NEODOSE

INDICATIONS

• Analgesia: There is insufficient evidence to support the routine use of opioids in mechanically ventilated neonates to reduce pain in a systematic review (n=13 studies; 1505 neonates)
• Neonatal abstinence syndrome (NAS): 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 buprenorphine: >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: >Methadone outperformed morphine for the treatment of NAS in a multicenter, randomized, double-blind study of 116 term infants (median length of hospital stay (LOS) (16 vs 20 days, p=0.005), LOS attributable to NAS (16 vs 19 days, p=0.005), and length of drug treatment (11.5 vs 15 days, p=0.009)). Initial oral doses were 0.3 mg/kg/day for Finnegan score (FS) of 8 to 10, 0.5 mg/kg/day for FS of 11 to 13, 0.7 mg/kg/day for FS 14 to 16, and 0.9 mg/kg/day for FS of 17 or more. The total daily doses were divided every 4 hours for morphine and every 8 hours for methadone. A nonalcoholic solution of methadone was compounded. Neonatal abstinence syndrome was treated for a median of 14 days with methadone compared with 21 days for morphine (p=0.008) in a double-blind, randomized trial (n=78). All neonates were 35 weeks gestational or more and prenatal exposure was either methadone or buprenorphine.
  • Compared with cloNIDine: Overall, cloNIDine monotherapy for NAS appeared to be as effective as morphine in a randomized, double-blind, pilot study of 31 neonates younger than 7 days (gestational age, 35 weeks or more). Rescue drugs were not necessary in any neonate. The initial cloNIDine dose was 0.625 mcg/kg/dose orally every 3 hours with dose titrations up to a maximum of 12 mcg/kg/day.
• Opioid dependence:
• Procedural Pain: Morphine 100 mcg/kg orally administered 60 minutes prior to retinopathy of prematurity screening in non-ventilated premature (less than 32 weeks’ gestation or with a birthweight of less than 1501 g)infants produced adverse cardiorespiratory effects for anaverage of 6 to 8 hours in a randomized blinded placebo-controlled trial (n=31). The stud was underpowered (early termination due to safety findings) to detect differences in efficacybetween morphine and placebo. Oxygen desaturation at 6 and 24 hours after procedure andbradycardia episodes at 24 hours after procedure occurred significantly more in themorphine-group than placebo-group. Apneic episodes requiring resuscitation with noninvasivepositive pressure ventilation within the 24 hours after administration occurred in20% of the morphine-group and 0% in the placebo-group
• sedation:

CONTRAINDICATIONS

• Significant respiratory depression.
• Acute or severe bronchial asthma in a unmonitored setting or in the absence of resuscitative equipment
• Concurrent use of monamine oxidase inhibitors (MAOIs) or within the last 14 days.
• Known or suspected gastrointestinal obstruction, including paralytic ileus.
• Neuraxial administration contraindications include: infection at injection microinfusion site, concomitant anticoagulant therapy, uncontrolled bleeding diathesis, or the presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous.

PRECAUTIONS

• Abuse :
  • Abuse of controlled-release capsules or tablets by parenteral route may result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury due to the presence of talc
• Cardiovascular:
  • Preexisting circulatory shock may reduce cardiac output and blood pressure; avoid use.
  • Severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients may occur; especially in patients with compromised ability to maintain blood pressure; monitoring recommended; consider alternative non-opioid analgesic if possible.
• Concomitant Use:
  • Avoid concomitant use with mixed agonist/antagonist (eg, pentazocine, nalbuphine, butorphanol) or partial agonists (eg, buprenorphine).
• Endocrine & Metabolic:
  • Opioids may rarely lead to adrenal insufficiency due to inadequate amounts of cortisol. If adrenal insufficiency is suspected, perform diagnostic testing, treat with corticosteroids if confirmed, wean patient off of opioid if appropriate, and continue to assess adrenal function .
• Gastrointestinal:
  • Difficulty with swallowing may occur due to tablet stickiness and swelling, including choking, gagging, regurgitation, and having a tablet stuck in the throat. Do not presoak, lick, or wet tablets prior to use. Take tablets singly and immediately after placing in the mouth with enough water to ensure complete swallowing; alternative therapy may be required.
  • Intestinal obstruction or exacerbation of diverticulitis may occur due to tablet stickiness and swelling, especially in patients with a small gastrointestinal lumen (eg esophageal or colon cancer); alternative therapy may be required.
• Hepatic:
  • Spasm of the sphincter of Oddi and increased serum amylase levels may occur in patients with biliary tract disease ; monitoring recommended.
  • Use caution with epidural administration in patients with hepatic dysfunction.
  • Respiratory depression, sedation, and hypotension may occur in patients with cirrhosis; monitoring recommended and titrate slowly in this population
• Immunologic:
  • Anaphylaxis has been reported .IM ADMINISTRATION Use caution when injecting intramuscularly
• IM ADMINISTRATION
  • Use caution when injecting intramuscularly into chilled areas or in patients with hypotension or shock, since impaired perfusion may prevent complete absorption. If repeated injections are administered, an excessive amount may be suddenly absorbed if normal circulation is re-established.
• IV ADMINISTRATION
  • Rapid intravenous administration may result in chest wall rigidity.
• Neurologic:
  • Impaired consciousness or coma; avoid use.
  • Potentially life-threatening serotonin syndrome may occur, particularly with concomitant use of serotonergic drugs.
  • Cordotomy or other interruption of pain transmission pathways; discontinue use prior to procedure.
  • Use caution in patients susceptible to intracranial effects of carbon dioxide retention (eg, those with brain tumors or increased intracranial pressure) as reduced respiratory drive may occur, further increasing intracranial pressure; monitoring recommended.
  • Opioids may obscure the clinical course in patients with head injury.
  • Myoclonic-like spasm of lower extremities has been reported with intrathecal doses of more than 20 mg/day.
  • Inflammatory masses such as granulomas, some of which have resulted in serious neurologic impairment including paralysis, have been reported in patients receiving continuous infusion of opioids via indwelling intrathecal catheter; monitoring recommended.
  • Seizure disorders may be inducedor aggravated; monitoring recommended.
• Prolonged Use
  • 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.
• Renal:
  • Urinary retention, which may persist 10 to 20 hours following single epidural or intrathecal administration, is a frequently associated with neuraxial opioid administration, more frequently in male patients than female patients. Urinary retention may also occur during the first several days of hospitalization for the initiation of continuous intrathecal or epidural morphine therapy; monitoring recommended and prompt intervention required.
  • Respiratory depression, sedation, and hypotension may occur in patients with renal failure; monitoring recommended; use lower starting dosages and titrate slowly in this population.
  • Use caution with epidural administration in patients with renal dysfunction.
• Respiratory :
  • Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive, especially during treatment initiation and titration; monitoring recommended, particularly during treatment initiation and titration or when using concomitant drugs that depress respiration; may consider non-opioid therapy.
  • Severe respiratory depression up to 24 hours following epidural or intrathecal administration has been reported; single-dose neuraxial administration may result in acute or delayed respiratory depression for periods at least as long as 24 hours.
  • 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
• Spacial Populations:
  • Fatal respiratory depression may occur in opioid-intolerant patients.
  • Debilitated patients are at increased risk for respiratory depression; monitor closely, particularly during treatment initiation and titration or when using concomitant CNS depressants and reduce dosage if necessary.
• Withdrawal :
  • Abrupt withdrawal may result in severe withdrawal symptoms and should be avoided . Serious withdrawal symptoms, including uncontrolled pain, psychological distress, and suicide, may occur upon sudden dose decrease or discontinuation in patients who are physically dependent on opioid medications; do notdiscontinue abruptly and create a patient-specific plan to taper the opioid gradually.

ADVERSE EFFECTS

Naloxone should be readily available to reverse adverse effects. Marked respiratory depression (decreases the responsiveness of the respiratory center to CO2 tension). Hypotension and bradycardia. Transient hypertonia. Ileus and delayed gastric emptying. Urine retention. Tolerance may develop after prolonged use; wean slowly. Seizures reported in two infants who received bolus plus infusion.

ADMINISTRATION

IV: The recommended standard concentrations of morphine solutions are 0.1 mg/mL for continuous infusion and 0.1 and 0.5 mg/mL for intermittent infusions. Typically, morphine intermittent infusion is administered over 15 to 30 minutes. Intermittent morphine was infused over 1 hour in some studies.

BLACK BOX WARNING

Injection route, solution

• Risk of Medication Errors: Improper or erroneous substitution of Infumorph(R) 200 or 500 (10 or 25 mg/mL, respectively) for regular Duramorph(R) (0.5 or 1 mg/mL) is likely to result in serious overdosage, leading to seizures, respiratory depression, and death.
• Risks with Neuroaxial Administration: Single-dose neuraxial administration may result in acute or delayed respiratory depression up to 24 hours. Because of the risk of severe adverse reactions when Duramorph is administered by the epidural or intrathecal route of administration, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial dose and, as appropriate, for the first several days after catheter implantation.
• Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur with use of morphine sulfate. Monitor for respiratory depression, especially during initiation of morphine sulfate or following a dose increase. Because of delay in maximum CNS effect with intravenously administered drug (30 min.), rapid IV administration may result in overdosing.
• Addiction, Abuse, and Misuse: Morphine sulfate exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing morphine sulfate, and monitor all patients regularly for the development of these behaviors and conditions.
• Neonatal Opioid Withdrawal Syndrome: Prolonged use of morphine sulfate during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
• Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Oral route

• Risk of Medication Errors: Ensure accuracy when prescribing, dispensing, and administering morphine sulfate oral solution. Dosing errors due to confusion between mg and mL, and other morphine solutions of different concentrations can result in accidental overdose and death.
• Addiction, Abuse, and Misuse: Morphine sulfate exposes users to risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions.
• Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS): To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products.
• Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow morphine sulfate extended-release capsules whole to avoid exposure to a potentially fatal dose of morphine sulfate.
• Accidental Ingestion: Accidental ingestion of morphine sulfate, especially in children, can result in a fatal overdose.
• Neonatal Opioid Withdrawal Syndrome: Prolonged use of morphine sulfate during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
• Interaction with Alcohol: Alcohol consumption should be avoided while taking morphine sulfate extended-release capsules. Consumption of alcohol may lead potentially fatal overdoses of morphine.
• Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants: Concomitant use of opioids and benzodiazepines or other CNS depressants may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for patients with inadequate alternative treatment options. Limit dosages and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation.

Rectal, suppositories

Morphine sulfate suppositories expose users to risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and monitor regularly for these behaviors or conditions. Serious, life-threatening , or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase Accidental exposure of morphine sulfate suppositories, especially by children, can result in a fatal overdose of opium. Prolonged use of morphine sulfate suppositories during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation.

MONITORING

Monitor respiratory and cardiovascular status closely. Observe for abdominal distention and loss of bowel sounds. Consider urine retention if output is decreased. For infants experiencing neonatal abstinence syndrome, monitor and score signs of drug withdrawal using a published abstinence assessment tool such as the modified Neonatal Abstinence Scoring System (Finnegan) or the Lipsitz tool. Monitor patients susceptible to the intracranial effects of carbon dioxide retention (eg, evidence of intracranial pressure or brain tumors) for signs and symptoms of sedation and respiratory depression, particularly during initiation of therapy