DEMEROL (meperidine hydrochloride), tablets

DEMEROL (meperidine hydrochloride), tablets

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DEMEROL (meperidine hydrochloride), tablets

DEMEROL (meperidine hydrochloride, USP) Tablet and Oral Solution are opioid agonists. DEMEROL Tablets are available as 50 mg and 100 mg Tablets for oral administration. The chemical name is 4-Piperidinecarboxylic acid, 1-methyl-4-phenyl-,ethyl ester, hydrochloride. The molecular weight is 283,80. Its molecular formula is C15H21NO2·HCl

Meperidine hydrochloride is a white crystalline substance with a melting point of 186°C to 189°C. It is readily soluble in water and has a neutral reaction and a slightly bitter taste. The solution is not decomposed by a short period of boiling.

The Tablets contain 50 mg or 100 mg of meperidine hydrochloride.

The DEMEROL Oral Solution is a pleasant-tasting, nonalcoholic, banana-flavored solution containing 50 mg of meperidine hydrochloride, per 5 mL (10 mg/mL).

The Inactive Ingredients in DEMEROL Tablets include: Calcium Sulfate, Dibasic Calcium Phosphate, Starch, Stearic Acid, and Talc. The Tablets are white, round and convex. The 50 mg is a scored tablet and has a stylized “W” on one side and “D” over “35” on the other side. The 100 mg is a scored tablet and has a stylized “W” on one side and “D” over “37” on the other side.

The Inactive Ingredients in DEMEROL Oral Solution include: Benzoic Acid, Flavor, Liquid Glucose, Purified Water, Saccharin Sodium.

Indications and usage

DEMEROL Tablets and Oral Solution are opioid agonists indicated for the management of pain, severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve DEMEROL Tablets and Oral Solution for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

  • Have not been tolerated, or are not expected to be tolerated,
  • Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

Mechanism of Action

Meperidine is an opioid agonist with multiple actions qualitatively similar to those of morphine; the most prominent of these involve the central nervous system and organs composed of smooth muscle. The principal actions of therapeutic value are analgesia and sedation.

Dosage and administration

  • Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
  • Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse.
  • Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with DEMEROL Tablets and Oral Solution. Consider prescribing naloxone based in the patient’s risk factors for overdose.
  • Adult Patients: Initiate treatment in adults with 50 mg to 150 mg every 3 to 4 hours as needed for pain.
  • Pediatric Patients: Initiate treatment with 1.1 mg/kg to 1.8 mg/kg orally, up to the adult dose, every 3 or 4 hours as needed for pain.
  • Do not abruptly discontinue DEMEROL Tablets and Oral Solution in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide

Contraindications

DEMEROL Tablets and Oral Solution are contraindicated in patients with:

  • Significant respiratory depression
  • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
  • Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days of having taken an MAOI
  • Known or suspected gastrointestinal obstruction, including paralytic ileus
  • Hypersensitivity to meperidine or to any of other ingredients of the product (e.g., anaphylaxis)

Warnings and precautions

  • Ensure accuracy when prescribing, dispensing, and administering DEMEROL Oral Solution. Dosing errors due to confusion between mg and mL, and other Meperidine Hydrochloride Oral Solutions of different concentrations can result in accidental overdose and death
  • DEMEROL Tablets and Oral Solution expose users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and monitor regularly for these behaviors and conditions
  • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase.
  • 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
  • Accidental ingestion of DEMEROL Tablets or Oral Solution, especially by children, can result in a fatal overdose of meperidine.
  • Prolonged use of DEMEROL Tablets or Oral Solution 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 with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in fatal overdose of meperidine
  • 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.
  • Concomitant use of DEMEROL Tablets or Oral Solution with monoamine oxidase inhibitors (MAOIs) can result in coma, severe respiratory depression, cyanosis and hypotension. Use of DEMEROL Tablets or Oral Solution with MAOIs within the last 14 days is contraindicated.

Adverse reactions

Most common adverse reactions were lightheadedness, dizziness, sedation, nausea, vomiting, and sweating.

Drug interactions

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Monoamine Oxidase Inhibitors (MAOIs)
phenelzine, tranylcypromine, linezolid
Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAOIs) or those who have recently received such agents. Therapeutic doses of meperidine have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear, but may be related to a preexisting hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of acute narcotic overdose.
Do not use DEMEROL Tablets or Oral Solution in patients taking MAOIs or within 14 days of stopping such treatment.
Intravenous hydrocortisone or prednisolone have been used to treat severe reactions, with the addition of intravenous chlorpromazine in those cases exhibiting hypertension and hyperpyrexia. The usefulness and safety of narcotic antagonists in the treatment of these reactions is unknown.)
Inhibitors of CYP3A4 and CYP2B6
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)
The concomitant use of DEMEROL Tablets or Oral Solution and CYP3A4 or CYP2B6 inhibitors can increase the plasma concentration of meperidine, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of DEMEROL Tablets or Oral Solution and CYP2B6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of DEMEROL Tablets or Oral Solution is achieved
If concomitant use is necessary, consider dosage reduction of DEMEROL Tablets or Oral Solution until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
If a CYP3A4 or CYP2B6 inhibitor is discontinued, consider increasing the DEMEROL Tablets or Oral Solution dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
CYP3A4 and CYP2B6 Inducers
Rifampin, carbamazepine, phenytoin
The concomitant use of DEMEROL Tablets or Oral Solution and CYP3A4 or CYP2B6 inducers can decrease the plasma concentration of meperidine, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to meperidine
If concomitant use is necessary, consider increasing the DEMEROL Tablets or Oral Solution dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 or CYP2B6 inducer is discontinued, consider DEMEROL Tablets or Oral Solution dosage reduction and monitor for signs of respiratory depression.
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol
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.
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. Follow patients closely for signs of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose
Serotonergic DrugsThe concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DEMEROL Tablets or Oral Solution if serotonin syndrome is suspected.
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase inhibitors (MAOIs) (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
butorphanol, nalbuphine, pentazocine, buprenorphine
May reduce the analgesic effect of DEMEROL Tablets or Oral Solution and/or precipitate withdrawal symptoms.
Avoid concomitant use.
Muscle RelaxantsMeperidine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DEMEROL Tablets or Oral Solution and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose
DiureticsOpioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic DrugsThe concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Monitor patients for signs of urinary retention or reduced gastric motility when DEMEROL Tablets or Oral Solution is used concomitantly with anticholinergic drugs
AcyclovirThe concomitant use of acyclovir may increase the plasma concentrations of meperidine and its metabolite, normeperidine.
If concomitant use of acyclovir and DEMEROL Tablets or Oral Solution is necessary, monitor patients for respiratory depression and sedation at frequent intervals.
CimetidineThe concomitant use of cimetidine may reduce the clearance and volume of distribution of meperidine also the formation of the metabolite, normeperidine, in healthy subjects.
If concomitant use cimetidine and DEMEROL Tablets or Oral Solution is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

Use in specific populations

Pregnancy: Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with DEMEROL Tablets or Oral Solution are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Formal animal reproduction studies have not been conducted with meperidine.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly

Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. Resuscitation may be required. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. DEMEROL Tablets and Oral Solution are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including DEMEROL Tablets or Oral Solution, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Lactation: Meperidine appears in the milk of nursing mothers receiving the drug. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DEMEROL Tablets or Oral Solution and any potential adverse effects on the breastfed infant from DEMEROL Tablets or Oral Solution or from the underlying maternal condition.

Monitor infants exposed to DEMEROL Tablets or Oral Solution through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Pediatric Use: The safety and effectiveness of meperidine in pediatric patients has not been established. Literature reports indicate that meperidine has a slower elimination rate in neonates and young infants compared to older children and adults. Neonates and young infants may also be more susceptible to the effects, especially the respiratory depressant effects. If meperidine use is contemplated in neonates or young infants, any potential benefits of the drug need to be weighed against the relative risk of the patient.

Hepatic Impairment: Accumulation of meperidine and/or its active metabolite, normeperidine, can occur in patients with hepatic impairment. Elevated serum levels have been reported to cause central nervous system excitatory effects. Meperidine should therefore be used with caution in patients with hepatic impairment. Titrate the dosage of DEMEROL Tablets or Oral Solution slowly in patients with hepatic impairment and monitor closely for signs of central nervous system and respiratory depression.

Renal Impairment: Accumulation of meperidine and/or its active metabolite, normeperidine, can also occur in patients with renal impairment. Meperidine should therefore be used with caution in patients with renal impairment. Titrate the dosage of DEMEROL Tablets or Oral Solution slowly in patients with renal impairment and monitor closely for signs of central nervous system and respiratory depression.

Drug abuse and dependence

Controlled Substance: DEMEROL Tablets and Oral Solution contain meperidine, a Schedule II controlled substance.

Abuse: DEMEROL Tablets and Oral Solution contain meperidine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. DEMEROL Tablets and Oral Solution can be abused and is subject to misuse, addiction, and criminal diversion

All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Dependence: Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Overdosage

Acute overdose with DEMEROL Tablets and Oral Solution can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Accumulation of normeperidine as in chronic use or possibly following introduction of a concomitant CYP3A4 inducer presents as excitatory syndrome including hallucinations, tremors, muscle twitches, dilated pupils, hyperactive reflexes, and convulsions.

Treatment of Overdose

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to meperidine overdose, administer an opioid antagonist.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

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