Buprenorphine hydrochloride contains buprenorphine, a Schedule III controlled substance. As an opioid, buprenorphine hydrochloride exposes users to the risks of addiction, abuse, and misuse.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed buprenorphine hydrochloride. Addiction can occur at recommended doses and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing buprenorphine hydrochloride, and reassess all patients receiving buprenorphine hydrochloride for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of buprenorphine hydrochloride for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as buprenorphine hydrochloride, but use in such patients necessitates intensive counseling about the risks and proper use of buprenorphine hydrochloride along with frequent reevaluation for signs of addiction, abuse, and misuse.
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing buprenorphine hydrochloride. Strategies to reduce these risks include proper product storage and control practices for a C-III 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.
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 (CO2) 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 hydrochloride, the risk is greatest during the initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of buprenorphine hydrochloride are essential. Overestimating the buprenorphine hydrochloride 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].
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of buprenorphine hydrochloride with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). 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. Monitor patients closely for signs and symptoms of respiratory depression and sedation.
Use of buprenorphine hydrochloride for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that management by neonatology experts will be available at delivery [see WARNINGS, PRECAUTIONS: Information for Patients, Pregnancy].
Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see DEPENDENCE]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.
Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see DOSAGE AND ADMINISTRATION, WARNINGS].
The use of buprenorphine hydrochloride 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 hydrochloride-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 hydrochloride [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 hydrochloride and when buprenorphine hydrochloride is given concomitantly with other drugs that depress respiration [see WARNINGS]. Alternatively, consider the use of non-opioid analgesics in these patients.
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.
Buprenorphine hydrochloride 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 hydrochloride. In patients with circulatory shock, buprenorphine hydrochloride may cause vasodilation that can further reduce cardiac output and blood pressure.
Avoid the use of buprenorphine hydrochloride in patients with circulatory shock.
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), buprenorphine hydrochloride may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with buprenorphine hydrochloride.
Opioids may also obscure the clinical course in a patient with a head injury.
Avoid the use of buprenorphine hydrochloride in patients with impaired consciousness or coma.
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 hydrochloride 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.
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 hydrochloride is contraindicated in patients with a history of hypersensitivity to buprenorphine.
Buprenorphine hydrochloride is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The buprenorphine in buprenorphine hydrochloride 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.
The buprenorphine in buprenorphine hydrochloride 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 hydrochloride therapy.
Buprenorphine hydrochloride 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 hydrochloride and know how they will react to the medication [see PRECAUTIONS: Information for Patients].
General: Buprenorphine hydrochloride should be administered with caution in the elderly, debilitated patients, in children and those with severe impairment of hepatic, pulmonary, or renal function; myxedema or hypothyroidism; adrenal cortical insufficiency (e.g., Addison’s disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis.
Because buprenorphine is metabolized by the liver, the activity of buprenorphine may be increased and/or extended in those individuals with impaired hepatic function or those receiving other agents known to decrease hepatic clearance.
Buprenorphine has been shown to increase intracholedochal pressure to a similar degree as other opioid analgesics, and thus should be administered with caution to patients with dysfunction of the biliary tract.
Inform patients that the use of buprenorphine hydrochloride, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see WARNINGS].
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting buprenorphine hydrochloride or when the dosage is increased, and that it can occur even at recommended dosages [see WARNINGS].
Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see WARNINGS, ADVERSE REACTIONS].
Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop after discharge from the hospital. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see PRECAUTIONS; Drug Interactions].
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see CLINICAL PHARMACOLOGY: Pharmacodynamics, ADVERSE REACTIONS].
Clinically significant drug interactions with Buprenorphine Hydrochloride
Benzodiazepines and Other Central Nervous System (CNS) Depressants | |
Clinical Impact: | Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
Intervention: | Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). |
Examples: | Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, alcohol. |
Inhibitors of CYP3A4 | |
Clinical Impact: | The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine hydrochloride is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see CLINICAL PHARMACOLOGY: Pharmacokinetics], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine. |
Intervention: | If concomitant use is necessary, consider dosage reduction of buprenorphine hydrochloride until stable drug effects are achieved. Monitor patients for respiratory depression and sedation.
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Examples: | Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir). |
CYP3A4 Inducers | |
Clinical Impact: | The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see CLINICAL PHARMACOLOGY: Pharmacokinetics], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see CLINICAL PHARMACOLOGY: Pharmacokinetics], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression. |
Intervention: | If concomitant use is necessary, consider increasing the buprenorphine hydrochloride dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
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Examples: | Rifampin, carbamazepine, phenytoin |
Serotonergic Drugs | |
Clinical Impact: | The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
Intervention: | If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine hydrochloride if serotonin syndrome is suspected. |
Examples: | Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
Monoamine Oxidase Inhibitors (MAOIs) | |
Clinical Impact: | MAOI interactions with opioids may manifest as serotonin syndrome opioid toxicity (e.g., respiratory depression, coma). |
Intervention: | The use of buprenorphine hydrochloride is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
Examples: | Phenelzine, tranylcypromine, linezolid |
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics | |
Clinical Impact: | May reduce the analgesic effect of buprenorphine hydrochloride and/or precipitate withdrawal symptoms. |
Intervention: | Avoid concomitant use. |
Examples: | Butorphanol, nalbuphine, pentazocine |
Muscle Relaxants | |
Clinical Impact: | Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
Intervention: | Monitor patients for signs of respiratory depression that may be greater than otherwise expected, decrease the dosage of buprenorphine hydrochloride and/or the muscle relaxant as necessary. |
Diuretics | |
Clinical Impact: | Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
Intervention: | Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
Anticholinergic Drugs | |
Clinical Impact: | The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
Intervention: | Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine hydrochloride is used concomitantly with anticholinergic drugs. |
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs) | |
Clinical Impact: | Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. |
Intervention: | None |
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) | |
Clinical Impact: | Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. |
Intervention: | If prescribing an NNRTI to a patient taking buprenorphine hydrochloride, frequently reevaluate for this interaction and adjust dosing as necessary. |
Examples: | Efavirenz, nevirapine, etravirine, delavirdine |
Antiretrovirals: Protease inhibitors (PIs) | |
Clinical Impact: | Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. |
Intervention: | Monitor patients taking buprenorphine hydrochloride and atazanavir with and without ritonavir, and dose reduction of buprenorphine hydrochloride may be warranted. |
Examples: | Atazanavir, ritonavir |
Carcinogenicity studies were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the diet at doses of 0.6, 5.5, and 56 mg/kg/day for 27 months in rats. These doses were approximately equivalent to 5.7, 52, and 534 times the recommended human dose (1.2 mg) on a mg/m2 body surface area basis. Statistically significant dose-related increases in testicular interstitial (Leydig's) cell tumors occurred, according to the trend test adjusted for survival. Pairwise comparison of the high dose against control failed to show statistical significance. In the mouse study, buprenorphine was administered in the diet at doses of 8, 50, and 100 mg/kg/day for 86 weeks.
The high dose was approximately equivalent to 477 times the recommended human dose (1.2 mg) on a mg/m2 basis. Buprenorphine was not carcinogenic in mice.
Buprenorphine was studied in a series of tests. Results were negative in Chinese hamster bone marrow and spermatogonia cells, and negative in mouse lymphoma L5178Y assay. Results were equivocal in the Ames test: negative in studies in two laboratories, but positive in frame shift mutation at high dose (5 mg/plate) in a third study.
Reproduction studies of buprenorphine in rats demonstrated no evidence of impaired fertility at daily oral doses up to 80 mg/kg (approximately 763 times the recommended human daily dose of 1.2 mg on a mg/m2 basis) or up to 5 mg/kg intramuscular or subcutaneous (approximately 48 times the recommended human daily dose of 1.2 mg on a mg/m2 basis).
Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see WARNINGS: Neonatal Opioid Withdrawal Syndrome]. Available data with buprenorphine hydrochloride in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.
Reproductive and developmental studies in rats and rabbits identified adverse events at approximately 2 times the maximum recommended human dose (MRHD) of 1.8 mg/day of buprenorphine hydrochloride. Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 54 and 2.2 times, respectively, the MRHD of 1.8 mg/day of buprenorphine. Pre-and postnatal development studies in rats demonstrated increased neonatal deaths at 2.7 times and above and dystocia at approximately 27 times the MRHD of 1.8 mg/day of buprenorphine. No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses 5 times or greater than the MRHD of 1.8 mg/day of buprenorphine. However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 5.4 and 10.8 times the MRHD of 1.8 mg/day of buprenorphine, respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see Data].
Based on animal data, advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see WARNINGS: Neonatal Opioid Withdrawal Syndrome].
The safety of buprenorphine hydrochloride given during labor and delivery has not been established. As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn.
Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate.
Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited published data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and there does not appear to be a dose-response relationship.
The exposure margins listed below are based on body surface area comparisons (mg/m2) to MRHD of 1.8 mg buprenorphine via buprenorphine hydrochloride.
Following oral administration to rats no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 1,351 times the MRHD of 1.8 mg) in the presence of maternal toxicity (mortality). Following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 432 times the MRHD of 1.8 mg) in the absence of clear maternal toxicity.
No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 161 times and 324 times, respectively, the MRHD of 1.8 mg). Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits. Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 54 times the MRHD of 1.8 mg).
In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day.
Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 27 and 54 times, respectively, the MRHD of 1.8 mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 4.3 and 8.7 times, respectively, the MRHD of 1.8 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 865 times the MRHD of 1.8 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 270 times the MRHD of 1.8 mg). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 5.4 times the MRHD of 1.8 mg), but were not observed at oral doses up to 160 mg/kg/day.
Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 54 times the MRHD of 1.8 mg) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately 10.8 times the MRHD of 1.8 mg) were not statistically significant.
In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 2.2 times the MRHD of 1.8 mg). No maternal toxicity was noted at doses causing post-implantation loss in this study.
Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from Gestation Day 14 through Lactation Day 21 at 5 mg/kg/day (approximately 27 times the MRHD of 1.8 mg).
Fertility, pre-, and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 4.3 times the MRHD of 1.8 mg), after IM doses of 0.5 mg/kg/day and up (approximately 2.7 times the MRHD of 1.8 mg), and after SC doses of 0.1 mg/kg/day and up (approximately 0.5 times the MRHD of 1.8 mg). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 432 times the MRHD of 1.8 mg).
Risk Summary
An apparent lack of milk production during general reproduction studies with buprenorphine in rats caused decreased viability and lactation indices. Use of high doses of sublingual buprenorphine in pregnant women showed that buprenorphine passes into the mother's milk.
Clinical Considerations
Breast-feeding is not advised in nursing mothers treated with buprenorphine hydrochloride.
Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS].
The safety and effectiveness of buprenorphine have been established for children between 2 and 12 years of age. Use of buprenorphine in children is supported by evidence from adequate and well-controlled trials of buprenorphine in adults, with additional data from studies of 960 children ranging in age from 9 months to 18 years of age. Data is available from a pharmacokinetic study, several controlled clinical trials, and several large post-marketing studies and case series. The available information provides reasonable evidence that buprenorphine may be used safely in children ranging from 2 to 12 years of age, and that it is of similar effectiveness in children as in adults.
Elderly patients (aged 65 years or older) may have increased sensitivity to buprenorphine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of buprenorphine hydrochloride slowly in geriatric patients and monitor for signs of central nervous system and respiratory depression [see WARNINGS, PRECAUTIONS].
Buprenorphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Buprenorphine hydrochloride contains buprenorphine, a Schedule III controlled substance. As an opioid, buprenorphine hydrochloride exposes users to the risks of addiction, abuse, and misuse.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed buprenorphine hydrochloride. Addiction can occur at recommended doses and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing buprenorphine hydrochloride, and reassess all patients receiving buprenorphine hydrochloride for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of buprenorphine hydrochloride for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as buprenorphine hydrochloride, but use in such patients necessitates intensive counseling about the risks and proper use of buprenorphine hydrochloride along with frequent reevaluation for signs of addiction, abuse, and misuse.
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing buprenorphine hydrochloride. Strategies to reduce these risks include proper product storage and control practices for a C-III 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.
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 (CO2) 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 hydrochloride, the risk is greatest during the initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of buprenorphine hydrochloride are essential. Overestimating the buprenorphine hydrochloride 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].
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of buprenorphine hydrochloride with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). 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. Monitor patients closely for signs and symptoms of respiratory depression and sedation.
Use of buprenorphine hydrochloride for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that management by neonatology experts will be available at delivery [see WARNINGS, PRECAUTIONS: Information for Patients, Pregnancy].
Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see DEPENDENCE]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.
Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see DOSAGE AND ADMINISTRATION, WARNINGS].
The use of buprenorphine hydrochloride 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 hydrochloride-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 hydrochloride [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 hydrochloride and when buprenorphine hydrochloride is given concomitantly with other drugs that depress respiration [see WARNINGS]. Alternatively, consider the use of non-opioid analgesics in these patients.
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.
Buprenorphine hydrochloride 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 hydrochloride. In patients with circulatory shock, buprenorphine hydrochloride may cause vasodilation that can further reduce cardiac output and blood pressure.
Avoid the use of buprenorphine hydrochloride in patients with circulatory shock.
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), buprenorphine hydrochloride may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with buprenorphine hydrochloride.
Opioids may also obscure the clinical course in a patient with a head injury.
Avoid the use of buprenorphine hydrochloride in patients with impaired consciousness or coma.
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 hydrochloride 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.
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 hydrochloride is contraindicated in patients with a history of hypersensitivity to buprenorphine.
Buprenorphine hydrochloride is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The buprenorphine in buprenorphine hydrochloride 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.
The buprenorphine in buprenorphine hydrochloride 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 hydrochloride therapy.
Buprenorphine hydrochloride 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 hydrochloride and know how they will react to the medication [see PRECAUTIONS: Information for Patients].
General: Buprenorphine hydrochloride should be administered with caution in the elderly, debilitated patients, in children and those with severe impairment of hepatic, pulmonary, or renal function; myxedema or hypothyroidism; adrenal cortical insufficiency (e.g., Addison’s disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis.
Because buprenorphine is metabolized by the liver, the activity of buprenorphine may be increased and/or extended in those individuals with impaired hepatic function or those receiving other agents known to decrease hepatic clearance.
Buprenorphine has been shown to increase intracholedochal pressure to a similar degree as other opioid analgesics, and thus should be administered with caution to patients with dysfunction of the biliary tract.
Inform patients that the use of buprenorphine hydrochloride, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see WARNINGS].
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting buprenorphine hydrochloride or when the dosage is increased, and that it can occur even at recommended dosages [see WARNINGS].
Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see WARNINGS, ADVERSE REACTIONS].
Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop after discharge from the hospital. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see PRECAUTIONS; Drug Interactions].
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see CLINICAL PHARMACOLOGY: Pharmacodynamics, ADVERSE REACTIONS].
Clinically significant drug interactions with Buprenorphine Hydrochloride
Benzodiazepines and Other Central Nervous System (CNS) Depressants | |
Clinical Impact: | Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
Intervention: | Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). |
Examples: | Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, alcohol. |
Inhibitors of CYP3A4 | |
Clinical Impact: | The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine hydrochloride is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see CLINICAL PHARMACOLOGY: Pharmacokinetics], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine. |
Intervention: | If concomitant use is necessary, consider dosage reduction of buprenorphine hydrochloride until stable drug effects are achieved. Monitor patients for respiratory depression and sedation.
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Examples: | Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir). |
CYP3A4 Inducers | |
Clinical Impact: | The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see CLINICAL PHARMACOLOGY: Pharmacokinetics], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see CLINICAL PHARMACOLOGY: Pharmacokinetics], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression. |
Intervention: | If concomitant use is necessary, consider increasing the buprenorphine hydrochloride dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
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Examples: | Rifampin, carbamazepine, phenytoin |
Serotonergic Drugs | |
Clinical Impact: | The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
Intervention: | If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine hydrochloride if serotonin syndrome is suspected. |
Examples: | Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
Monoamine Oxidase Inhibitors (MAOIs) | |
Clinical Impact: | MAOI interactions with opioids may manifest as serotonin syndrome opioid toxicity (e.g., respiratory depression, coma). |
Intervention: | The use of buprenorphine hydrochloride is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
Examples: | Phenelzine, tranylcypromine, linezolid |
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics | |
Clinical Impact: | May reduce the analgesic effect of buprenorphine hydrochloride and/or precipitate withdrawal symptoms. |
Intervention: | Avoid concomitant use. |
Examples: | Butorphanol, nalbuphine, pentazocine |
Muscle Relaxants | |
Clinical Impact: | Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
Intervention: | Monitor patients for signs of respiratory depression that may be greater than otherwise expected, decrease the dosage of buprenorphine hydrochloride and/or the muscle relaxant as necessary. |
Diuretics | |
Clinical Impact: | Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
Intervention: | Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
Anticholinergic Drugs | |
Clinical Impact: | The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
Intervention: | Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine hydrochloride is used concomitantly with anticholinergic drugs. |
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs) | |
Clinical Impact: | Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. |
Intervention: | None |
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) | |
Clinical Impact: | Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. |
Intervention: | If prescribing an NNRTI to a patient taking buprenorphine hydrochloride, frequently reevaluate for this interaction and adjust dosing as necessary. |
Examples: | Efavirenz, nevirapine, etravirine, delavirdine |
Antiretrovirals: Protease inhibitors (PIs) | |
Clinical Impact: | Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. |
Intervention: | Monitor patients taking buprenorphine hydrochloride and atazanavir with and without ritonavir, and dose reduction of buprenorphine hydrochloride may be warranted. |
Examples: | Atazanavir, ritonavir |
Carcinogenicity studies were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the diet at doses of 0.6, 5.5, and 56 mg/kg/day for 27 months in rats. These doses were approximately equivalent to 5.7, 52, and 534 times the recommended human dose (1.2 mg) on a mg/m2 body surface area basis. Statistically significant dose-related increases in testicular interstitial (Leydig's) cell tumors occurred, according to the trend test adjusted for survival. Pairwise comparison of the high dose against control failed to show statistical significance. In the mouse study, buprenorphine was administered in the diet at doses of 8, 50, and 100 mg/kg/day for 86 weeks.
The high dose was approximately equivalent to 477 times the recommended human dose (1.2 mg) on a mg/m2 basis. Buprenorphine was not carcinogenic in mice.
Buprenorphine was studied in a series of tests. Results were negative in Chinese hamster bone marrow and spermatogonia cells, and negative in mouse lymphoma L5178Y assay. Results were equivocal in the Ames test: negative in studies in two laboratories, but positive in frame shift mutation at high dose (5 mg/plate) in a third study.
Reproduction studies of buprenorphine in rats demonstrated no evidence of impaired fertility at daily oral doses up to 80 mg/kg (approximately 763 times the recommended human daily dose of 1.2 mg on a mg/m2 basis) or up to 5 mg/kg intramuscular or subcutaneous (approximately 48 times the recommended human daily dose of 1.2 mg on a mg/m2 basis).
Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see WARNINGS: Neonatal Opioid Withdrawal Syndrome]. Available data with buprenorphine hydrochloride in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.
Reproductive and developmental studies in rats and rabbits identified adverse events at approximately 2 times the maximum recommended human dose (MRHD) of 1.8 mg/day of buprenorphine hydrochloride. Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 54 and 2.2 times, respectively, the MRHD of 1.8 mg/day of buprenorphine. Pre-and postnatal development studies in rats demonstrated increased neonatal deaths at 2.7 times and above and dystocia at approximately 27 times the MRHD of 1.8 mg/day of buprenorphine. No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses 5 times or greater than the MRHD of 1.8 mg/day of buprenorphine. However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 5.4 and 10.8 times the MRHD of 1.8 mg/day of buprenorphine, respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see Data].
Based on animal data, advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see WARNINGS: Neonatal Opioid Withdrawal Syndrome].
The safety of buprenorphine hydrochloride given during labor and delivery has not been established. As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn.
Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate.
Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited published data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and there does not appear to be a dose-response relationship.
The exposure margins listed below are based on body surface area comparisons (mg/m2) to MRHD of 1.8 mg buprenorphine via buprenorphine hydrochloride.
Following oral administration to rats no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 1,351 times the MRHD of 1.8 mg) in the presence of maternal toxicity (mortality). Following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 432 times the MRHD of 1.8 mg) in the absence of clear maternal toxicity.
No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 161 times and 324 times, respectively, the MRHD of 1.8 mg). Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits. Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 54 times the MRHD of 1.8 mg).
In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day.
Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 27 and 54 times, respectively, the MRHD of 1.8 mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 4.3 and 8.7 times, respectively, the MRHD of 1.8 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 865 times the MRHD of 1.8 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 270 times the MRHD of 1.8 mg). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 5.4 times the MRHD of 1.8 mg), but were not observed at oral doses up to 160 mg/kg/day.
Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 54 times the MRHD of 1.8 mg) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately 10.8 times the MRHD of 1.8 mg) were not statistically significant.
In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 2.2 times the MRHD of 1.8 mg). No maternal toxicity was noted at doses causing post-implantation loss in this study.
Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from Gestation Day 14 through Lactation Day 21 at 5 mg/kg/day (approximately 27 times the MRHD of 1.8 mg).
Fertility, pre-, and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 4.3 times the MRHD of 1.8 mg), after IM doses of 0.5 mg/kg/day and up (approximately 2.7 times the MRHD of 1.8 mg), and after SC doses of 0.1 mg/kg/day and up (approximately 0.5 times the MRHD of 1.8 mg). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 432 times the MRHD of 1.8 mg).
Risk Summary
An apparent lack of milk production during general reproduction studies with buprenorphine in rats caused decreased viability and lactation indices. Use of high doses of sublingual buprenorphine in pregnant women showed that buprenorphine passes into the mother's milk.
Clinical Considerations
Breast-feeding is not advised in nursing mothers treated with buprenorphine hydrochloride.
Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS].
The safety and effectiveness of buprenorphine have been established for children between 2 and 12 years of age. Use of buprenorphine in children is supported by evidence from adequate and well-controlled trials of buprenorphine in adults, with additional data from studies of 960 children ranging in age from 9 months to 18 years of age. Data is available from a pharmacokinetic study, several controlled clinical trials, and several large post-marketing studies and case series. The available information provides reasonable evidence that buprenorphine may be used safely in children ranging from 2 to 12 years of age, and that it is of similar effectiveness in children as in adults.
Elderly patients (aged 65 years or older) may have increased sensitivity to buprenorphine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of buprenorphine hydrochloride slowly in geriatric patients and monitor for signs of central nervous system and respiratory depression [see WARNINGS, PRECAUTIONS].
Buprenorphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
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