Thursday, May 19, 2022

Can Patients With Impaired Hepatic Function Be Treated With Buprenorphine

Effects In Acute Abdominal Conditions

Hepatic Failure

As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

  • The following serious adverse reactions are described elsewhere in the labeling:

  • Addiction, Abuse, and Misuse
  • Respiratory and CNS Depression
  • Neonatal Opioid Withdrawal Syndrome
  • Adrenal Insufficiency
  • Opioid Withdrawal
  • Hepatitis, Hepatic Events
  • Hypersensitivity Reactions
  • Orthostatic Hypotension
  • Elevation of Cerebrospinal Fluid Pressure
  • Elevation of Intracholedochal Pressure [see Warnings and Precautions
  • Switching Between Sublingual And Buccal Sites Of Administration

    The systemic exposure of buprenorphine between buccal and sublingual administration of buprenorphine and naloxone sublingual film is similar. Therefore, once induction is complete, patients can switch between buccal and sublingual administration without significant risk of under or overdosing.

  • 3 DOSAGE FORMS AND STRENGTHS

    Buprenorphine and naloxone sublingual film, 4 mg/1 mg or 12 mg/3 mg is available as orange rectangular film, imprinted with “4” or “12” in blue ink as a strength identifier , in dosage strengths:

  • Buprenorphine 4 mg/naloxone 1 mg and
  • Buprenorphine 12 mg/naloxone 3 mg
  • Important Dosage And Administration Instructions

    Buprenorphine Sublingual tablets are administered sublingually as a single daily dose.

    Buprenorphine Sublingual tablets do not contain naloxone and is preferred for use only during induction. Following induction, buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablet is preferred due to the presence of naloxone when clinical use includes unsupervised administration. The use of Buprenorphine Sublingual tablets for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablet for example, those patients who have been shown to be hypersensitive to naloxone.

    Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is not advised early in treatment or without appropriate patient follow-up visits.

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    Carcinogenesis Mutagenesis Impairment Of Fertility

    Carcinogenicity

    Carcinogenicity data on buprenorphine and naloxone sublingual film are not available.

    A carcinogenicity study of buprenorphine/naloxone was performed in Alderley Park rats. Buprenorphine/naloxone was administered in the diet at doses of approximately 7, 31, and 123 mg/kg/day for 104 weeks . A statistically significant increase in Leydig cell adenomas was observed in all dose groups. No other drug-related tumors were noted.

    Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day for 27 months. As in the buprenorphine/naloxone carcinogenicity study in rats, statistically significant dose-related increases in Leydig cell tumors occurred. In an 86 week study in CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day .

    Mutagenicity

    The 4:1 combination of buprenorphine and naloxone was not mutagenic in a bacterial mutation assay using four strains of S. typhimurium and two strains of E. coli. The combination was not clastogenic in an in vitro cytogenetic assay in human lymphocytes or in an IV micronucleus test in the rat.

    Impairment of Fertility

    Dietary administration of buprenorphine in the rat at dose levels of 500 ppm or greater produced a reduction in fertility demonstrated by reduced female conception rates. A dietary dose of 100 ppm had no adverse effect on fertility.

    Use In Specific Populations

    Oral Anticoagulation in Patients With Liver Disease ...
    • Lactation: Buprenorphine passes into motherâs milk.
    • Geriatric Patients: Monitor for sedation and respiratory depression.
    • Moderate or Severe Hepatic Impairment: Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment.

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    Patient Access To Naloxone For The Emergency Treatment Of Opioid Overdose

    Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with buprenorphine and naloxone sublingual film. Also consider prescribing naloxone if the patient has household members or other close contacts at risk for accidental ingestion or opioid overdose .

    Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine and naloxone sublingual film itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine and naloxone sublingual film and its affinity for the muâopioid receptor .

    Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines .

    Data Extraction And Quality Assessment

    Two independent authors managed and ran the data extraction and quality assessment. The quality of clinical trials, cohort studies and case control studies were assessed using CASP with their checklists. Furthermore, for cross sectional studies STROBE was used. Studies scoring more than 50% were included in the review.

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    Neonatal Opioid Withdrawal Syndrome

    Neonatal opioid withdrawal syndrome is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly .

    Advise pregnant women receiving opioid addiction treatment with buprenorphine and naloxone sublingual film of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available . This risk must be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.

    Pain Management Considerations In Cirrhosis

    Office-based Buprenorphine Treatment for OUD

    Megan Wehrer, PharmD, MBAOmaha, Nebraska

    US Pharm. 2015 40:HS5-HS11.ABSTRACT:Cirrhosis is a heterogeneous diagnosis that impacts liver function, including the metabolism and clearance of medications, but the exact effect remains unclear. Misconceptions and significant practice variability exist among healthcare professionals regarding analgesic use in patients with liver dysfunction. Based on limited safety and efficacy data, acetaminophen is the preferred analgesic in patients with liver disease who are not actively drinking, and it may be dosed up to 2 to 3 g/day. Nonsteroidal anti-inflammatory drugs should be avoided due to their adverse effects of renal impairment, fluid retention, and increased bleeding risk. Opioids should be used cautiously and initiated with immediate-release products at low doses with extended intervals and close monitoring. All pain medications should be titrated carefully to achieve safe and adequate pain relief in patients with hepatic impairment.

    Unfortunately, these numbers may be underestimated due to diagnostic criteria limitations of International Classification of Diseases codes, which lack consideration for cirrhosis-related complications. One study suggests that liver-related deaths may be as much as twice as high as what is currently reported by the CDC.3

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    Addiction Abuse And Misuse

    Buprenorphine and naloxone sublingual film contains buprenorphine, a schedule III controlled substance that can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patientâs level of stability is essential. Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits .

    Buvidal 8 Mg Prolonged

    This information is intended for use by health professionals

    Buvidal 8 mg prolonged-release solution for injection

    Buvidal 16 mg prolonged-release solution for injection

    Buvidal 24 mg prolonged-release solution for injection

    Buvidal 32 mg prolonged-release solution for injection

    8 mg prolonged-release solution for injection

    Each pre-filled syringe contains 8 mg buprenorphine

    16 mg prolonged-release solution for injection

    Each pre-filled syringe contains 16 mg buprenorphine

    24 mg prolonged-release solution for injection

    Each pre-filled syringe contains 24 mg buprenorphine

    32 mg prolonged-release solution for injection

    Each pre-filled syringe contains 32 mg buprenorphine

    Excipient with known effect

    The 8 mg, 16 mg, 24 mg and 32 mg strengths contain small amounts of ethanol , less than 100 mg per dose.

    For the full list of excipients, see section 6.1.

    Yellowish to yellow clear liquid.

    Treatment of opioid dependence within a framework of medical, social and psychological treatment. Treatment is intended for use in adults and adolescents aged 16 years or over.

    Administration of Buvidal is restricted to healthcare professionals. Appropriate precautions, such as to conduct patient follow-up visits with clinical monitoring according to the patient’s needs, should be taken when prescribing and dispensing buprenorphine. Take-home use or self-administration of the product by patients is not allowed.

    Precautions to be taken before initiation of treatment

    Posology

    128 mg

    Missed doses

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    Drug Addiction Treatment Act

    Under the Drug Addiction Treatment Act codified at 21 U.S.C. 823, prescription use of this product in the treatment of opioid dependence is limited to healthcare providers who meet certain qualifying requirements, and who have notified the Secretary of Health and Human Services of their intent to prescribe this product for the treatment of opioid dependence and have been assigned a unique identification number that must be included on every prescription.

    Drug Addiction And Treatment Act

    CLINICAL PHARMACOKINETICS OF TELBIVUDINE, A POTENT ...

    Under the Drug Addiction Treatment Act codified at 21 U.S.C. 823, prescription use of this product in the treatment of opioid dependence is limited to healthcare providers who meet certain qualifying requirements, and who have notified the Secretary of Health and Human Services of their intent to prescribe this product for the treatment of opioid dependence and have been assigned a unique identification number that must be included on every prescription.

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    Hepatic Metabolism Of Opioids

    There are two different types of chemical reactions in the liver metabolism of drugs. The first type is transfer-oxidation reaction that is catalyzed by the cytochrome P450 enzyme system and metabolizes most opioids. Clearance of opioids decreases in liver failure and their bioavailability increases. These changes may be considered as secondary outcomes of the reduction in liver blood flow or the reduction of the cytochrome P450 enzymes levels. The second group of chemical reactions consists of conjugation and glucuronidation in the liver. The reactions are less affected, since the glucuronidase are preserved in patients with liver disease moreover, extra-hepatic glucuronidation is less affected by the hepatic criteria, and the opioid metabolites are generally exerted by the kidneys. The reduction in the serum albumin level changes the quality of opioid distribution volumes that either increases or decreases the accumulation of drugs. Although there is no practical method to test or predict the clinical observations, at least a part of most opiates are metabolized by the liver. Therefore, the administration of opioids to patients with liver failure is high risk and requires precaution be taken to minimize their side effects .

    The current study used articles that population were over the age of eighteen and had liver disease, intervention was use of opioid drugs and outcome was: whether or not to use opioids in patients with liver disease.

    Risk Of Opioid Withdrawal With Abrupt Discontinuation

    Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset . When discontinuing buprenorphine and naloxone sublingual film, gradually taper the dosage .

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    Buvidal 128 Mg Prolonged

    Buprenorphine â Suboxone

    This information is intended for use by health professionals

    Buvidal 64 mg prolonged-release solution for injection

    Buvidal 96 mg prolonged-release solution for injection

    Buvidal 128 mg prolonged-release solution for injection

    64 mg prolonged-release solution for injection

    Each pre-filled syringe contains 64 mg buprenorphine

    96 mg prolonged-release solution for injection

    Each pre-filled syringe contains 96 mg buprenorphine

    128 mg prolonged-release solution for injection

    Each pre-filled syringe contains 128 mg buprenorphine

    For the full list of excipients, see section 6.1.

    Yellowish to yellow clear liquid.

    Treatment of opioid dependence within a framework of medical, social and psychological treatment. Treatment is intended for use in adults and adolescents aged 16 years or over.

    Administration of Buvidal is restricted to healthcare professionals. Appropriate precautions, such as to conduct patient follow-up visits with clinical monitoring according to the patient’s needs, should be taken when prescribing and dispensing buprenorphine. Take-home use or self-administration of the product by patients is not allowed.

    Precautions to be taken before initiation of treatment

    To avoid precipitating symptoms of withdrawal, treatment with Buvidal should be started when objective and clear signs of mild to moderate withdrawal are evident . Consideration should be given to the types of opioid used , time since last opioid use and the degree of opioid dependence.

    Posology

    128 mg

    Elderly

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    Opioid Drugs In Patients With Liver Disease: A Systematic Review

    1Road Traffic Injury Research Center, Tabriz University of Medical Sciences, Tabriz, IR Iran

    2Pain Research Center, Iran University of Medical Sciences, Tehran, IR Iran

    3Emergency Medicine Research Team, Tabriz University of Medical Sciences, Tabriz, IR Iran

    4Tuberculosis and Lung Research Center, Tabriz University of Medical Sciences, Tabriz, IR Iran

    5Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran

    6Tehran Hepatitis Center, Tehran, IR Iran

    How to Cite:SoleimanpourH, SafariS, Shahsavari NiaK, SanaieS, AlavianS M. Opioid Drugs in Patients With Liver Disease: A Systematic Review,Hepat Mon.2016 16:e32636. doi: 10.5812/hepatmon.32636.

    ARTICLE INFORMATION

    Hepatitis Monthly:Article Type:

    Managing Risks From Concomitant Use Of Benzodiazepines Or Other Cns Depressants

    Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

    As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol.

    Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate.

    If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in buprenorphine treatment for opioid use disorder .

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    Use In Patients With Impaired Hepatic Function

    Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. The doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually titrated, and hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine. Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment and may interfere with buprenorphineâs efficacy throughout treatment. In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment. However, buprenorphine/naloxone products are not recommended for initiation of treatment in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal.

    Buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone. However, patients should be carefully monitored and consideration given to the possibility of naloxone interfering with buprenorphineâs efficacy .

    Impairment Of Ability To Drive Or Operate Machinery

    Buprenorphine Resources: Finding Suboxone Doctors and ...

    Buprenorphine and naloxone sublingual film may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction and dose adjustment. Caution patients about driving or operating hazardous machinery until they are reasonably certain that buprenorphine and naloxone sublingual film therapy does not adversely affect his or her ability to engage in such activities.

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    Analgesic Use In Cirrhosis

    Pain management is often a challenge for healthcare professionals, but it remains a very important component of providing quality patient care and is a common factor in patient satisfaction.5 A high prevalence of pain has been found among patients with chronic liver disease, reported between 32% and 77%.6-8 Pain and opioid-based pain regimens have been found to be significant predictors of healthcare utilization among liver disease patients.8

    One retrospective review found that 77% of preliver transplant patients reported bodily pain, with more than one-third indicating multiple sites.7 The pain reportedly affected work, sleep, mobility, appetite, enjoyment, and mood. Approximately 90% reported receiving pharmacologic therapy however, only 33% perceived relief. Short-acting opioids were prescribed 40% of the time, and 32% of patients reported being prescribed five or more pain medications. The authors concluded that pain in end-stage liver disease patients is very common, impacts functionality, and is often undertreated, despite the numerous pharmacologic therapies prescribed.7

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