Each sublingual tablet contains buprenorphine hydrochloride equivalent to 0.2 mg of buprenorphine.
Each ml of ampoule contains buprenorphine hydrochloride 324 μg, equivalent to 300 μg of buprenorphine base.
Tablet: Buprenorphine hydrochloride, the active ingredient in Temgesic Sublingual Tablets is a potent, long-acting analgesic, which exhibits powerful narcotic agonistic and antagonistic characteristics. Buprenorphine is more potent than morphine, and at therapeutically equivalent doses has similar onset of action and quality of analgesia, but a longer duration of action; when given by the parenteral route, 0.3 mg of buprenorphine is approximately equivalent to 10 mg of morphine sulfate in analgesic and respiratory depressant effects in adults.
Temgesic Sublingual Tablets allow buprenorphine to be absorbed through the buccal mucosa within minutes.
Ampoule: Buprenorphine hydrochloride is a white to off-white powder, weakly acidic in character and with a limited solubility in water.
Temgesic Injection is a terminally sterilised solution for injection.
Excipients/Inactive Ingredients: Tablet: Lactose, mannitol, maize starch, povidone, citric acid, magnesium stearate, sodium citrate, purified water, alcohol (96%).
Ampoule: Dextrose, hydrochloric acid, water for injection.
Ampoule: Pharmacology: Pharmacodynamics: Buprenorphine hydrochloride, the active ingredient in Temgesic Injection is a potent, long-acting analgesic. Buprenorphine is a μ (mu) opioid partial agonist and k (kappa) antagonist. It is a strong analgesic of the partial agonist (mixed agonist/antagonist) class. Buprenorphine is approximately 30 times more potent than morphine, and at therapeutically equivalent doses, has a similar onset of action and quality of analgesia, but a longer duration of action.
Pharmacokinetics: Buprenorphine is readily available by i.v. or i.m. routes; the relative bioavailability i.m. to i.v. was 1.07. Peak plasma levels are achieved within a few minutes of i.m. administration and after 10 minutes are not significantly different from those observed after the same dose given i.v.
Buprenorphine is oxidatively metabolised by 14-N-dealkylation to N-desalkyl-buprenorphine (also known as norbuprenorphine) via cytochrome P450 CYP3A4 and by glucuroconjungation of the parent molecule and the dealkylated metabolite. Norbuprenorphine is a μ (mu) agonist with weak intrinsic activity.
Elimination of buprenorphine is bi- or tri exponential, with a long terminal elimination phase 20 to 25 hours, due in part to reabsorption of buprenorphine after intestinal hydrolysis of the conjugated derivative, and in part to the highly lipophilic nature of the molecule.
Buprenorphine is essentially eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (80 %), the rest being eliminated in the urine.
Toxicology: Preclinical safety data: No preclinical findings of relevance to the prescriber have been reported.
Tablet: Temgesic Sublingual Tablets are indicated for the relief of moderate to severe pain, for example, following surgery, trauma, or in patients with pain secondary to malignancy or terminal illness.
Ampoule: As a strong analgesic for the relief of moderate to severe pain.
Tablet: Adults: The usual recommended dose is 0.2 - 0.4 mg buprenorphine dissolved under the tongue every six to eight hours or as required. The recommended initial dose is one 0.2 mg tablet every eight hours. The tablets should be kept under the tongue until dissolved, which occurs in 5 to 10 minutes, and should not be chewed or swallowed.
Children 2 to 12 years of age: Temgesic 0.2 mg Sublingual Tablets may be administered to children who weigh at least 16 kg and are able to take a sublingual dosage form:
16 - 25 kg, one-half tablet (100 micrograms);
25 - 37.5 kg, on-half to one tablet (100 - 200 micrograms);
37.5 - 50 kg, one to one and one-half tablets (200 - 300 micrograms).
The tablets should be kept under the tongue until dissolved, which occurs in 5 to 10 minutes, and should not be chewed to swallowed. Doses may be repeated every six to eight hours.
Since not all children may clear buprenorphine faster than adults, fixed interval or "round-the-clock" dosing should not be undertaken until the proper inter-dose interval has been established by clinical observation of the child.
Ampoule: Administration by i.m. or slow i.v. injection.
Adults and children over 12 years: 1-2 ml (300 - 600 micrograms of buprenorphine) every 6 to 8 hours as required.
Children aged under 12 years: 3 - 6 micrograms/kg of body weight every 6 to 8 hours. In refractory cases up to 9 micrograms/kg may be administered. There is no clinical experience in infants below the age of 6 months.
There is no evidence that dosage need to be modified for the elderly.
Temgesic Injection maybe employed in balanced anaesthetic techniques as a pre-medication at a dose of 300 micrograms i.m., or as an analgesic supplement at doses of 300 to 450 micrograms i.v.
Hepatic impairment: The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a postmarketing study. Buprenorphine is extensively metabolized in the liver, and plasma levels were found to be higher for buprenorphine in patients with moderate and severe hepatic impairment compared to healthy subjects. Patients should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. Temgesic should be used with caution in patients with moderate to severe hepatic impairment (See Pharmacology: Pharmacokinetics under Actions).
Tablet: Symptoms: The expected symptoms would be drowsiness, nausea and vomiting; marked miosis may occur. Buprenorphine appears to have a wide margin of safety because of its partial opioid agonist/antagonist properties.
If Temgesic Sublingual Tablets are swallowed, symptoms are less likely because the absorbed active ingredient is rapidly metabolized by the liver. In the event of accidental overdose, general supportive measures should be instituted, including close monitoring of respiratory and cardiac status of the patient. The major symptom requiring intervention is respiratory depression, which could lead to respiratory arrest and death. If the patient vomits, care must be taken to prevent aspiration of the vomitus.
Treatment: Symptomatic treatment of respiratory depression, following standard intensive care measures, should be performed. 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. 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. If an opioid antagonist (i.e., naloxone) is used, the long duration of action of Temgesic Sublingual Tablets should be taken into consideration.
Ampoule: Symptoms: Buprenorphine appears to have a wide margin of safety because of its partial opioid agonist/antagonist properties. Although the antagonist activity of buprenorphine may become manifest at doses somewhat above the recommended therapeutic range, therapeutic doses may produce clinically significant respiratory depression in certain circumstances.
In the event of accidental overdosage, general supportive measures should be instituted, including close monitoring of respiratory and cardiac status of the patient. The major symptom requiring intervention is respiratory depression, which could lead to respiratory arrest and death. If the patient vomits, care must be taken to prevent aspiration of the vomitus.
Treatment: Symptomatic treatment of respiratory depression, following standard intensive care measures, should be performed. 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. 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.
If an opioid antagonist (i.e., naloxone) is used, the long duration of action of Temgesic should be taken into consideration
Tablet: Temgesic Sublingual Tablets should not be administered to patients who have shown hypersensitivity to this drug or to other centrally-acting analgesics; severe respiratory insufficiency; severe hepatic insufficiency.
Ampoule: Not to be given to patients who are known to be allergic to Temgesic or other opiates.
Hypersensitivity to any of the constituents.
Tablet: Human and animal studies show burepnorphine to have a substantially lower dependence liability than pure agonist analgesics. However, Temgesic Sublingual Tablets should be prescribed and administered with caution to patients with a history of drug abuse and to patients with emotional instability. Temgesic Sublingual Tablets have certain opioid properties, which may lead to psychic dependence of the morphine type due to an opiate-like euphoric component of the drug.
Temgesic Sublingual Tablets should be administered for the relief of pain and not in anticipation of pain.
Caution and close patient observation are recommended when Temgesic Sublingual Tablets are used in ambulatory patients. Since Temgesic may cause drowsiness or dizziness, and these could be potentiated by other centrally acting agents, including alcohol, ambulant patients should be cautioned against engaging in activities requiring mental alertness, such as driving a car or operating machinery/appliances.
As with other potent opioids, respiratory depression may occur within the recommended therapeutic dose range in patients receiving buprenorphine. Therefore, Temgesic Sublingual Tablets should be used with caution in patients with impaired respiratory function: those with acute asthmatic attack, chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve or those with pre-existing respiratory depression, hypoxia or hypercapnia. Caution is also advised if Temgesic Sublingual Tablets are administered to patient taking drugs with respiratory depressant effects. In patients with these physical and/-or pharmacologic risk factors, the dose should be reduced by approximately on-half.
Hepatic impairment: Buprenorphine is metabolized by the liver and its clearance is related to hepatic blood flow. Decreased metabolism of the drug in patients with extensive liver disease may predispose such patients to an accentuation of drug effects at recommended therapeutic dosage. Therefore, Temgesic Sublingual Tablets should be administered with caution to patient with hepatic impairment and to those receiving other agents (e.g. halothane) that decrease hepatic clearance. Temgesic has been shown to increase intracholedochal pressure to a similar degree as other opioid analgesics and therefore, Temgesic Sublingual Tablets should be administered with caution to patients with biliary tract dysfunction. Temgesic Sublingual Tablets should be administered with caution to elderly or debilitated patients and to those with severe impairment of renal function, myxedema or hypothyroidism, adrenal insufficiency (e.g. Addison's disease), CNS depression or coma, toxic psychoses, prostatic hypertrophy or urethral stricture, acute alcoholism, delirium tremens or kyphoscoliosis.
As with other potent analgesics, Temgesic Sublingual Tablets have the potential for elevating cerebrospinal fluid pressure. This effect, coupled with a respiratory depressant effect, may be markedly exaggerated in the presence of head injury, other intracranial lesions or when there is a preexisting increase in intracranial pressure. Temgesic can produce miosis and changes in the level of consciousness which may obscure the clinical course of patients with head injuries. Therefore, in such patients Temgesic Sublingual Tablets should be used with caution.
Because Temgesic has narcotic antagonistic properties, it may precipitate withdrawal symptoms in narcotic addicts. Temgesic Sublingual Tablets are not recommended for patients who have developed physical dependence to narcotics except when buprenorphine is administered within a framework of medical, social and psychological treatment. Temgesic Sublingual Tablets should be administered with caution to patients previously treated with narcotic analgesics.
Use in children: Temgesic 0.2 mg Sublingual Tablets may be administered as recommended to children 2 to 12 years of age and who weigh at least 16 kg.
Ampoule: Temgesic occasionally causes respiratory depression and, as with other strong centrally acting analgesics, care should be taken when treating patients with impaired respiratory function or patients who are receiving drugs which can cause respiratory depression.
Although volunteer studies have indicated that opiate antagonists may not fully reverse the effects of Temgesic, clinical experience has shown that naloxone may be of benefit in reversing a reduced respiratory rate. Respiratory stimulants such as doxapram are also effective. The intensity and duration of action may be affected in patients with impaired liver failure.
Controlled human and animal studies indicate that buprenorphine has a substantially lower dependence liability than pure agonist analgesics. In patients abusing opioids in moderate doses substitution with buprenorphine may prevent withdrawal symptoms. In man limited euphorigenic effects have been observed. This has resulted in some abuse of the products and caution should be exercised when prescribing it to patients known to have, or suspected of having, problems with drug abuse.
Diversion: Diversion of Temgesic has been reported. Diversion refers to the introduction of buprenorphine into the illicit market either by patients or by individuals who obtain the medicinal product through theft from patients or pharmacies. The diversion may lead to new cases of dependence using buprenorphine as the primary drug of abuse, with the risks of overdose, spread of blood borne viral infections and respiratory depression.
Hepatic impairment: The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a postmarketing study. Since buprenorphine is extensively metabolized, plasma levels were found to be elevated for buprenorphine 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. Temgesic Injection should be used with caution in patients with moderate to severe hepatic impairment (See Pharmacology: Pharmacokinetics under Actions).
Athletes must be aware that this medicine may cause a positive reaction to 'anti-doping' tests.
Effects on ability to drive and Use Machines: Ambulant patients should be warned not to operate machinery until they are certain they can tolerate Temgesic.
This medicine can impair cognitive function and can affect a patient's ability to drive safely.
When prescribing this medicine, patients should be told: The medicine is likely to affect the ability to drive. Do not drive until the patient knows how the medicine affects him/her.
Tablet: Data are insufficient to evaluate the effects of Temgesic Sublingual Tablets on pregnant women. At the end of pregnancy, high doses, even for a short duration of time, may induce respiratory depression in neonates. During the last three months of pregnancy, chronic use of buprenorphine may be responsible for a withdrawal syndrome in neonates. Consequently, the use of buprenorphine is not recommended during pregnancy.
As evidenced in rats, buprenorphine has the potential to inhibit lactation or milk production. In addition, because buprenorphine passes into the mother's milk, breast-feeding is contraindicated.
Ampoule: Temgesic is not recommended for use during pregnancy. Animal studies indicate that the amounts of buprenorphine excreted in milk are very low and in human use are likely to be of clinical significance to the baby.
There is indirect evidence in animal studies to suggest that Temgesic may cause a reduction in milk flow during lactation. Although this occurred only at doses well in excess of the human dose, it should be borne in mind when treating lactation women.
Sedation has been the most frequently reported side effect. Sleep, from which patients can easily be aroused, may also occur particularly during the post-operative period.
Cases of bronchospasm, angioneurotic edema and anaphylactic shock have also been reported.
Other less frequently reported adverse reactions occurring in 5 - 10% of the patients were nausea and dizziness/vertigo.
Reported adverse reactions occurring in 1 - 5% of the patients included sweating, hypotension, vomiting, miosis, heachache, hypoventilation.
The following adverse reactions were reported to have occurred in less than 1% of the patients: confusion, euphoria, weakness/fatigue, dry mouth, nervousness, depression, slurred speech, paresthesia, hypertension, tachycardia, bradycardia, constipation, dyspnea, cyanosis, pruritus, diplopia, visual abnormalities, urinary retention, tinnitus, conjunctivitis, Wenckeback block, and psychosis.
Other effects observed infrequently include hallucination, depersonalization, coma, dyspepsia, apnea, rash, tremor, pallor, loss of appetite, dysphoria/agitation, diarrhea, urticarial, and convulsions/lack of muscle coordination.
During use of buprenorphine as substitution treatment the following adverse reactions have also been observed: insomnia, drowsiness, fainting, orthostatic hypotension, respiratory depression, hepatic necrosis and hepatitis.
Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported.
In patients presenting with marked drug dependence, initial administration of buprenorphine can produce a withdrawal effect similar to that associated with naloxone.
The safety profile of Temgesic in children is comparable to that in adults.
Nausea, vomiting, dizziness, sweating and drowsiness have been reported and may be more frequent in ambulant patients. Hallucinations and other psychotomimetic effects have occurred although more rarely than with the other agonists/antagonists. Elderly patients would be expected to be more susceptible to these effects. Hypotension leading to syncope may occur. Rashes, headache, urinary retention and blurring of vision have occasionally been reported. Rarely, a serious allergic reaction may occur following a single dose. Temgesic occasionally causes significant respiratory depression (see Precautions).
Cases of bronchospasm, angioneurotic edema and anaphylactic shock have also been reported.
During use of buprenorphine as substitution treatment the following adverse reactions have also been observed: hepatic necrosis and hepatitis.
Tablet: Temgesic Sublingual Tablets should not be taken together with alcoholic drinks or medications containing alcohol. Alcohol increases the sedative effect of buprenorphine, which can make driving vehicles and operating machinery hazardous. Temgesic Sublingual Tablets should be used cautiously together with:
Benzodiazepines: This combination may potentiate respiratory depression of central origin, with risk of death; therefore, dosages must be limited. The risk of drug abuse should also be considered. (See Precautions.)
Other central nervous system depressants; other opioid derivatives (analgesics and antitussives); certain antidepressants, sedative H1-receptor antagonists, barbiturates, benzodiazepines, anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances. This combination increases central nervous system depression and can make driving vehicles and operating machinery hazardous.
Monoamine oxidase inhibitors (MAOI): Possible exaggeration of the effects of opioids, based on experience with morphine.
Respiratory and cardiovascular collapses have been reported in patients receiving therapeutic doses of diazepam and Temgesic concomitantly.
To date, no notable interaction has been observed with cocaine.
A suspected interaction between Temgesic Sublingual Tablets and phenoprocoumon resulting in purpura has been reported.
An interaction study of buprenorphine with ketoconazole resulted in increases in buprenorphine and norbuprenorphine concentrations. Subjects receiving Temgesic should be closely monitored, and may require dose-reduction if inhibitors of CYP3A4 (e.g. ketoconazole, gestodene, TAO, the HIV protease inhibitors ritonavir, indinavir and saquinavir) are co-administered. The interaction of buprenorphine with CYP3A4 inducers has not been investigated, therefore it is recommended that patients receiving Temgesic should be closely monitored if enzyme inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered.
Ampoule: There is no evidence to indicate that therapeutic doses of buprenorphine do not reduce the analgesic efficacy or standard doses of an opioid and that when buprenorphine is employed within the normal therapeutic range, standard doses of opioid agonist may be administered before the effects of the former have ended without compromising analgesia. However, in individuals on high doses of opioids buprenorphine may precipitate abstinence effects due to its properties as a partial agonist.
Temgesic may cause some drowsiness which may be potentiated by other centrally acting agents, including alcohol, tranquilisers, sedatives and hypnotics. Temgesic should be used with caution in patients receiving monoamine oxidase inhibitors, although animal studies have given no evidence of interactions.
Although interaction studies have not yet been performed, since the drug is metabolised by CYP3A4 (see Pharmacology: Pharmacokinetics under Actions), it is expected that gestodene, troleandomycin, ketoconazole, norfluoxetine, ritonavir, indinavir and saquinavir inhibit its metabolism. Alternatively, inducers of this enzyme such as phenobarbital, carbamazepine, phenytoin, rifampicin may reduce the levels of the drug. Since the magnitude of an inducing or inhibitory effect is unknown, such drug combinations should be avoided.
Temgesic has no known effects on diagnostic laboratory tests.
Ampoule: Incompatibilities: None stated.
Tablet: Store in a dry, cool (below 25°C), dark place.
Ampoule: Store below 30°C.
N02AE01 - buprenorphine ; Belongs to the class of oripavine derivative opioids. Used to relieve pain.
SL tab 0.2 mg (white to creamy white, circular, biconvex tablets, embossed with L on the front of the tablet) x 10 x 5's. Inj 0.3 mg/mL (white to off-white powder) x 1 mL x 5's.