Sovenor

Sovenor

buprenorphine

Manufacturer:

Mundipharma

Distributor:

DKSH
Full Prescribing Info
Contents
Buprenorphine.
Description
Buprenorphine is a white or almost white crystalline powder very slightly soluble in water, freely soluble in acetone, soluble in methanol, ethanol and diethyl ether and slightly soluble in cyclohexane. The chemical name is (2S)-2-[(-)-(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy 6,14-ethanomorphinan-7-yl]-3-hydroxy-6-methoxy-3,3-dimethylbutan-2-ol (CAS No: 52485-79-7). The molecular formula is C29H41NO4 and molecular weight is 467.6.
The companents in Sovenor transdermal patches are as follows: Adhesive Matrix (Containing Buprenorphine): [(Z)-octadec-9-en-1-yl] oleate, povidone K90, 4-oxopentanic acid, poly[acrylic acid-co-butylacrylate-co-(2-ethylhexyl)acrylate-co-vinylacetate] (5:15:75:5), crosslinked. Adhesive Matrix (Without Buprenorphine): Poly[acrylic acid-co-butylacrylate-co-(2-ethylhexyl) acrylate-co-vinylacetate] (5:15:75:5). Separating Foil Between the Adhesive Matrices With and Without Buprenorphine: Poly(ethyleneterephthalate)-foil. Backing Layer: Poly(ethyleneterephthalate)-tissue. Release Liner (Covers the Adhesive Matrix that Contains Buprenorphine): Poly(ethyleneterephthalate)-foil, siliconised, coated on one side with aluminum. Release liner should be removed before applying the patch. Sovenor transdermal patch also contains the following excipients: Anhydrous ethanol, ethylacetate, aluminum acetylacetonate.
Action
Pharmacotherapeutic Group: Analgesics, opioids. ATC Code: N02 AE01.
Pharmacology: Pharmacodynamics: Buprenorphine is a partial agonist opioid, acting at the μ-opioid receptor. It also has antagonistic activity at the κ-opioid receptor.
Clinical Studies: The efficacy of Sovenor has been evaluated in four 12-week double-blind, controlled clinical trials in opioid-naive and opioid-experienced patients with moderate to severe chronic low back pain or osteoarthritis using pain scores as the primary efficacy variable. Two of these studies, described as follow, demonstrated efficacy in patients with low back pain. One study in low back pain and one study in osteoarthritis did not show a statistically significant pain reduction for either Sovenor or the respective active comparators.
12-Week Study in Opioid-Naive Patients with Chronic Low Back Pain: A total of 1,024 patients with chronic low back pain who were suboptimally responsive to their non-opioid therapy entered an open-label, dose-titration period for up to 4 weeks. Patients initiated therapy with 3 days of treatment with Sovenor 5 mcg/hr. After 3 days, if adverse events were tolerated, the dose was increased to Sovenor 10 mcg/hr. If adverse effects were tolerated but adequate analgesia was not reached, the dose was increased to Sovenor 20 mcg/hr for an additional 10-12 days. Patients who achieved adequate analgesia and tolerable adverse effects on Sovenor 10 or 20 mcg/hr were then randomized to remain on their titrated dose of Sovenor or matching placebo. Fifty-three (53)% of the patients who entered the open-label titration period were able to titrate to a tolerable and effective dose and were randomized into a 12-week, double-blind treatment period. Twenty-three (23)% of patients discontinued due to an adverse event from the open-label titration period and 14% discontinued due to lack of a therapeutic effect. The remaining 10% of patients were dropped due to various administrative reasons.
During the first 7 days of double-blind treatment patients were allowed up to 2 tablets/day of immediate-release oxycodone 5 mg as supplemental analgesia to minimize opioid withdrawal symptoms in patients randomized to placebo. Thereafter, the supplemental analgesia was limited to either acetaminophen 500 mg or ibuprofen 200 mg at a maximum of 4 tablets/day. Sixty-six (66)% of the patients treated with Sovenor completed the 12-week treatment compared to 70% of the patients treated with placebo.
Of the 256 patients randomized to Sovenor, 9% discontinued due to lack of efficacy and 16% due to adverse events. Of the 283 patients randomized to placebo, 13% discontinued due to lack of efficacy and 7% due to adverse events.
Of the patients who were randomized, the mean pain (SE) NRS scores were 7.2 (0.08) and 7.2 (0.07) at screening and 2.6 (0.08) and 2.6 (0.07) at pre-randomization (beginning of double-blind phase) for the Sovenor and placebo groups, respectively.
The score for average pain over the last 24 hrs at the end of the study (week 12/early termination) was statistically significantly lower for patients treated with Sovenor compared with patients treated with placebo. The proportion of patients with various degrees of improvement, from screening to study endpoint, is shown in Figure 1. (See Figure 1.)

Click on icon to see table/diagram/image

12-Week Study in Opioid-Experienced Patients with Chronic Low Back Pain: One thousand one hundred and sixty (1,160) patients on chronic opioid therapy (total daily dose 30-80 mg morphine equivalent) entered an open-label, dose-titration period with Sovenor for up to 3 weeks, following taper of prior opioids. Patients initiated therapy with Sovenor 10 mcg/hr for 3 days. After 3 days, if the patient tolerated the adverse effects, the dose was increased to Sovenor 20 mcg/hr for up to 18 days. Patients with adequate analgesia and tolerable adverse effects on Sovenor 20 mcg/hr were randomized to remain on Sovenor 20 mcg/hr or were switched to a low-dose control (Sovenor 5 mcg/hr) or an active control. Fifty-seven (57)% of the patients who entered the open-label titration period were able to titrate to and tolerate the adverse effects of Sovenor 20 mcg/hr and were randomized into a 12-week double-blind treatment phase. Twelve (12)% of patients discontinued due to an adverse event and 21% discontinued due to lack of a therapeutic effect during the open-label titration period.
During the double-blind period, patients were permitted to take ibuprofen (200 mg tablets) or acetaminophen (500 mg tablets) every 4 hrs as needed for supplemental analgesia (up to 3,200 mg of ibuprofen and 4 grams of acetaminophen daily). Sixty-seven (67)% of patients treated with Sovenor 20 mcg/hr and 58% of patients treated with Sovenor 5 mcg/hr completed the 12-week treatment. Of the 219 patients randomized to Sovenor 20 mcg/hr, 11% discontinued due to lack of efficacy and 13% due to adverse events. Of the 221 patients randomized to Sovenor 5 mcg/hr, 24% discontinued due to lack of efficacy and 6% due to adverse events.
Of the patients who were able to be randomized in the double-blind period, the mean pain (SE) NRS scores were 6.4 (0.08) and 6.5 (0.08) at screening and were 2.8 (0.08) and 2.9 (0.08) at prerandomization (beginning of double-blind period) for the Sovenor 5 mcg/hr and Sovenor 20 mcg/hr, respectively.
The score for average pain over the last 24 hrs at week 12 was statistically significantly lower for subjects treated with Sovenor 20 mcg/hr compared to subjects treated with Sovenor 5 mcg/hr. A higher proportion of Sovenor 20 mcg/hr patients (49%) had at least a 30% reduction in pain score from screening to study endpoint when compared to Sovenor 5 mcg/hr patients (33%). The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 2. (See Figure 2.)

Click on icon to see table/diagram/image

Pharmacokinetics: There is evidence of enterohepatic recirculation.
Studies in non-pregnant and pregnant rats have shown that buprenorphine passes the blood-brain and placental barriers.
Concentrations in the brain (which contained only unchanged buprenorphine) after parenteral administration were 2-3 times higher than after oral administration.
After intramuscular or oral administration buprenorphine apparently accumulates in the foetal gastrointestinal lumen-presumably due to biliary excretion, as enterohepatic circulation has not fully developed.
Each patch provides a steady delivery of buprenorphine for up to 7 days. Steady state is achieved during the 1st application. After removal of Sovenor, buprenorphine concentrations decline, decreasing approximately 50% in 12 hrs (range 10-24 hrs).
Absorption: Following Sovenor transdermal patch application, buprenorphine diffuses from the patch through the skin. In clinical pharmacology studies, the median time for Sovenor 10 mcg/hr transdermal patch to deliver detectable buprenorphine concentrations (25 picograms/mL) was approximately 17 hrs. Analysis of residual buprenorphine in patches after 7-day use shows 15% of the original load delivered. A study of bioavailability, relative to intravenous administration, confirms that this amount is systemically absorbed.
Buprenorphine concentrations remain relatively constant during the 7-day patch application.
Application Site: A study in healthy subjects demonstrated that the pharmacokinetic profile of buprenorphine delivered by Sovenor transdermal patch is similar when applied to upper outer arm, upper chest, upper back or the side of the chest (midaxillary line, 5th intercostal space). The absorption varies to some extent depending on the application site and the exposure is at the most approximately 26% higher when applied to the upper back compared to the side of the chest.
In a study of healthy subjects receiving Sovenor transdermal patch repeatedly to the same site, an almost doubled exposure was seen with a 14 day rest period. For this reason, rotation of application sites is recommended and a new patch should not be applied to the same skin site for 3-4 weeks.
In a study of healthy subjects, application of a heating pad directly on the transdermal patch caused a transient 26-55% increase in blood concentrations of buprenorphine. Concentrations returned to normal within 5 hrs after the heat was removed. For this reason, applying direct heat sources eg, hot water bottles, heat pads or electric blankets directly to the patch is not recommended. A heating pad applied to a Sovenor transdermal patch site immediately after patch removal did not alter absorption from the skin depot.
Distribution: Buprenorphine is approximately 96% bound to plasma proteins.
Studies of intravenous buprenorphine have shown a large volume of distribution, implying extensive distribution of buprenorphine. In a study of intravenous buprenorphine in healthy subjects, the volume of distribution at steady state was 430 L, reflecting the large volume of distribution and lipophilicity of the active substance.
Following intravenous administration, buprenorphine and its metabolites are secreted into bile and within several minutes, distributed into the cerebrospinal fluid. Buprenorphine concentrations in the cerebrospinal fluid appear to be approximately 15-25% of concurrent plasma concentrations.
Biotransformation and Elimination: Buprenorphine metabolism in the skin following Sovenor transdermal patch application is negligible.
Following transdermal application, buprenorphine is eliminated via hepatic metabolism, with subsequent biliary excretion and renal excretion of soluble metabolites. Hepatic metabolism, through CYP3A4 and UGT1A1/1A3 enzymes, results in 2 primary metabolites, norbuprenorphine and buprenorphine 3-O-glucuronide, respectively. Norbuprenorphine is glucuronidated before elimination. Buprenorphine is also eliminated in the faeces. In a study in post-operative patients, the total elimination of buprenorphine was shown to be approximately 55 L/hr. Norbuprenorphine is the only known active metabolite of buprenorphine.
Effect of Buprenorphine on the Pharmacokinetics of Other Active Substances: Based on in vitro studies in human microsomes and hepatocytes, buprenorphine does not have the potential to inhibit metabolism catalysed by the CYP450 enzymes CYP1A2, CYP2A6 and CYP3A4 at concentrations obtained with use of Sovenor 20 mcg/hr transdermal patch. The effect on metabolism catalysed by CYP2C8, CYP2C9 and CYP2C19 has not been studied.
Indications/Uses
Treatment of non-malignant pain of moderate to severe intensity requiring continuous opioid analgesia for an extended period of time.
Sovenor is not suitable for the treatment of acute pain.
Dosage/Direction for Use
Adults (≥18 years): The lowest Sovenor dose (Sovenor 5 mcg/hr transdermal patch) should be used as the initial dose. Consideration should be given to the previous opioid history of the patient as well as to the current general condition and medical status of the patient.
Titration: During initiation and titration with Sovenor, patients should use the usual recommended doses of short-acting supplemental analgesics as needed until analgesic efficacy with Sovenor is attained.
The dose should not be increased before 3 days, when the maximum effect of a given dose is established. Subsequent dosage increases may then be titrated based on the need for supplemental pain relief and the patient's analgesic response to the patch.
To increase the dose, a larger patch should replace the patch that is currently being worn or a combination of patches should be applied in different places to achieve the desired dose. It is recommended that no >2 patches are applied at the same time, regardless of the patch strength. The total dose from all patches should not exceed 20 mcg/hr. A new patch should not be applied to the same skin site for the subsequent 3-4 weeks. Patients should be carefully and regularly monitored to assess the optimum dose and duration of treatment. The maximum Sovenor dose is 20 mcg/hr.
Conversion from Opioids: Sovenor can be used as an alternative to treatment with other opioids. Such patients should be started on the lowest available dose (Sovenor 5 mcg/hr transdermal patch) and continue taking short-acting supplemental analgesics during titration, as required.
Discontinue all other around-the-clock opioid drugs when Sovenor therapy is initiated.
There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids.
Prior Total Daily Dose of Opioid <30 mg of Oral Morphine Equivalents per Day: Initiate treatment with Sovenor 5 mcg/hr at the next dosing interval.
Prior Total Daily Dose of Opioid Between 30-80 mg of Oral Morphine Equivalents per Day: Taper the patient's current around-the-clock opioids for up to 7 days to no >30 mg of morphine or equivalent per day before beginning treatment with Sovenor. Then initiate treatment with Sovenor 10 mcg/hr at the next dosing interval. Patients may use short-acting analgesics as needed until analgesic efficacy with Sovenor is attained.
Prior Total Daily Dose of Opioid >80 mg of Oral Morphine Equivalents per Day: Sovenor 20 mcg/hr may not provide adequate analgesia for patients requiring >80 mg/day oral morphine equivalents. Consider the use of an alternate analgesic.
Elderly: No dosage adjustment of Sovenor is required in elderly patients.
Renal impairment: No special dose adjustment of Sovenor is necessary in patients with renal impairment.
Hepatic impairment: Buprenorphine is metabolised in the liver. The intensity and duration of its action may be affected in patients with impaired liver function. Therefore patients with hepatic insufficiency should be carefully monitored during treatment with Sovenor.
Patients with severe hepatic impairment may accumulate buprenorphine during Sovenor treatment. Consideration of alternate therapy should be considered and Sovenor should be used with caution, if not all, in such patients.
Administration: Sovenor should be administered every 7th day.
Patch Application: Sovenor should be applied to non-irritated, intact skin of the upper outer arm, upper chest, upper back or the side of the chest, but not to any parts of the skin with large scars. Sovenor should be applied to a relatively hairless or nearly hairless skin site. If none are available, the hair at the site should be cut with scissors, not shaven.
If the application site must be cleaned, it should be done with clean water only. Soaps, alcohol, oils, lotions or abrasive devices must not be used. The skin must be dry before the patch is applied. Sovenor should be applied immediately after removal from the sealed sachet.
Following removal of the protective layer, the transdermal patch should be pressed firmly in place with the palm of the hand for approximately 30 sec, making sure the contact is complete, especially around the edges. If the edges of the patch begin to peel off, the edges may be taped down with suitable skin tape.
The patch should be worn continuously for 7 days. Bathing, showering or swimming should not affect the patch. If a patch falls off, a new one should be applied.
Duration of Administration: Sovenor should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with Sovenor is necessary in view of the nature and severity of the illness, then careful and regular monitoring should be carried out (if necessary with breaks in treatment) to establish whether and to what extent further treatment is necessary.
Discontinuation: After removal of the patch, buprenorphine serum concentrations decrease gradually and thus the analgesic effect is maintained for a certain amount of time. This should be considered when therapy with Sovenor is to be followed by other opioids. As a general rule, a subsequent opioid should not be administered within 24 hrs after removal of the patch. At present, only limited information is available on the starting dose of other opioids administered after discontinuation of the transdermal patch.
Patients with Fever or Exposed to External Heat: While wearing the patch, patients should be advised to avoid exposing the application site to external heat sources eg, heating pads, electric blankets, heat lamps, sauna, hot tubs and heated water beds, etc, as an increase in absorption of buprenorphine may occur. When treating febrile patients, one should be aware that fever may also increase absorption resulting in increased plasma concentrations of buprenorphine and thereby increased risk of opioid reactions.
Cessation of Therapy: When the patient no longer requires therapy with Sovenor, use a gradual downward titration of the dose every 7 days to prevent signs and symptoms of withdrawal in the physically dependent patient; consider introduction of an appropriate immediate-release opioid medication. Do not abruptly discontinue Sovenor.
Changing the Patch: Take the old patch off; fold it in half with the sticky side inwards; open and take out a new patch. Use the empty pouch to dispose of the old patch. Discard the pouch safely; used patches contain some active ingredient that may harm children or animals, ensure that used patches are always kept out of the reach and sight; stick a new patch on a different appropriate skin site (as described previously). Do not apply a new patch to the same site for 3-4 weeks; change patch at the same time of day. It is important to make a note of the time of day.
Overdosage
Symptoms: Symptoms similar to those of other centrally acting analgesics are to be expected.
These include respiratory depression, sedation, drowsiness, nausea, vomiting, cardiovascular collapse and marked miosis.
Treatment: Remove any patches from the patient's skin. Establish and maintain a patent airway, assist or control respiration as indicated and maintain adequate body temperature and fluid balance. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated.
A specific opioid antagonist eg, naloxone may reverse the effects of buprenorphine. The dose of naloxone may be in the range 5-12 mg intravenously. The onset of the naloxone effect may be delayed by ≥30 min. Maintenance of adequate ventilation is more important than treatment with naloxone.
Contraindications
Patients with known hypersensitivity to buprenorphine or to any of the excipients of Sovenor. The treatment of opioid dependence and narcotic withdrawal. Conditions in which the respiratory centre and function are severely impaired or may become so. Patients who are receiving MAO inhibitors or have taken them within the last 2 weeks; suffering from myasthenia gravis; suffering from delirium tremens.
Special Precautions
Sovenor should be used with particular caution in patients with convulsive disorders, head injury, shock, a reduced level of consciousness of uncertain origin, intracranial lesions or increased intracranial pressure or in patients with severe hepatic impairment. Significant respiratory depression has been associated with buprenorphine, particularly by the intravenous route. A number of overdose deaths have occurred when addicts have intravenously abused buprenorphine, usually with benzodiazepines concomitantly. Additional overdose deaths due to ethanol and benzodiazepines in combination with buprenorphine have been reported.
Sovenor is not recommended for analgesia in the immediate post-operative period or in other situations characterised by a narrow therapeutic index or a rapidly varying analgesic requirement.
Sovenor may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (eg, phenothiazines or general anaesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dose of Sovenor.
The buprenorphine in Sovenor may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioid may cause increases in the serum amylase.
In a positive-controlled study of the effect of Sovenor patches on the QTc interval in healthy males, therapeutic dosages (10 mcg/hr) had no effect on the QTc interval but higher dosages (40 mcg/hr) were associated with a mean prolongation of the QTc interval of 5.9 msec compared to placebo. This observation should be considered when prescribing Sovenor patches for patients with congenital QT prolongation and for patients taking antiarrhythmic medications in either Class 1A, Class III or any other medication which prolongs the QT interval.
Controlled human and animal studies indicate that buprenorphine has a lower dependence liability than pure agonist analgesics. In humans, limited euphorigenic effects have been observed with buprenorphine. This may result in some abuse of Sovenor and caution should be exercised when prescribing to patients known to have or suspected of having, a history of drug abuse.
As with all opioids, chronic use of buprenorphine can result in the development of physical dependence. Withdrawal (abstinence syndrome), when it occurs, is generally mild, begins after 2 days and may last up to 2 weeks. Withdrawal symptoms include agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal disorders.
Effects on the Ability to Drive or Operate Machinery: Sovenor has a major influence on the ability to drive and use machines. Even when used according to instructions, Sovenor transdermal patch may affect the patient's reactions to such an extent that road safety and the ability to operate machinery may be impaired. This applies particularly in the beginning of treatment and in conjunction with other centrally acting substances including alcohol, tranquillisers, sedatives and hypnotics. An individual recommendation should be given by the physician. A general restriction is not necessary in cases where a stable dose is used. In patients who are affected eg, during treatment initiation or titration to a higher dose, these patients should not drive or use machines, nor for at least 24 hrs after the patch has been removed.
Use in pregnancy: There are no data from the use of Sovenor in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Towards the end of pregnancy high doses of buprenorphine may induce respiratory depression in the neonate even after a short period of administration. Long-term administration of buprenorphine during the last 3 months of pregnancy may cause a withdrawal syndrome in the neonate. Therefore, Sovenor is contraindicated during pregnancy.
Use in lactation: Studies in rats have shown that buprenorphine may inhibit lactation. Excretion of buprenorphine into the milk in rats has been observed. Data on excretion into human milk are not available. Therefore, the use of Sovenor transdermal patch during lactation should be avoided.
Use in children: As Sovenor has not been studied in patients <18 years, the use of Sovenor in patients below this age is not recommended.
Use In Pregnancy & Lactation
Use in pregnancy: There are no data from the use of Sovenor in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Towards the end of pregnancy high doses of buprenorphine may induce respiratory depression in the neonate even after a short period of administration. Long-term administration of buprenorphine during the last 3 months of pregnancy may cause a withdrawal syndrome in the neonate. Therefore, Sovenor is contraindicated during pregnancy.
Use in lactation: Studies in rats have shown that buprenorphine may inhibit lactation. Excretion of buprenorphine into the milk in rats has been observed. Data on excretion into human milk are not available. Therefore, the use of Sovenor transdermal patch during lactation should be avoided.
Adverse Reactions
Serious adverse reactions that may be associated with Sovenor therapy in clinical use are similar to those observed with other opioid analgesics, including respiratory depression (especially when used with other CNS depressants) and hypotension.
The following undesirable effects have occurred: Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data).
Immune System Disorders: Uncommon: Hypersensitivity. Very Rare: Anaphylactic reaction, anaphylactoid reaction.
Metabolism and Nutrition Disorders: Common: Anorexia. Uncommon: Dehydration.
Psychiatric Disorders: Common: Confusion, depression, insomnia, nervousness. Uncommon: Sleep disorder, restlessness, agitation, depersonalisation, euphoric mood, affective lability, anxiety, hallucinations, nightmares. Rare: Psychotomimetic effects, decreased libido. Very Rare: Drug dependence, mood swings.
Nervous System Disorders: Very Common: Headache, dizziness, somnolence. Common: Paresthesia. Uncommon: Sedation, dysgeusia, dysarthria, hypoaesthesia, memory impairment, migraine, syncope, tremor, abnormal coordination, disturbance in attention. Rare: Balance disorder, speech disorder. Very Rare: Involuntary muscle contractions.
Eye Disorders: Uncommon: Dry eye, blurred vision. Rare: Visual disturbance, blurring of vision, eyelid oedema, miosis.
Ear and Labyrinth Disorders: Uncommon: Tinnitus, vertigo. Very Rare: Ear pain.
Cardiac Disorders: Uncommon: Angina pectoris, palpitations, tachycardia.
Vascular Disorders: Common: Vasodilatation. Uncommon: Hypotension, circulatory collapse, hypertension, flushing.
Respiratory, Thoracic and Mediastinal Disorders: Common: Dyspnoea. Uncommon: Aggravated asthma, cough, hypoxia, rhinitis, wheezing, hyperventilation, hiccups. Rare: Respiratory depression, respiratory failure.
Gastrointestinal Disorders: Very Common: Constipation, dry mouth, nausea, vomiting. Common: Abdominal pain, diarrhoea, dyspepsia. Uncommon: Flatulence. Rare: Diverticulitis, dysphagia, ileus.
Hepatobiliary Disorders: Rare: Biliary colic.
Skin and Subcutaneous Tissue Disorders: Very Common: Pruritus, erythema. Common: Rash, sweating, exanthema. Uncommon: Dry skin, face oedema, urticaria Very Rare: Pustules, vesicles.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Muscle cramp, myalgia, muscular weakness, muscle spasms.
Renal and Urinary Disorders: Uncommon: Urinary retention, micturition disorders.
Reproductive System and Breast Disorders: Rare: Erectile dysfunction, sexual dysfunction.
General Disorders and Administration Site Conditions: Very Common: Application site pruritus, application site reaction. Common: Tiredness, asthenia, pain, peripheral oedema, application site erythema, application site rash, chest pain. Uncommon: Fatigue, influenza-like illness, pyrexia, rigors, malaise, oedema, drug withdrawal syndrome. Rare: Application site inflammation*.
Investigations: Uncommon: Increased alanine aminotransferase, decreased weight.
Injury, Poisoning and Procedural Complications: Uncommon: Accidental injury, fall.
* In some cases delayed local allergic reactions occurred with marked signs of inflammation. In such cases, treatment with Sovenor should be terminated.
Buprenorphine has a low risk of physical dependence. After discontinuation of Sovenor transdermal patch, withdrawal symptoms are unlikely. This may be due to the very slow dissociation of buprenorphine from the opioid receptors and to the gradual decrease of buprenorphine plasma concentrations (usually over a period of 30 hrs after removal of the last patch). However, after long-term use of Sovenor transdermal patch, withdrawal symptoms similar to those occurring during opioid withdrawal, cannot be entirely excluded. These symptoms include agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal disorders.
Drug Interactions
Sovenor must not be used concomitantly with MAOIs or in patients who have received MAOIs within the previous 2 weeks.
Effect of Other Active Substances on the Pharmacokinetics of Buprenorphine: Buprenorphine is primarily metabolised by glucuronidation and to a lesser extent (about 30%) by CYP3A4 .
Concomitant treatment with CYP3A4 inhibitors may lead to elevated plasma concentrations with intensified efficacy of buprenorphine.
A drug interaction study with the CYP3A4 inhibitor ketoconazole did not produce clinically relevant increases in mean maximum (Cmax) or total (AUC) buprenorphine exposure following Sovenor with ketoconazole as compared to Sovenor alone.
The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied.
Co-administration of Sovenor and enzyme inducers (eg, phenobarbital, carbamazepine, phenytoin and rifampicin) could lead to increased clearance which might result in reduced efficacy. Reductions in hepatic blood flow induced by some general anaesthetics (eg, halothane) and other medicinal products may result in a decreased rate of hepatic elimination of buprenorphine.
Pharmacodynamic Interactions: Sovenor should be used cautiously with: Benzodiazepines: This combination can potentiate respiratory depression of central origin, with risk of death.
Other Central Nervous System Depressants: Other opioid derivatives (analgesics and antitussives containing eg, morphine, dextropropoxyphene, codeine, dextromethorphan or noscapine). Certain antidepressants, sedative H1-receptor antagonists, alcohol, anxiolytics, neuroleptics, clonidine and related substances. These combinations increase the CNS depressant activity.
Buprenorphine is a partial μ-receptor agonist but it is described to function as a pure μ-receptor agonist at typical analgesic doses. These doses produce buprenorphine exposures comparable to or greater than those produced by Sovenor 5, 10 and 20 mcg/hr transdermal patches. In Sovenor clinical studies, where subjects receiving full μ-agonist opioids (up to 90 mg oral morphine or oral morphine equivalents per day) were transferred to Sovenor transdermal patch, there were no reports of abstinence syndrome or opioid withdrawal during conversion from entry opioid to Sovenor transdermal patch.
Caution For Usage
Instructions for Disposal: Used patches must be folded over on themselves with the adhesive layer inwards and discarded safely out of sight and reach of children. Unused patches should be returned to the pharmacy.
Storage
Do not store above 30°C.
Shelf-Life: 2 years.
MIMS Class
ATC Classification
N02AE01 - buprenorphine ; Belongs to the class of oripavine derivative opioids. Used to relieve pain.
Presentation/Packing
Transdermal patch 5 mcg (square, beige, with rounded corners marked 'Sovenor 5 mg 5 mcg/hr') x 2's. 10 mcg (square, beige, with rounded corners marked 'Sovenor 10 mg 10 mcg/hr') x 2's.
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