Buprenorphine Hydrochloride

BUPRENORPHINE HYDROCHLORIDE- buprenorphine hydrochloride injection
Hikma Pharmaceuticals USA Inc.

BOXED WARNING

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Addiction, Abuse, and Misuse

Buprenorphine HCl exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing buprenorphine HCl, and monitor all patients regularly for the development of these behaviors and conditions (see WARNINGS ).

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of buprenorphine HCl. Monitor for respiratory depression, especially during initiation of buprenorphine HCl or following a dose increase (see WARNINGS ).

Neonatal Opioid Withdrawal Syndrome

Prolonged use of buprenorphine HCl during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see WARNINGS ).

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death (see WARNINGS , PRECAUTIONS ).

  • Reserve concomitant prescribing of buprenorphine HCl and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.

  • Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.


DESCRIPTION

Buprenorphine Hydrochloride Injection is a partial opioid agonist.

The chemical name of buprenorphine hydrochloride is 21-(Cyclopropyl-7α-[(S)-1-hydroxy-1,2,2- trimethylpropyl]-6,14-endo -ethano-6,7,8,14-tetrahydrooripavine hydrochloride.

Buprenorphine hydrochloride is a white powder, weakly acidic and with limited solubility in water.

Buprenorphine HCl Injection is a clear, sterile, injectable agonist-antagonist analgesic intended for intravenous or intramuscular administration. Each mL of Buprenorphine HCl Injection contains 0.324 mg buprenorphine hydrochloride (equivalent to 0.3 mg buprenorphine), 50 mg anhydrous dextrose, water for injection and HCl to adjust pH.

Buprenorphine hydrochloride has the molecular formula, C29 H41 NO4 HCl, and the following structure:

Molecular weight: 504.10chemical structure

CLINICAL PHARMACOLOGY

Mechanism of Action

Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. One unusual property of buprenorphine HCl observed in vitro studies is its very slow rate of dissociation from its receptor. This could account for its longer duration of action than morphine, the unpredictability of its reversal by opioid antagonists, and its low level of manifest physical dependence.

Pharmacodynamics

Buprenorphine HCl is a parenteral opioid analgesic with 0.3 mg buprenorphine being approximately equivalent to 10 mg morphine sulfate in analgesic and respiratory depressant effects in adults. Pharmacological effects occur as soon as 15 minutes after intramuscular injection and persist for 6 hours or longer. Peak pharmacologic effects usually are observed at 1 hour. When used intravenously, the times to onset and peak effect are shortened.

Buprenorphine demonstrates narcotic antagonist activity and has been shown to be equipotent with naloxone as an antagonist of morphine in the mouse tail flick test.

Effects on the Central Nervous System

The principal action of therapeutic value of buprenorphine is analgesia and is thought to be due to buprenorphine binding with high affinity to opioid receptors on neurons in the brain and spinal cord.

Buprenorphine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Under usual conditions of use in adults, both buprenorphine HCl and morphine show similar dose-related respiratory depressant effects. At adult therapeutic doses, buprenorphine HCl (0.3 mg buprenorphine) can decrease respiratory rate in an equivalent manner to an equianalgesic dose of morphine (10 mg). [See WARNINGS].

Buprenorphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Buprenorphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Buprenorphine produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Buprenorphine HCl may cause a decrease or, rarely, an increase in pulse rate and blood pressure in some patients.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date.

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of buprenorphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance.

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