activity and has been shown to reverse the effects of peri-operatively administered opioids. It may, therefore, precipitate withdrawal symptoms in opioid dependent patients and it should be given with care, initially, to patients previously treated with narcotic analgesics.

Serotonergic drugs.

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine if serotonin syndrome is suspected. Examples of serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, serotonin precursors (e.g. tryptophan), drugs that affect the serotonin neurotransmitter system (e.g. mirtazapine, trazodone, tramadol, lithium, St. John's wort), certain muscle relaxants (i.e. cyclobenzaprine, metaxalone), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Other.

Halothane is known to decrease hepatic clearance. Since hepatic elimination plays a relatively large role (~ 70%) in the overall clearance of buprenorphine, lower initial doses and cautious titration of dosage may be required when used with halothane.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no effects on mating performance or on fertility of male rats following short-term treatment with buprenorphine.
(Category C)
Temgesic is contraindicated in pregnant women (see Section 4.3 Contraindications).
There are no adequate and well-controlled studies in pregnant women.
The safety of buprenorphine in pregnancy has not been established and therefore, it should not be used in women who are pregnant or who are likely to become pregnant.
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.
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 similar to the maximum anticipated human exposure of buprenorphine used for opioid addiction treatment (32 mg/day); this is 20-fold the recommended upper analgesic dose of 1.6 mg/day. Evidence for teratology was not evident in animal studies.
Maternal oral administration at high doses (80 mg/kg/day) during gestation and lactation resulted in a delayed postnatal development of some neurological functions (surface righting reflex and startle response) in neonatal rats with a NOEL of 8 mg/kg/day PO (representing a six-fold systemic exposure at the maximum anticipated clinical exposure for analgesia).
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. Because buprenorphine passes into the mother's milk, Temgesic should not be used in breast-feeding women.

4.7 Effects on Ability to Drive and Use Machines

Temgesic may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Temgesic can cause drowsiness, particularly when taken together with alcohol or central nervous system depressants. Patients should be cautioned accordingly.

4.8 Adverse Effects (Undesirable Effects)

Very commonly reported adverse reactions reported in clinical studies were sedation, vertigo, dizziness and nausea.
Table 1 lists adverse drug reactions reported in clinical studies.
The frequency of possible side effects listed in Table 1 is defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (events not reported in registration trials cannot be estimated from the available post-marketing spontaneous reports).

Post-marketing data.

The following list of the most commonly reported adverse drug reactions reported during post-marketing surveillance. Events occurring in at least 1% of reports by healthcare professionals and considered expected are included. Serious reactions of anaphylactic shock, bronchospasm and angioneurotic oedema have occurred at unknown rates and are also included in Table 2. These adverse drug reactions are presented by MedDRA system organ class in internationally agreed order by preferred term and frequency of reporting.

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.

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.

Treatment.

In the event of overdose, 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 performed. In the event of depression of respiratory or cardiac function, primary attention should be given to the re-establishment of adequate respiratory exchange through the 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.
If the patient vomits, care must be taken to prevent aspiration of the vomitus.
Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. 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. High doses of naloxone hydrochloride 10-35 mg/70 kg may be of limited value in the management of buprenorphine overdose. If naloxone is used 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.
For further information on the management of overdose, contact the Poison Information Centre on 131 126 (Australia) or the National Poisons Centre on 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Buprenorphine is a mu-opioid partial agonist with high affinity for the mu-opioid receptor, demonstrating both agonist and antagonist properties. The drug receptor complex is very stable and dissociates slowly. Buprenorphine is also an antagonist at the κ-opioid receptor.

Pharmacodynamics.

In a number of standard animal antinociceptive tests, buprenorphine displays potent analgesic activity, often with a curvilinear or bell-shaped dose response in which higher doses produce a lesser effect than lower doses.
In such tests, buprenorphine is more potent than other opioid analgesics such as morphine (30 x) and pentazocine (100 x) and at equi-analgesic doses, the duration of action of buprenorphine in these animal tests is at least 4 x as long as morphine.
Buprenorphine does not substitute for morphine in dependent rats; rather, it precipitates signs of abstinence and is at least as potent as naloxone in antagonising morphine-induced analgesia in rodents.
In animal tests for physical dependence liability, buprenorphine has the least capability of any opioid tested, being lower than codeine and pentazocine. In chronically-treated primates, neither abrupt withdrawal nor administration of narcotic antagonists could precipitate abstinence. In view of the receptor kinetics of buprenorphine, this is not an unexpected result.
Although buprenorphine produces initial immobility in rodents, followed by increased locomotor activity, higher doses in primates produce only mild signs of CNS depression.
Buprenorphine slightly decreases the respiratory rate in mice, cats and dogs. Arterial blood gas measurements in rats showed that buprenorphine, unlike morphine, has a bell-shaped dose-response curve in the dose range 0.01-30 mg/kg intra-arterially, with a ceiling effect such that the maximum depression of respiration seen with buprenorphine was significantly less than that with morphine. In man, respiratory depression in the CO2 response model increased linearly with doses up to 1.2 mg, which was the highest tested. The peak depressant effect with buprenorphine occurred at 3-5 hours compared to 1-2 hours with morphine. However, doses up to 7 mg i.v. (equivalent to 200 mg morphine) have been given to patients without clinically significant respiratory effects.
Buprenorphine at high doses causes a slight reduction in heart rate in rats and dogs, but has little effect on arterial blood pressure. Major cardiovascular changes are unlikely to occur after therapeutic doses. At therapeutic doses, blood pressure and pulse rate may fall slightly, the maximum changes observed being 10-15%. A clinical trial of intravenous buprenorphine to treat chest pain associated with myocardial infarction showed no significant changes in systemic or pulmonary arterial blood pressure or in heart rate. During the period of reduced cardiac reserve after open heart surgery, intravenous buprenorphine effected no significant changes in cardiac output, mean arterial pressure or peripheral resistance.
Because of the stability of the complex formed between buprenorphine and the opioid receptor, antagonists are only partially effective in reversing the effect of established buprenorphine compared to the situation when the antagonist is administered prior to buprenorphine.
At very high doses there is evidence from animal studies for developing tolerance to buprenorphine and cross tolerance with morphine.
Animal studies have shown evidence for a potentiation of action between buprenorphine and centrally-acting drugs likely to be used concurrently, such as halothane, fluothane and thiopentone sodium.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Systemic availability of parenterally administered buprenorphine is generally close to 100%. Plasma levels in patients following an intravenous or intramuscular dose of 300 micrograms are maximal at 2 minutes and 5 minutes, respectively. At 10 minutes the plasma concentration from intramuscular and intravenous doses are essentially identical. The buprenorphine plasma level data achieved after these doses most closely fit a tri-exponential decay curve, with a very fast initial distribution phase (t1/2 2 minutes) and a slow elimination phase (t1/2 approximately 5 hours).
When buprenorphine is taken at much higher doses, for the treatment of opioid addiction, a long terminal elimination phase half-life 34.6 hours is observed. This phase follows the elimination phase with the half-life of 5 hours and cannot be measured following normal analgesic doses because plasma levels are too low to be measured. The 5 hour half-life should be considered the clinically relevant elimination rate for Temgesic.
Buprenorphine from Temgesic sublingual tablets has been formulated to allow the active ingredient to be absorbed through the sublingual mucosa within minutes and consequently, buprenorphine by-passes first-pass metabolism by the intestinal mucosa and the liver, which is known to be significant following oral administration. Peak concentrations of buprenorphine following sublingual administration are achieved within 2-4 hours. The absolute bioavailability of buprenorphine by the sublingual route is approximately 35%. Following sublingual buprenorphine, the terminal half-life was not significantly different from that calculated following the parenteral route.
The clinical efficacy observed for buprenorphine administered by both the parenteral and sublingual routes in conjunction with the different pharmacokinetic profile indicates that there is no obvious correlation between plasma level and clinical effect. At therapeutic doses the drug is highly protein bound (approximately 96%), primarily to alpha- and beta-globulin fractions.
After intramuscular administration of [3H]-buprenorphine to one volunteer, 68% of the radioactivity was recovered in the faeces and 27% in the urine. Metabolism of buprenorphine administered either parenterally or sublingually is predominantly in the liver with the principal metabolites being the N-dealkylated product and its glucuronide together with glucuronides of the parent drug. Excretion is predominantly by the biliary route with some evidence for enterohepatic cycling following intestinal deconjugation.

5.3 Preclinical Safety Data

Genotoxicity.

There was no evidence of genotoxicity for buprenorphine in bacterial gene mutation assays, chromosomal aberration studies and a mouse lymphoma assay.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Temgesic injection.

Glucose 55 mg (equivalent to anhydrous glucose 50 mg), water for injections and hydrochloric acid (to pH 4.0).

Temgesic sublingual tablets.

Lactose monohydrate, mannitol, maize starch, povidone, magnesium stearate, citric acid and sodium citrate dihydrate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

Temgesic injection and tablets in Al/Al blister pack and HDPE bottle: 3 years.
Temgesic sublingual tablets in PVC/PVdC/Al blister pack: 9 months.

6.4 Special Precautions for Storage

Temgesic injection and sublingual tablets in Al/Al blister pack and HDPE bottle: store below 30°C. Protect from light.
Temgesic sublingual tablets in PVC/PVdC/Al blister pack: store below 25°C and protect from light.
Keep out of reach of children.

6.5 Nature and Contents of Container

Temgesic injection.

1 mL clear glass snap-ampoules in packs of 5 (AUST R 15394).

Temgesic sublingual tablets.

Al/Al blister packs of 10 tablets each in cartons containing 20 tablets or 50 tablets (AUST R 34091; not marketed in New Zealand).
PVC/PVdC/Al blister packs of 10 tablets each in cartons containing 20 tablets or 50 tablets (AUST R 34091; not marketed in Australia or New Zealand).
HDPE bottles with child-resistant reclosable cap containing 20 tablets or 50 tablets (AUST R 150453; not marketed in Australia or New Zealand).

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

The chemical structure of buprenorphine is:

CAS number.

The CAS number is 53152-21-9.

7 Medicine Schedule (Poisons Standard)

Schedule 8 - Controlled Drug.

Summary Table of Changes