Each modified release uncoated bilayered

tablet contains :

Pregabalin IP 75 mg

(As prolonged release)

Methylcobalamin IP 1500 mcg

(As immediate release)

Excipients q.s.

Appropriate overages of Vitamin added.

MethyPreg is the combination of sustained release Pregabalin with Methylcobalamin. Pregabalin is a 3-substituted analogue of gamma-amino butyric acid (GABA) with an empirical formula of C H NO and 8 17 2 molecular weight of 159.2. Methylcobalamin is the active form of vitamin B with an empirical formula of C H CoN O P and molecular weight of 1344.4.

Pharmacodynamics

Pregabalin binds with high affinity to α2δ subunits of voltage activated calcium channels, blocks Ca influx into nerve terminals, and decreases neurotransmitter release. This reduction in the transmitter release is probably responsible for reduction in transmission of pain impulses by decreasing release of excitatory neurotransmitters glutamate, adrenaline and substance P. Pregabalin also enhances the activity of glutamic acid decarboxylase, an enzyme that converts excitatory neurotransmitter glutamate to inhibitory neurotransmitter GABA (gamma amino butyric acid) in a single step. Methylcobalamin is the neurologically active form of B ; it is the methyl donor in DNA metabolism, which is needed to up-regulate gene transcription for peripheral nerve repair and regeneration. Additionally, 12 Methylcobalamin enhances protein metabolism in Schwann cells which are supporting cells of peripheral nervous system and also form myelin sheath around the nerves.

Pharmacokinetics

Pregabalin is rapidly absorbed with peak plasma concentrations occurring within 1.5 hours following both single and multiple dose administration. Oral bioavailability of Pregabalin is > 90% and is independent of dose. Cmax and AUC values increase proportionally following single and multiple dose administration. The rate of absorption of Pregabalin is decreased when given with food, but there is no clinically relevant effect on the total absorption. In humans, the apparent volume of distribution of Pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is not bound to plasma proteins. Pregabalin undergoes negligible metabolism in humans. Approximately 98% of the drug is excreted unchanged. Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. Mean t½of Pregabalin is 6.3 hours. Its elimination is proportional to creatinine clearance. Pregabalin clearance is reduced in patients with impaired renal function. Methylcobalamin binds to intrinsic factor, and then is actively absorbed from the gastrointestinal tract. Methylcobalamin is extensively bound to specific plasma proteins called transcobalamins; transcobalamin II appears to be involved in the rapid transport of the cobalamins to tissues. Methylcobalamin is stored in the liver, excreted in the bile, and undergoes extensive enterohepatic recycling; part of a dose is excreted in the urine, most of it in the first 8 hours.

MethyPreg is indicated for

• For the treatment of adult patients with peripheral neuropathy

The dose range is 150 to 600 mg per day given in either two or three divided doses.

The treatment can be started at a dose of 150 mg per day given as two or three divided doses. Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg per day after an additional 7-day interval.

Renal impairment

Table 1 : Pregabalin Dose Adjustment Based on Renal Function

TID = Three divided doses

BID = Two divided doses

* Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose

+ Supplementary dose is a single additional dose

Hepatic Impairment

No dose adjustment is required for patients with hepatic impairment.

Paediatric Population

The safety and efficacy of Pregabalin in children below the age of 12 years and in adolescents (12-17 years of age) have not been established.

Elderly

Elderly patients may require a dose reduction of Pregabalin due to a decreased renal function

Method of administration

Methypreg may be taken with or without food.

This combination is contraindicated in patients who are hypersensitive to Pregabalin, Methylcobalamin or to any ingredient in the formulation. It is also contraindicated in patients with Leber’s disease and Tobacco amblyopia.

Warnings & Precautions

Caution must be advocated in heart failure and diabetic patients in view of possibility of edema and weight gain induced by Pregabalin. Diabetic patients taking Pregabalin may develop skin ulcerations. This combination should not be discontinued abruptly due to the possibility of increasing seizure frequency, insomnia, nausea or diarrhea caused by Pregabalin, the anti-epileptic component of the combination. If it is to be stopped, it must be done gradually over 1 week.

Since Pregabalin can cause dizziness, somnolence and other manifestations of central nervous system like depression, patients should be advised neither to drive nor to operate complex machinery until they have gained sufficient experience on the combination to gauge whether or not it affects their mental and / or motor performance adversely.

If vision disturbances occur during Pregabalin therapy, medical advice must be sought. Also unexplained muscle pain, tenderness, or weakness, especially accompanied by malaise or fever requires prompt medical attention.

It is not to be taken along with alcohol, or be combined with other central nervous depressants.

Women of childbearing potential/Contraception in males and females.

As the potential risk for humans is unknown, effective contraception must be used in women of child bearing potential.

Pregnancy

There are no adequate data from the use of Pregabalin in pregnant women. Pregabalin should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the foetus).

Breast-feeding

Pregabalin is excreted into human milk. The effect of Pregabalin on newborns/infants is unknown. A decision must be made whether to discontinue breast-feeding or to discontinue Pregabalin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman

Fertility

There are no clinical data on the effects of Pregabalin on female fertility

The common adverse effects of Pregabalin given alone or in combination with other anti-epileptic agents are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and "thinking abnormal" (primarily difficulty with concentration / attention). Asthenia, ataxia, abnormal gait, paresthesias, diplopia, blurred vision, visual field defect, nystagmus, nausea, tremor, vertigo, headache, nervousness, confusion and edema are other significant side effects of Pregabalin. Methylcobalamin is relatively safe and devoid of side effects.

Lorazepam, Ethanol and other CNS depressants

Pregabalin may potentiate the effects of these drugs and lead to additive CNS depression.

Phenytoin, phenobarbital, and primidone

These drugs have been associated with reduced vitamin B12 absorption and reduced serum and cerebrospinal fluid levels in some patients

Oxycodone

Additive cognitive impairment and gross motor function.

Thiazolidinedione antidiabetic agents

Higher frequencies of weight gain and peripheral edema were observed in patients taking both Pregabalin and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone.

Histamine-2 receptor antagonists and PPI’s

Reduced secretion of gastric acid and pepsin produced by H2-blockers and PPI’s can reduce absorption of Methylcobalamin.

Colchicine

Co-administration with colchicines reduces Methylcobalamin absorption as colchicines disrupts normal mucosa and causes malabsorption

There is limited experience with overdose of Pregabalin. The highest reported accidental overdose of Pregabalin during the clinical development program was 8000 mg, and there were no notable clinical consequences. There is no specific antidote for overdose with Pregabalin. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; usual precautions should be observed to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient.

Toxicity due to overdosage with Methylcobalamin is not known.

Store below 30°C. Protect from light and moisture.

Keep out of reach of children

Buprenorphine Transdermal Patch

BuprePLAST 5 mcg/hr

Each 6.25 cm2 transdermal patch contains :

Buprenorphine Ph.     Eur. 5 mg

Excipients     q.s.

Each patch delivers 5 mcg/hr Buprenorphine

BuprePLAST 10 mcg/hr

Each 12.5 cm2 transdermal patch contains :

Buprenorphine Ph. Eur.    10 mg

Excipients    q.s.

Each patch delivers 10 mcg/hr Buprenorphine

Transdermal Patch

4.1 Therapeutic indication

For the treatment of severe opioid responsive pain conditions which are not adequately responding to nonopioid analgesics.

4.2 Posology and method of administration

Bupreplast patch should be administered every 7th day. Bupreplast patch is not suitable for the treatment of acute pain.

Patients aged 18 years and over

The lowest Bupreplast patch dose (Bupreplast 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 Bupreplast, patients should use the usual recommended doses of short acting supplemental analgesics as needed until analgesic efficacy with Bupreplast patch 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 more than two patches are applied at the same time, regardless of the patch strength. 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.

Conversion from opioids

Patch can be used as an alternative to treatment with other opioids. Such patients should be started on the lowest available dose (Bupreplast 5 mcg/hr transdermal patch) and continue taking short-acting supplemental analgesics during titration as required.

Patients under 18 years of age

As buprenorphine patch has not been studied in patients under 18 years of age,the use of Bupreplast patch in patients below this age is not recommended.

Elderly

No dosage adjustment of Bupreplast patch is required in elderly patients.

Renal impairment

No special dose adjustment of Bupreplast patch 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 Bupreplast patch. Patients with severe hepatic impairment may accumulate buprenorphine during Bupreplast patch treatment. Consideration of alternate therapy should be considered, and Bupreplast should be used with caution, if at all, in such patients.

Patch application

Bupreplast should be applied to non-lrritated, Intact skin of the upper outer arm, upper chest, upper back or side of the chest, but not to any parts of the skin with large scars. Bupreplast patch 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, oil, lotions of abrasive devices must not be used. The skin must be dry before the patch is applied. Bupreplast 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 seconds, 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

Bupreplast should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with Bupreplast is necessary in view of the nature and severity to 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 Bupreplast is to be followed by other opioids. As a general rule, a subsequent opioid should not be administered within 24 hours 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, such as 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.

4.3 Contraindications

Buprenorphine patch is contraindicated in :

• Patients with known hypersensitivity to the active substance buprenorphine or to any of the excipients.
• 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 two weeks.
• Patients suffering from myasthenia gravis
• Patients suffering from delirium tremens
• Pregnancy (see "Warnings & Precautions").

4.4 Special warnings and precautions for use

• Buprenorphine should be used with particular caution in patients with acute alcohol intoxication, head injury, shock, a reduced level of consciousness of uncertain origin, intracranial lesions or increased intracranial pressure, or in patients with severe hepatic impairment.
• Buprenorphine may lower the seizure threshold in patients with a history of seizure disorder.
• 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.
• Since CYP3A4 inhibitors may increase concentrations of buprenorphine, patients already treated with CYP3A4 inhibitors should have their dose of Buprenorphine carefully titrated since a reduced dosage might be sufficient in these patients.
• Buprenorphine 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.
• 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 the medicinal product and caution should be exercised when prescribing to patients known to have, or suspected of having, a history of drug abuse or alcohol abuse or serious mental illness.
• 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.
• Athletes should be aware that this medicine may cause a positive reaction to sports doping control tests.
• Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs : Concomitant use of Buprenorphine and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Buprenorphine concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
• The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms.

Serotonin syndrome

Concomitant administration of Buprenorphine and other serotonergic agents, such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants may result in serotonin syndrome, a potentially life-threatening condition.

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

4.5 Drugs interactions

Buprenorphine must not be used concomitantly with MAOIs or in patients who have received MAOIs within the previous two 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.
• Studies with the CYP3A4 inhibitor ketoconazole did not produce clinically relevant increases in mean maximum (Cmax) or total (AUC) buprenorphine exposure following buprenorphine with ketoconazole as compared to buprenorphine alone.
• The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied.
• Co-administration of buprenorphine and enzyme inducers (e.g. 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 (e.g. halothane) and other medicinal products may result in a decreased rate of hepatic elimination of buprenorphine.

Pharmacodynamic interactions

Buprenorphine should be used cautiously with :

• Other central nervous system depressants : other opioid derivatives (analgesics and antitussives containing e.g. morphine, dextropro-poxyphene, codeine, dextromethorphan or noscapine). Certain anti-depressants, sedative H1-receptor antagonists, alcohol, anxiolytics, neuroleptics, clonidine and related substances. These combinations increase the CNS depressant activity. Benzodiazepines : This combination can potentiate respiratory depression of central origin.
• At typical analgesic doses buprenorphine is described to function as a pure mu receptor agonist. In buprenorphine clinical studies subjects receiving full mu agonist opioids (up to 90 mg oral morphine or oral morphine equivalents per day) were transferred to buprenorphine. There were no reports of abstinence syndrome or opioid withdrawal during conversion from entry opioid to buprenorphine.
• Sedative medicines such as benzodiazepines or related drugs The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited Co-administration of Serotonergic medicinal products, such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants as the risk of serotonin syndrome, a potentially life-threatening condition, is increased.

4.6 Use in special populations

Pregnancy

There are no or limited amount of data from the use of buprenorphine 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. Prolonged use of buprenorphine during pregnancy can result in neonatal opioid withdrawal. Therefore, buprenorphine should not be used during pregnancy and in women of childbearing potential who are not using effective contraception.

Nursing Mothers

Buprenorphine is excreted in human milk. Studies in rats have shown that buprenorphine may inhibit lactation. Available pharmacodynamic / toxicological data in animals has shown excretion of buprenorphine in milk. Therefore, the use of buprenorphine during lactation should be avoided.

Fertility

No human data on the effect of buprenorphine on fertility are available. In a fertility and early embryonic development study, no effects on reproductive parameters were observed in male or female rats

4.7 Effects on ability to drive and use machines

Buprenorphine has major influence on the ability to drive and use machines. Even when used according to instructions, buprenorphine 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, such as during treatment initiation or titration to a higher dose, these patients should not drive or use machines, nor for at least 24 hours after the patch has been removed.

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 your ability to drive.
• Do not drive until you know how the medicine affects you.

4.8 Undesirable effects

Serious adverse reactions that may be associated with buprenorphine patch 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 (>/1000, < 1/100), rare (> 1/10,000 < 1/1000), very rare (< 1/10,000 including isolated reports).

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, depersonalization, euphoric mood, affect lability, anxiety, hallucinations, nightmares

Rare : psychotic disorder, 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, eyelid oedema, miosis

Ear and labyrinth disorders

Uncommon : tinnitus, vertigo

Very rare : ear pain

Cardiac disorders

Uncommon : angina pectoris, palpitations, tachycardia

Vascular disorders

Common : vasodilation

Uncommon : hypotension, circulatory collapse, hypertension, flushing

Respiratory, thoracic and mediastinal disorders

Common : dyspnoea

Uncommon : asthma aggravated, cough, hypoxia, rhinitis, wheezing, hyperventilation, hiccups Rare: respirator y depression, respirator y 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 reaction, erythema at site, rash at site, oedema, chest pain

Uncommon : fatigue, influenza like illness, pyrexia, rigors, malaise, oedema, drug withdrawal syndrome

Rare : application site inflammation

Investigations

Uncommon : alanine aminotransferase increased, weight decreased

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 buprenorphine patch should be terminated.

Buprenorphine has a low risk of physical dependence. After discontinuation of buprenorphine 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 hours after removal of the last patch). However, after long-term use of buprenorphine 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via email to :medico@zuventus.com

Website : https://www.zuventus.com/drug-safety-reporting

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

4.9 Overdose

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 such as naloxone may reverse the effects of buprenorphine. The dose of naloxone may be in the range 5 to 12 mg intravenously.

5.1 Mechanism of action

Buprenorphine is a partial agonist opioid, acting at the mu opioid receptor. It also has antagonistic activity at the kappa opioid receptor.

5.2 Pharmacodynamic properties

Buprenorphine can displace or block morphine binding to µ-receptor thus contributes to reduced opioid dependence. Buprenorphine agonist activity on µ receptor is the primary contributing factor to its analgesic signaling events. Buprenorphine interacts with nociceptin / ORL1 with much lower affinity and thus is unlikely to contribute to analgesic effects at therapeutic doses. Buprenorphine is a potent antagonist of κ-opioid receptor and this interaction could contribute to reduced tolerance and antidepressant like activity.

5.3 Pharmacokinetic properties

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 seven days. Steady state is achieved during the first application. After removal of buprenorphine, buprenorphine concentrations decline, decreasing approximately 50% in 12 hours (range 10 - 24 h).

Absorption

Following buprenorphine application, buprenorphine diffuses from the patch through the skin. In clinical pharmacology studies, the median time for “buprenorphine 10 microgram/hour” to deliver detectable buprenorphine concentrations (25 picograms/ml) was approximately 17 hours. 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 buprenorphine 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 buprenorphine 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 hours after the heat was removed. For this reason, applying direct heat sources such as hot water bottles, heat pads or electric blankets directly to the patch is not recommended. A heating pad applied to a buprenorphine 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% to 25% of concurrent plasma concentrations.

Biotransformation and elimination

Buprenorphine metabolism in the skin following buprenorphine 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 two 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 551/h. 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 buprenorphine 20μg/h transdermal patch. The effect on metabolism catalysed by CYP2C8, CYP2C9 and CYP2C19 has not been studied.

6.1 Animal toxicology or pharmacology

Systemic toxicity and dermal toxicity

In single- and repeat-dose toxicity studies in rats, rabbits, guinea pigs, dogs and minipigs, buprenorphine caused minimal or no adverse systemic events, whereas skin irritation was observed in all species examined. Toxicological data available did not indicate a sensitising potential of the additives of the transdermal patches.

Reproductive and developmental toxicity

No effect on fertility or general reproductive performance was observed in rats treated with buprenorphine. In embryofoetal developmental toxicity studies conducted in rats and rabbits using buprenorphine, no embryofoetal toxicity effects were observed. In a rat pre- and post-natal developmental toxicity study with buprenorphine there was pup mortality, decreased pup body weight and concomitant maternal reduced food consumption and clinical signs.

Genotoxicity

A standard battery of genotoxicity tests indicated that buprenorphine is non-genotoxic.

Carcinogenicity

In long-term studies in rats and mice there was no evidence of any carcinogenic potential relevant for humans.

Buprenorphine is a semi synthetic derivative of an opiate alkaloid thebaine that is isolated from the poppy Papaver somniferum. Buprenorphine is a hydrophobic molecule and carries a complex chemical structure with multiple chiral centers.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A pouch of 1 patch.

8.4 Storage and handling instructions

Store in a cool & dry place. Protect from light & moisture.

Keep out of reach of children.

• These patches contain a strong pain killer.
• Ensure that old patches are removed before applying a new one.
• Patches must not be cut.
• Do not expose the patches to a heat source (such as a hot water bottle).
• Do not soak in a hot bath or take a hot shower whilst wearing a patch.
• If you develop a fever tell your doctor immediately.
• Follow the dosage instructions carefully and only change your patch on the same day and at the same time 7 days later.
• If your breathing becomes shallow and weak take the patch off and seek medical help.

21 August 2024