ibed opioids such as buprenorphine hcl, but use in such patients necessitates intensive counseling about the risks and proper use of buprenorphine hcl along with the intensive monitoring for signs of addiction, abuse, and misuse. opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. consider these risks when prescribing or dispensing buprenorphine hcl. strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. life-threatening respiratory depression serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. respiratory depression, if not immediately recognized and treated, may lead to respiratory depression and death. management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status. carbon dioxide (co 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. while serious, life-threatening, or fatal respiratory depression can occur at any time during the use of buprenorphine hcl, the risk is greatest during the initiation of therapy or following a dosage increase. monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of buprenorphine hcl. to reduce the risk of respiratory depression, proper dosing and titration of buprenorphine hcl are essential. overestimating the buprenorphine hcl dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. opioids can cause sleep-related breathing disorders including central sleep apnea (csa) and sleep-related hypoxemia. opioid use increases the risk of csa in a dose-dependent fashion. in patients who present with csa, consider decreasing the opioid dosage using best practices for opioid taper [see dosage and administration]. neonatal opioid withdrawal syndrome prolonged use of buprenorphine hcl during pregnancy can result in withdrawal in the neonate. neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see warnings , precautions: information for patients, pregnancy ]. risks from concomitant use with benzodiazepines or other cns depressants profound sedation, respiratory depression, coma, and death may result from the concomitant use of buprenorphine hcl with benzodiazepines or other cns depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other cns depressant drugs with opioid analgesics [see drug interactions ]. if the decision is made to prescribe a benzodiazepine or other cns depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. in patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other cns depressant than indicated in the absence of an opioid, and titrate based on clinical response. if an opioid analgesic is initiated in a patient already taking a benzodiazepine or other cns depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. follow patients closely for signs and symptoms of respiratory depression and sedation. advise both patients and caregivers about the risks of respiratory depression and sedation when buprenorphine hcl is used with benzodiazepines or other cns depressants (including alcohol and illicit drugs). advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other cns depressant have been determined. screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional cns depressants including alcohol and illicit drugs [see drug interactions , and information for patients ]. risk of life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients the use of buprenorphine hcl in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. patients with chronic pulmonary disease : buprenorphine hcl-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive, including apnea, even at recommended dosages of buprenorphine hcl [see warnings ] . elderly, cachectic, or debilitated patients : life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. monitor such patients closely, particularly when initiating and titrating buprenorphine hcl and when buprenorphine hcl is given concomitantly with other drugs that depress respiration [see warnings ]. alternatively, consider the use of non-opioid analgesics in these patients. adrenal insufficiency cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. if adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. the information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. severe hypotension buprenorphine hcl may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. there is 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 (e.g., phenothiazines or general anesthetics). monitor these patients for signs of hypotension after initiating or titrating the dosage of buprenorphine hcl. in patients with circulatory shock, buprenorphine hcl may cause vasodilation that can further reduce cardiac output and blood pressure. avoid the use of buprenorphine hcl in patients with circulatory shock. risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness in patients who may be susceptible to the intracranial effects of co 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), buprenorphine hcl may reduce respiratory drive, and the resultant co 2 retention can further increase intracranial pressure. monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with buprenorphine hcl. opioids may also obscure the clinical course in a patient with a head injury. avoid the use of buprenorphine hcl in patients with impaired consciousness or coma. qtc prolongation thorough qt studies with buprenorphine products have demonstrated qt prolongation ≤ 15 msec. this qtc prolongation effect does not appear to be mediated by herg channels. based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. the risk of combining buprenorphine with other qt-prolonging agents is not known. consider these observations in clinical decisions when prescribing buprenorphine hcl to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline qt prolongation, subclinical long-qt syndrome, or severe hypomagnesemia. anaphylactic/allergic reactions cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in post-marketing experience. the most common signs and symptoms include rashes, hives, and pruritus. cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. buprenorphine hcl is contraindicated in patients with a history of hypersensitivity to buprenorphine. risks of use in patients with gastrointestinal conditions buprenorphine hcl is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. the buprenorphine in buprenorphine hcl injection may cause spasm of the sphincter of oddi. opioids may cause increases in the serum amylase. monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. increased risk of seizures in patients with seizure disorders the buprenorphine in buprenorphine hcl injection may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. monitor patients with a history of seizure disorders for worsened seizure control during buprenorphine hcl therapy. risks driving and operating machinery buprenorphine hcl may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of buprenorphine hcl and know how they will react to the medication [see precautions: information for patients ].

and thereafter only as needed. in high-risk patients (e.g., elderly, debilitated, presence of respiratory disease, etc.) and/or in patients where other cns depressants are present, such as in the immediate postoperative period, the dose should be limited to the minimum required. extra caution should be exercised with the intravenous route of administration, particularly with the initial dose. occasionally, it may be necessary to administer single doses of up to 0.6 mg to adults depending on the severity of the pain and the response of the patient. this dose should only be given i.m. and only to adult patients who are not in a high-risk category [see warnings and precautions ] . at this time, there are insufficient data to recommend single doses greater than 0.6 mg for long-term use. pediatric patients buprenorphine hcl has been used in pediatric patients 2 to 12 years of age at doses between 2 to 6 micrograms/kg of body weight given every 4 to 6 hours. there is insufficient experience to recommend a dose in infants below the age of two years, single doses greater than 6 micrograms/kg of body weight, or the use of a repeat or second dose at 30 to 60 minutes (such as is used in adults). since there is some evidence that not all pediatric patients 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. healthcare providers should recognize that, as with adults, some pediatric patients may not need to be remedicated for 6 to 8 hours. safety and handling buprenorphine hcl is supplied in sealed vials and poses no known environmental risk to health care providers. accidental dermal exposure should be treated by removal of any contaminated clothing and rinsing the affected area with water. buprenorphine hcl is a potent opioid, and like all drugs of this class has been associated with abuse and dependence among healthcare providers. to control the risk of diversion, it is recommended that measures appropriate to the health care setting be taken to provide rigid accounting, control of wastage, and restriction of access. parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

njunctivitis, wenckebach block, and psychosis. other effects observed infrequently include malaise, hallucinations, depersonalization, coma, dyspepsia, flatulence, apnea, rash, amblyopia, tremor, and pallor. the following reactions have been reported to occur rarely: loss of appetite, dysphoria/agitation, diarrhea, urticaria, and convulsions/lack of muscle coordination. allergic reactions: cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the postmarketing experience of buprenorphine hcl injection and other buprenorphine-containing products. the most common signs and symptoms include rashes, hives, and pruritus. cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. a history of hypersensitivity to buprenorphine is a contraindication to buprenorphine hcl injection. in the united kingdom, buprenorphine hcl was made available under monitored release regulation during the first year of sale, and yielded data from 1,736 physicians on 9,123 patients (17,120 administrations). data on 240 children under the age of 18 years were included in this monitored release program. no important new adverse effects attributable to buprenorphine hcl were observed. postmarketing experience serotonin syndrome : cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. adrenal insufficiency : cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. androgen deficiency : cases of androgen deficiency have occurred with chronic use of opioids [see clinical pharmacology: pharmacodynamics ] .

ipotent 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. thorough qt studies with buprenorphine products have demonstrated qt prolongation ≤ 15 msec. 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. concentration–adverse reaction relationships there is a relationship between increasing buprenorphine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, cns effects, and respiratory depression. in opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions. pharmacokinetics the limits of sensitivity of available analytical methodology precluded demonstration of bioequivalence between intramuscular and intravenous routes of administration. elimination in postoperative adults, pharmacokinetic studies have shown elimination half-lives ranging from 1.2 to 7.2 hours (mean 2.2 hours) after intravenous administration of 0.3 mg of buprenorphine. a single, ten-patient, pharmacokinetic study of doses of 3 mcg/kg in children (age 5 to 7 years) showed a high inter-patient variability, but suggests that the clearance of the drug may be higher in children than in adults. this is supported by at least one repeat-dose study in postoperative pain that showed an optimal inter-dose interval of 4 to 5 hours in pediatric patients as opposed to the recommended 6 to 8 hours in adults. metabolism buprenorphine undergoes both n-dealkylation to norbuprenorphine and glucuronidation. the n-dealkylation pathway is mediated primarily by cyp3a4. norbuprenorphine, the major metabolite, can further undergo glucuronidation. its clearance is related to hepatic blood flow. studies in patients anesthetized with 0.5% halothane have shown that this anesthetic decreases hepatic blood flow by about 30%.

rome and to seek medical attention right away if symptoms develop. instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see precautions; drug interactions ] . constipation advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see clinical pharmacology: pharmacodynamics , adverse reactions ].