Buprenorphine hydrochloride Injection Uses, Dosage & Side Effects

Buprenorphine hydrochloride injection is indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate.

Limitations of Use:

Because of the risks of addiction, abuse, misuse, overdose, and death which can occur at any dosage or duration and persist over the course of therapy [see WARNINGS], reserve opioid analgesics, including buprenorphine, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. 

Buprenorphine hydrochloride is contraindicated in patients with:
• Significant respiratory depression [see WARNINGS].
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS].
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS].
• Hypersensitivity to buprenorphine (e.g. anaphylaxis) or any other ingredient in buprenorphine hydrochloride [see WARNINGS].

Postmarketing Experience
The most frequent side effect in clinical studies involving 1,133 patients was sedation which occurred in approximately two-thirds of the patients. Although sedated, these patients could easily be aroused to an alert state.

Other less frequent adverse reactions occurring in 5-10% of the patients were: 
Nausea Dizziness/Vertigo

Occurring in 1-5% of the patients:
Sweating Headache 
Hypotension Nausea/Vomiting 
Vomiting Hypoventilation 
Miosis

The following adverse reactions were reported to have occurred in less than 1% of the patients: 
CNS Effect: confusion, blurred vision, euphoria, weakness/fatigue, dry mouth, nervousness, depression, slurred speech, paresthesia.

Cardiovascular: hypertension, tachycardia, bradycardia.

Gastrointestinal: constipation. 

Respiratory: dyspnea, cyanosis. 

Dermatological: pruritus.

Ophthalmological: diplopia, visual abnormalities.

Miscellaneous: injection site reaction, urinary retention, dreaming, flushing/warmth, chills/cold, tinnitus, conjunctivitis, 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 hydrochloride 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 hydrochloride.

In the United Kingdom, buprenorphine hydrochloride 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 hydrochloride were observed.  
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 use of opioids for an extended period of time [see CLINICAL PHARMACOLOGY: Pharmacodynamics].

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see WARNINGS].

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term (see WARNINGS).

Adverse Reactions from Observational Studies

A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months.

Over 12 months:
• approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and
• approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in DRUG ABUSE AND DEPENDENCE], respectively, as measured with a validated self-reported instrument.

A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.

The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.
For medical advice about adverse reactions contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma Limited at 866-770-7144 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch."

Addiction, Abuse, and Misuse
Buprenorphine hydrochloride injection 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. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see ADVERSE REACTIONS].


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.
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 overdose reversal agents (e.g., naloxone, nalmefene), depending on the patient's clinical status [see OVERDOSAGE]. 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].
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 hydrochloride with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and 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.
Neonatal Opioid Withdrawal Syndrome
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 and Allodynia
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].
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
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.
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 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.
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 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.

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 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.
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 hydrochloride is contraindicated in patients with a history of hypersensitivity to buprenorphine.

Risks of Gastrointestinal Complications
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. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Cases of opioid-induced esophageal dysfunction (OIED): have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see CLINICAL PHARMACOLOGY].

Increased Risk of Seizures in Patients with Seizure Disorders
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.

Risks Driving and Operating Machinery
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].

1. Buprenorphine hydrochloride injection should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids      and how to mitigate the associated risks.

1. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see WARNINGS]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of buprenorphine hydrochloride injection for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
2. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.
3. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see WARNINGS].
4. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with buprenorphine hydrochloride injection. Consider this risk when selecting an initial dose and when making dose adjustments [see WARNINGS].

Inspect buprenorphine hydrochloride injection for particulate matter and discoloration prior to administration.

Dosing
Adults and Pediatric Patients over 12 years of age

The initial starting dose is 1 mL buprenorphine hydrochloride injection (0.3 mg buprenorphine) given by deep intramuscular or slow (over at least 2 minutes) intravenous injection at up to 6-hour intervals, as needed.

Repeat once (up to 0.3 mg) if required, 30 to 60 minutes after initial dosage, giving consideration to previous dose pharmacokinetics, 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 hydrochloride injection has been used in pediatric patients 2-12 years of age at doses between 2-6 micrograms/kg of body weight given every 4-6 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 30-60 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 6-8 hours.

Safety and Handling

Buprenorphine hydrochloride injection 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 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.

Clinically significant drug interactions with buprenorphine hydrochloride injection.