NEODOSE

INDICATIONS

• Neonatal abstinence syndrome (NAS): Buprenorphine would be a reasonable choice for NAS if the neonate was exposed prenatally to buprenorphine. Sublingual buprenorphine was associated with the largest reduction in length of treatment and length of stay for NAS in a network meta-analysis of 18 randomized controlled trials (n=1072) of buprenorphine, clonidine, diluted tincture of opium and clonidine, diluted tincture of opium, morphine, methadone, and phenobarbital. Morphine was the least effective opioid. The findings should be interpreted with caution due to significant study limitations.
  • Compared with Methadone or Morphine: There was a 3-day reduction in the length of treatment with sublingual buprenorphine compared with conventional opioids (either morphine or methadone) in an observational trial of 360 infants (34 weeks or longer gestation) with NAS. Opioid treatment duration was 7.4 days (6.3 to 8.5 days) in the buprenorphine group compared with 10.4 days (9.3 to 11.5 days; p less than 0.001) in the conventional opioid group and the length of stay was 12.4 days (11.3 to 13.6 days) and 15.2 days (14.1 to 16.4 days; p less than 0.001), respectively. These reductions were consistent across the different types of intrauterine opioid exposure (short-acting opioids, methadone, buprenorphine, or combination of types). The initial dosage of buprenorphine was 4.5 mcg/kg/dose sublingual every 8 hours; with titrations/tapering of 1.5 mcg/kg/dose. Clonidine and/or phenobarbital were optional adjunct agents. Compared with Methadone: A shorter duration of opioid treatment (9.4 vs 14 days) and shorter length of inpatient stay (16.3 vs 20.7 days) with a sublingual buprenorphine protocol compared with oral methadone protocol was demonstrated in a retrospective analysis of 201 infants (34 weeks’ gestation or older) with NAS. Infants exposed in utero to methadone were excluded.
  • Compared with Morphine: Sublingual buprenorphine reduced the duration of treatment for neonatal abstinence syndrome compared with oral morphine (15 days vs 28 days; p less than 0.001) in a double-blind, double-dummy, single-center study (n=63). Preterm infants and infants exposed to benzodiazepines in utero were excluded. Median length of hospital stay was 21 vs 33 days (p less than 0.001) and use of supplemental phenobarbital was 15% vs 23% (p=0.36) for buprenorphine and morphine, respectively. Rates of adverse events were not different between the 2 groups.
  • Compared with Methadone: A shorter duration of opioid treatment (9.4 vs 14 days) and shorter length of inpatient stay (16.3 vs 20.7 days) with a sublingual buprenorphine protocol compared with oral methadone protocol was demonstrated in a retrospective analysis of 201 infants (34 weeks’ gestation or older) with NAS. Infants exposed in utero to methadone were excluded.

CONTRAINDICATIONS

Contraindicated with significant respiratory depression, acute or severe bronchial asthma (in an unmonitored setting or in the absence of resuscitative equipment), or known or suspected gastrointestinal obstruction (including paralytic ileus).

PRECAUTIONS

• Addiction potential:
  • Opioid-type physical dependence may occur.
• Alcoholism:
  Use cautiously in patients with acute alcoholism and delirium tremens
• Cardiovascular:
  • QTc prolongation has been reported.
  • Avoid use in patients with a history of long QT Syndrome, or an immediate family member with the syndrome.
  • Severe orthostatic hypotension and syncope in ambulatory patients may occur, especially in patients with compromised ability to maintain blood pressure, and in patients with reduced blood volume, or with concurrent administration of CNS depressants (eg, general anesthetics, phenothiazines).
  • Avoid use in patients with circulatory shock.
• Concomitant Use:
  • Avoid use with Class 1A antiarrhythmic medications (eg, quinidine, procainamide, disopyramide) or Class 3 antiarrhythmic medications (eg, sotalol, amiodarone, dofetilide), or other medications that prolong the QT interval.
  • Patients requiring acute pain management or anesthesia are at risk. use non-opioid analgesia when possible; if opioid needed treat with high-affinity full opioid analgesia under supervision of physician with particular attention to respiratory function. Higher doses may be required. Use extreme care when using opioids as part of anesthesia.
• Dermatologic:
  • Use implant with caution in patients with history of keloid formation or connective tissue disease (eg, scleroderma).
• Endocrine & Metabolic:
  • Use with caution in patients with myxedema, hypothyroidism, or adrenal cortical insufficiency.
  • Adrenal insufficiency may occur with opioids. If suspected, perform diagnostic testing. If confirmed wean patient off of opioid if appropriate, treat with corticosteroids, and continue to assess adrenal function.
• Gastrointestinal:
  • Use may obscure diagnosis or clinical course in patients with acute abdominal conditions.
  • Severe constipation may occur.
• Hepatic:
  • Sphincter of Oddi spasm may occur with morphine use.
  • Use caution with severe hepatic impairment.
  • Use cautiously in patients with biliary dysfunction.
  • Cytolytic hepatitis, hepatitis with jaundice, and hepatotoxicity, sometimes fatal, has been reported, with an increased risk with pre-existing liver enzyme abnormalities, comorbid hepatitis B or C virus, concomitant hepatotoxic drugs, or IV drug abuse.
  • Avoid use with preexisting moderate to severe hepatic impairment and discontinuation may be necessary if this occurs during treatment (subdermal implants).
  • Increased intracholedochal pressure has been reported. Use cautiously in patients with biliary dysfunction.
• Immunologic:
  • Anaphylactic shock, bronchospasm, and angioneurotic edema has been reported.
  • Hypersensitivity reactions (eg, pruritus, rashes, hives) have been reported including acute and chronic reactions.
  • Infection may occur at site of implant insertio or removal. Increased risk with excessive palpation after insertion and improper removal.
  • Use implant with caution in patients with history of recurrent MRSA infections.
• Musculoskeletal:
  • Use cautiously with kyphoscoliosis.
  • Use implant with caution in patients with kyphoscoliosis.
• Neurologic:
  • Increased intracranial pressure may occur in susceptible patients (eg, brain tumors or head injury) due to decreased respiratory drive and carbon dioxide retention.
  • Avoid use with impaired consciousness or coma.
  • Use implant with caution in patients with CNS depression or coma.
  • New or worsening seizures may occur.
  • Potentially life-threatening serotonin syndrome may occur, particularly with concomitant use of serotonergic drugs.
• Psychologic:
  • Use with caution in patients with toxic psychoses, acute alcoholism, or delirium tremens.
  • Use with caution in patients with toxic psychoses.
• Renal:
  • Use with caution in prostate hypertrophy or urethral stricture.
  • Use caution with severe renal impairment.
• Reproductive:
  • Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as reduced interest in sex, impotence, or infertility. Laboratory evaluation may be warranted.
• Respiratory:
  • Increased risk for further respiratory depression, particularly during treatment initiation and titration in patients with chronic pulmonary disease or otherwise impaired respiration.
  • Life-threatening respiratory depression may occur, especially with concomitant use of benzodiazepines or other CNS depressants and particularly in the elderly, cachectic, or debilitated patients, those with chronic obstructive pulmonary disease or cor pulmonale, and patients with substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression.
  • Sleep-related breathing disorders including central sleep apnea and sleeprelated hypoxemia may occur and risk increases in a dose-dependent fashion; dose reduction may be necessary
• Special Population:
  • Mental or physical impairment may occur, especially when beginning treatment or adjusting dosage. Avoid driving or operating dangerous machinery.
  • Fatal respiratory depression may occur in children who are accidentally exposed to buprenorphine. Keep expelled implants away from children.
  • Use implant with caution in debilitated patients.
• Withdrawal:
  • Abrupt withdrawal may result in severe withdrawal symptoms and should be avoided.

ADVERSE EFFECTS

No buprenorphine-related adverse effects were reported in 2 open-label trials (n=50).

BLACK BOX WARNING

There are serious risks, including profound sedation, respiratory depression, coma, and/or death, associated with combined use of opioids and benzodiazepines, other drugs that depress the CNS, or alcohol. Concomitant use should be reserved for patients with no alternative treatment. If necessary, use the lowest initial dose and titrate based on clinical response. Monitor patients closely for sedation and respiratory depression. Screen patients for risk of substance-use disorders.

ADMINISTRATION

After administration sublingually, place a pacifier in the infant’s mouth. For a volume of the dose greater than 0.5 mL, give in 2 administrations separated by at least 2 minutes.