Carlosafine

Uses

Carlosafine is used for Moderate to severe pain, Anaesth premed, Opioid dependence, Anaesth premed, Perioperative analgesia

Carlosafine is also used to associated treatment for these conditions: Opioid Dependence, Severe Pain, Moderate Pain

How Carlosafine works

Carlosafine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. It demonstrates a high affinity for the mu-opioid receptor but has lower intrinsic activity compared to other full mu-opioid agonists such as heroin, oxycodone, or methadone. This means that buprenorphine preferentially binds the opioid receptor and displaces lower affinity opioids without activating the receptor to a comparable degree. Clinically, this results in a slow onset of action and a clinical phenomenon known as the "ceiling effect" where once a certain dose is reached buprenorphine's effects plateau. This effect can be beneficial, however, as dose-related side effects such as respiratory depression, sedation, and intoxication also plateau at around 32mg, resulting in a lower risk of overdose compared to methadone and other full agonist opioids. It also means that opioid-dependent patients do not experience sedation or euphoria at the same rate that they might experience with more potent opioids, improving quality of life for patients with severe pain and reducing the reinforcing effects of opioids which can lead to drug-seeking behaviours.

Carlosafine's high affinity, but low intrinsic activity for the mu-opioid receptor also means that if it is started in opioid-dependent individuals, it will displace the other opioids without creating an equal opioid effect and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms (i.e. anxiety, restlessness, gastrointestinal distress, diaphoresis, intense drug cravings, and tachycardia). Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine.

Carlosafine is commercially available as the brand name product Suboxone which is formulated in a 4:1 fixed-dose combination product along with naloxone, a non-selective competitive opioid receptor antagonist. Combination of an opioid agonist with an opioid antagonist may seem counterintuitive, however this combination with naloxone is intended to reduce the abuse potential of Suboxone, as naloxone is poorly absorbed by the oral route (and has no effect when taken orally), but would reverse the opioid agonist effects of buprenorphine if injected intravenously.

Dosage

Carlosafine dosage

Adult:

• Oral: Sublingual Moderate to severe pain: 200-400 mcg 6-8 hourly.
• IV: Perioperative analgesia: 300-450 mcg via slow inj.
• IV/IM: Moderate to severe pain: 300-600 meg 6-8 hourly.
• IM: Anesthesia premed: 300 meg.

Severe hepatic Impairment: Dose adjustment needed.

Side Effects

Common side effects are CNS depression, including somnolence, dizziness, alterations in judgment and levels of consciousness, including coma; sedation, dizziness, sweating, vertigo, headache; nausea, vomiting, dry mouth, constipation, dyspepsia, abdominal cramps, flatulence, diaphoresis; rash, urticaria, pruritus; miosis, blurred vision, hallucinations and other psychotomimetic effects; hypotension leading to syncope, HTN, tachycardia, bradycardia, ECG abnormalities.

Toxicity

Manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression and death.

Precaution

Patient with pulmonary impairment or compromised respiratory iratory function (e.g. COPD, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, pre-existing respiratory depression). Patient with hypothyroidism, myxedema, adrenocortical insufficiency (e.g. Addison's disease), dysfunction of biliary tract including acute pancreatitis, acute alcoholism, delirium tremens, toxic psychoses, kyphoscoliosis, prostatic hypertrophy or urethral stricture; comatose patients. Patient with CNS depression, history of seizure disorders, head injury, intracranial lesions or conditions in which intracranial pressure may be increased. Patient with personal or family history of QT interval prolongation, hypokalaemia or unstable cardiac disease (e.g. AF, CHF, myocardial ischaemia), particularly in transdermal admin. Hepatic or renal impairment. Pregnancy and lactation.

Interaction

Plasma-buprenorphine concentrations may be affected when co-administered with drugs that induce or inhibit CYP3A4 isoenzyme. Enhanced depressant effects of other CNS depressants, other opiate agonists, anaesth, antihistamines, muscle relaxants, tranquilisers (e.g. phenothiazines), sedatives and hypnotics (e.g. benzodiazepines). Increased and/or prolonged activity with drugs that may reduce hepatic blood flow (e.g. halothane). Receiving class IA (e.g. quinidine, procainamide) or class III (e.g. sotalol, amiodarone) antiarrhythmic agents with transdermal buprenorphine may increase the risk of QT interval prolongation.

Food Interaction

• Avoid alcohol. Ingesting alcohol may increase the sedative and CNS depressant effects of buprenorphine.
• Avoid grapefruit products. Grapefruit inhibits the metabolism of buprenorphine through CYP3A4, which increases the serum levels buprenorphine.
• Take separate from meals. When buprenorphine is formulated as a sublingual tablet or buccal film, avoid eating or drinking until the dosage form is completely dissolved.

Carlosafine Alcohol interaction

[Major] GENERALLY AVOID:

Concomitant use of buprenorphine with benzodiazepines or other central nervous system (CNS) depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol) may increase the risk of buprenorphine overdose, severe respiratory depression, coma, and death.

Reported cases have primarily occurred in the setting of buprenorphine maintenance treatment for opiate addiction, and many, but not all, involved abuse or misuse of buprenorphine including intravenous self-injection.

The mechanism of interaction probably involves some degree of additive pharmacologic effects.

Preclinical studies also suggest that benzodiazepines can alter the usual ceiling effect on buprenorphine-induced respiratory depression and render the respiratory effects of buprenorphine appear similar to those of full opioid agonists.

Coadministration of buprenorphine with some CNS depressants such as alcohol, benzodiazepines, and phenothiazines may also increase the risk of hypotension.

The use of opioids in conjunction with benzodiazepines or other CNS depressants should generally be avoided unless alternative treatment options are inadequate.

If coadministration is necessary, the dosage and duration of each drug should be limited to the minimum required to achieve desired clinical effect.

Patients should be monitored closely for signs and symptoms of respiratory depression and sedation, and advised to avoid driving or operating hazardous machinery until they know how these medications affect them.

Extreme caution is advised when prescribing buprenorphine to patients who are addicted to opioids and also abusing benzodiazepines or alcohol.

Due to potential risk of overdose and death, dependence on sedative-hypnotics such as benzodiazepines or alcohol is considered a relative contraindication for office-based buprenorphine treatment of opioid addiction.

For patients who have been receiving extended therapy with both an opioid and a benzodiazepine and require discontinuation of either medication, a gradual tapering of dose is advised, since abrupt withdrawal may lead to withdrawal symptoms.

Severe cases of benzodiazepine withdrawal, primarily in patients who have received excessive doses over a prolonged period, may result in numbness and tingling of extremities, hypersensitivity to light and noise, hallucinations, and epileptic seizures.

Carlosafine Drug Interaction

Major: pregabalin, pregabalin, diazepam, diazepam, alprazolam, alprazolamModerate: albuterol / ipratropium, albuterol / ipratropium, duloxetine, duloxetine, quetiapine, quetiapineUnknown: aspirin, aspirin, amphetamine / dextroamphetamine, amphetamine / dextroamphetamine, acetaminophen, acetaminophen, cholecalciferol, cholecalciferol

Carlosafine Disease Interaction

Major: impaired GI motility, infectious diarrhea, liver disease, prematurity, gastrointestinal obstruction, acute MI, drug dependence, intracranial pressure, respiratory depressionModerate: adrenal insufficiency, biliary spasm, hypothyroidism, renal dysfunction, seizure disorders, urinary retention

Volume of Distribution

Carlosafine is highly lipophilic, and therefore extensively distributed, with rapid penetration through the blood-brain barrier. The estimated volume of distribution is 188 - 335 L when given intravenously. It is able to cross into the placenta and breast milk.

Elimination Route

Bioavailablity of buprenorphine/naloxone is very high following intravenous or subcutaneous administration, lower by the sublingual or buccal route, and very low when administered by the oral route. It is therefore provided as a sublingual tablet that is absorbed from the oral mucosa directly into systemic circulation.

Clinical pharmacokinetic studies found that there was wide inter-patient variability in the sublingual absorption of buprenorphine and naloxone, but within subjects the variability was low. Both Cmax and AUC of buprenorphine increased in a linear fashion with the increase in dose (in the range of 4 to 16 mg), although the increase was not directly dose-proportional. Carlosafine combination with naloxone (2mg/0.5mg) provided in sublingual tablets demonstrated a Cmax of 0.780 ng/mL with a Tmax of 1.50 hr and AUC of 7.651 ng.hr/mL.

Coadministration with naloxone does not effect the pharmacokinetics of buprenorphine.

Half Life

Carlosafine demonstrates slow dissociation kinetics (~166 min), which contributes to its long duration of action and allows for once-daily or even every-second-day dosing. In clinical trial studies, the half-life of sublingually administered buprenorphine/naloxone 2mg/0.5mg was found to be 30.75 hours.

Clearance

Clearance may be higher in children than in adults. Plasma clearance rate, IV administration, anaesthetized patients = 901.2 ± 39.7 mL/min; Plasma clearance rate, IV administration, healthy subjects = 1042 - 1280 mL/min.

Elimination Route

Carlosafine, like morphine and other phenolic opioid analgesics, is metabolized by the liver and its clearance is related to hepatic blood flow. It is primarily eliminated via feces (as free forms of buprenorphine and norbuprenorphine) while 10 - 30% of the dose is excreted in urine (as conjugated forms of buprenorphine and norbuprenorphine).

The overall mean elimination half-life of buprenorphine in plasma ranges from 31 to 42 hours, although the levels are very low 10 hours after dosing (majority of AUC of buprenorphine is captured within 10 hours), indicating that the effective half-life may be shorter.

Pregnancy & Breastfeeding use

Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

Transdermal: Patient with known or suspected paralytic ileus, substantial respiratory depression or severe bronchial asthma. Management of acute, intermittent, mild, or short-term (including post-op) pain. Concomitant admin of IV buprenorphine and oral diazepam. Concurrent use or w/in 14 days of discontinuation of MAOIs.

Acute Overdose

Symptoms: Resp depression, sedation, somnolence, nausea, vomiting, CV collapse and marked miosis.

Management: Supportive treatment. May use naloxone or resp stimulants if appropriate.

Storage Condition

Store between 15-30° C. Protect from prolonged exposure to light. Avoid freezing.

Innovators Monograph

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