Demerol - Meperidine Hydrochloride tablet prescribing information
WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF DEMEROL TABLETS AND ORAL SOLUTION
Risk of Medication Errors
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 [see Dosage and Administration (2.1 ), Warning and Precautions (5.1 )].
Addiction, Abuse, and Misuse
Because the use of DEMEROL Tablets and Oral Solution expose s patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death , a ssess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.2 )].
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of DEMEROL Tablets and Oral Solution , especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of DEMEROL Tablets or Oral Solution are essential [see Warnings and Precautions (5.3 )].
Accidental Ingestion
Accidental ingestion of DEMEROL Tablets and Oral Solution , especially by children, can result in a fatal overdose of meperidine [see Warnings and Precautions (5.3 )].
Risk 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. Reserve concomitant prescribing of DEMEROL Tablets and Oral Solution and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.4 ), Drug Interactions (7 )].
Neonatal Opioid Withdrawal Syndrome
If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.5 )].
Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [seeWarnings and Precautions (5.6 )].
Cytochrome P450 3A4(CYP3A4)Interaction
The concomitant use of DEMEROL Tablets or Oral Solution with all cytochrome P450 3A4 (CYP3A4) inhibitors may result in an increase in meperidine plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 (CYP3A4) inducer may result in an increase in meperidine plasma concentration. Monitor patients receiving DEMEROL Tablets or Oral Solution, and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.7 ), Drug Interactions (7 )].
Concomitant use of DEMEROLTablets and Oral Solutionwith MonoamineOxidaseInhibitors(MAOIs)
Concomitant use of DEMEROL Tablets or Oral Solution with monoamine oxidase inhibitors (MAO Is ) can result in coma, severe respiratory depression, cyanosis, and hypotension. Use of DEMEROL Tablets or Oral Solution with MAO Is within last 14 days is contraindicated [see Contraindications(4 ), Warnings and Precautions (5.8 ), Drug Interactions (7 )].
1 INDICATIONS AND USAGE
DEMEROL Tablets and Oral Solution are indicated for the management of acute 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, which can occur at any dosage or duration [see Warnings and Precautions (5.2 ) ] , reserve DEMEROL Tablets or 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.
DEMEROL Tablets and Oral Solution should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.
DEMEROL Tablets or Oral Solution should not be used for the treatment of chronic pain. Use of DEMEROL Tablet or Oral Solution for an extended period of time may increase the risk of toxicity (e.g., seizures) from the accumulation of the meperidine metabolite, normeperidine.
2 DOSAGE AND ADMINISTRATION
- DEMEROL Tablets and Oral Solution should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associate risks. (2.1 )
- Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of DEMEROL Tablets and Oral Solution 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. (2.1 , 5 )
- 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. (2.1 )
- 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. (2.1 , 5.2 )
- Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with DEMEROL Tablets and Oral Solution. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1 , 5.3 )
- 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. (2.2 , 5.2 , 5.4 , 5.7 )
- Adult Patients: Initiate treatment in adults with 50 mg to 150 mg orally, every 3 to 4 hours as needed for pain, and at lowest dose necessary to achieve adequate analgesia (2.3 ). Titrate the dose based upon the individual patient’s response to their initial dose of DEMEROL Tablets and Oral Solution.
- Pediatric Patients: Initiate treatment in pediatric patients with 1.1 mg/kg to 1.8 mg/kg orally, up to the adult dose, every 3 or 4 hours as needed and at the lowest dose necessary to achieve adequate analgesia (2.3 ). Titrate the dose based upon the individual patient’s response to their initial dose of DEMEROL Tablets and Oral Solution.
- 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. (2.6 )
2.1 Important Dosage and Administration Instructions
DEMEROL Oral Solution
Ensure accuracy when prescribing, dispensing, and administering DEMEROL Oral Solution to avoid dosing errors due to confusion between mg and mL, and with other meperidine solutions of different concentrations, which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume.
Instruct patients and caregivers on how to accurately measure and take or administer the correct dose of DEMEROL Oral Solution.
Strongly advise patients and caregivers to always use a graduated oral syringe or measuring cup, with metric units of measurements (i.e., mL), to correctly measure the prescribed amount of medication.
Inform patients and caregivers that oral dosing devices may be obtained from their pharmacy and to never use household teaspoons or tablespoons to measure DEMEROL Oral Solution.
DEMEROL Tablets and Oral Solution
DEMEROL Tablets and Oral Solution should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.
Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5 )]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of DEMEROL Tablets and Oral Solution 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.
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.
There is variability in the opioid analgesic dose and duration needed to adequately manage pain due to both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account that patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1 )].
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with DEMEROL Tablets and Oral Solution. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5 )].
2.2 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 and assess the potential need for access to naloxone, both when initiating and renewing treatment with DEMEROL Tablets or Oral Solution [see Warnings and Precautions (5.4 )].
Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).
Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.2 , 5.4 , 5.7 )].
Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose .
2.000000000000000e+00 3 Initial Dosage
Adults
Initiate treatment with DEMEROL Tablets or Oral Solution in a dosing range of 50 mg to 150 mg orally, every 3 or 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of DEMEROL Tablets and Oral Solution.
Pediatric Patients
Initiate treatment with DEMEROL in a dosing range of 1.1 mg/kg to 1.8 mg/kg orally, up to the adult dose, every 3 or 4 hours as needed, at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of DEMEROL Tablets and Oral Solution.
2.000000000000000e+00 4 Dosage Modification with Concomitant Use with Phenothiazines
The dose of DEMEROL Tablets or Oral Solution should be reduced by 25 to 50% when administered concomitantly with phenothiazines and other tranquilizers.
2.000000000000000e+00 5 Titration and Maintenance of Therapy
Individually titrate DEMEROL Tablets and Oral Solution to a dose that provides adequate analgesia and minimizes adverse reactions. If adequate pain management cannot be achieved with a total daily dosage of 600 mg or less, discontinue treatment with DEMEROL Tablets or Oral Solution by tapering the dose and select an alternate analgesic.
Continually reevaluate patients receiving DEMEROL Tablets or Oral Solution to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.2 )] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.
If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the DEMEROL Tablets or Oral Solution dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions (5 )] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
2.000000000000000e+00 6 Safe Reduction or Discontinuation of DEMEROL Tablets and Oral Solution
Do not abruptly discontinue DEMEROL Tablets and Oral Solution in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.
When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking DEMEROL Tablets and Oral Solution, there are a variety of factors that should be considered, including the total daily dose of opioid (including DEMEROL Tablets and Oral Solution) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder.
Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.
There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on DEMEROL Tablets and Oral Solution who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.
It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.
When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.16 ), Drug Abuse and Dependence (9.3 ) ] .
3 DOSAGE FORMS AND STRENGTHS
Tablets
- 50 mg scored tablet (white, round and convex with a stylized “W” on one side and “D” over “35” on the other side)
- 100 mg scored tablet (white, round and convex with a stylized “W” on one side and “D” over “37” on the other side)
Oral Solution
- Nonalcoholic, banana-flavored 50mg per 5mL (10 mg/mL), bottles of 16 fl. oz.
8 USE IN SPECIFIC POPULATIONS
- Pregnancy : May cause fetal harm (8.1 ).
8.1 Pregnancy
Risk Summary
Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.5 )] . Available data with DEMEROL Tablets or Oral Solution are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. Formal animal reproduction studies have not been conducted with meperidine. Neural tube defects (exencephaly and cranioschisis) have been reported in hamsters administered a single bolus dose of meperidine during a critical period of organogenesis at 0.85 and 1.5 times the total human daily dose of 1200 mg [see Data ] .
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.
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 [see Warnings and Precautions (5.5 )] .
Labor or Delivery
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. Resuscitation may be required [ see Overdose (10 ) ]. 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.
Data
Animal Data
Formal reproductive and developmental toxicology studies for meperidine have not been completed.
In a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of meperidine hydrochloride (127 and 218 mg/kg, respectively) on Gestation Day 8 to pregnant hamsters (0.85 and 1.5 times the total daily dose of 1200 mg/day based on body surface area). The findings cannot be clearly attributed to maternal toxicity.
8.2 Lactation
Risk Summary
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.
Clinical Considerations
Monitor infants exposed to DEMEROL Tablets or Oral Solution through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.
8.3 Females and Males of Reproductive Potential
8.4 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.
8.5 Geriatric Use
Clinical studies of DEMEROL Tablets and Oral Solution during product development did not include sufficient numbers of subjects aged 65 and over to evaluate age-related differences in safety or efficacy. Literature reports indicate that geriatric patients have a slower elimination rate compared to young patients and they may be more susceptible to the effects of meperidine. Reducing the total daily dose of meperidine is recommended in elderly patients, and the potential benefits of the drug should be weighed against the relative risk to a geriatric patient.
Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of DEMEROL slowly in geriatric patients and frequent reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.11 )] .
Meperidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.
8.6 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 regularly evaluate for signs of central nervous system and respiratory depression.
8.7 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 regularly evaluate for signs of central nervous system and respiratory depression.
4 CONTRAINDICATIONS
DEMEROL Tablets and Oral Solution are contraindicated in patients with:
- Significant respiratory depression [see Warnings and Precautions (5.4 )]
- Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9 )]
- Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days of having taken an MAOI [see Drug Interactions (7 )]
- Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.14 )]
- Hypersensitivity to meperidine or to any of other ingredients of the product (e.g., anaphylaxis) [see Adverse Reactions (6 )]
5 WARNINGS AND PRECAUTIONS
- 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. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safety switching the patient to a different opioid moiety). (5.9 )
- Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue DEMEROL Tablets or Oral Solution if serotonin syndrome is suspected. (5.10 )
- Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor Regularly evaluate closely, particularly during initiation and titration. (5.11 )
- Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.12 )
- Severe Hypotension : Regularly evaluate during dosage initiation and titration. Avoid use of DEMEROL Tablets or Oral Solution in patients with circulatory shock. (5.13 )
- Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of DEMEROL Tablets or Oral Solution in patients with impaired consciousness or coma. (5.14 )
5.1 Risks of Accidental Overdose and Death Due to Medication Errors
Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with meperidine solutions of different concentrations, when prescribing, dispensing, and administering DEMEROL Oral Solution. Ensure that the dose is communicated clearly and dispensed accurately.
Instruct patients and caregivers on how to measure and take or administer the correct dose of DEMEROL Oral Solution and to use extreme caution when measuring the dose. Strongly advise patients to obtain and always use a graduated device that can measure and deliver the prescribed dose accurately, and to never use household teaspoons or tablespoons to measure a dose because these are not accurate measuring devices [see Dosage and Administration (2.1 )].
5.000000000000000e+00 2 Addiction, Abuse, and Misuse
DEMEROL Tablets and Oral Solution contain meperidine, a Schedule II controlled substance. As an opioid, DEMEROL Tablets and Oral Solution expose users to the risks of addiction, abuse and misuse [see Drug Abuse and Dependence (9 )] .
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed DEMEROL Tablets or Oral Solution. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing DEMEROL Tablets and Oral Solution, and reassess all patients receiving DEMEROL Tablets or Oral Solution 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 abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient.
Patients at increased risk may be prescribed opioids such as DEMEROL Tablets and Oral Solution, but use in such patients necessitates intensive counseling about the risks and proper use of DEMEROL Tablets and Oral Solution along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2 ), Warnings and Precautions (5.4 )].
Opioids are sought for non-medical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing DEMEROL Tablets or Oral Solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused 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.
DEMEROL Tablets have been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose or death.
5.3 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 arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10 )] . Carbon dioxide (CO 2 ) 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 DEMEROL Tablets or Oral Solution, the risk is greatest during the initiation of therapy or following a dosage increase of DEMEROL Tablets or Oral Solution.
To reduce the risk of respiratory depression, proper dosing and titration of DEMEROL Tablets and Oral Solution are essential [see Dosage and Administration (2 )] . Overestimating the DEMEROL Tablets or Oral Solution dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of DEMEROL Tablets or Oral Solution, especially by children, can result in respiratory depression and death due to an overdose of meperidine.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose .
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 (2.6 )].
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 and assess the potential need for access to naloxone, both when initiating and renewing treatment with DEMEROL Tablets or Oral Solution. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered .
Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Dosage and Administration (2.2 ), Warnings and Precautions (5.2 , 5.4 ), Overdosage (10 )].
5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of DEMEROL Tablets or Oral Solution with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, 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 (7 )] .
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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).
If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2 ), Warnings and Precautions (5.4 )].
Advise both patients and caregivers about the risks of respiratory depression and sedation when DEMEROL Tablets or Oral Solution is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7 )] .
5.5 Neonatal Opioid Withdrawal Syndrome
Use of DEMEROL Tablets and Oral Solution 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 appropriate treatment will be available [see Use in Specific Populations (8.1 )] .
5.000000000000000e+00 6 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. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:
- Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
- Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medications are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG .
- Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
- Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.
To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com . The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint .
5.000000000000000e+00 7 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 (CYP3A4) Inhibitors and Inducers
Concomitant use of DEMEROL Tablets or Oral Solution with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of meperidine and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of DEMEROL Tablets or Oral Solution is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in DEMEROL Tablets or Oral Solution-treated patients may increase meperidine plasma concentrations and prolong opioid adverse reactions. When using DEMEROL and Oral Solution with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in DEMEROL Tablets and Oral Solution-treated patients, evaluate patients at frequent intervals and consider dosage reduction of DEMEROL Tablets and Oral Solution until stable drug effects are achieved .
Concomitant use of DEMEROL Tablets or Oral Solution with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease meperidine plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to meperidine. When using DEMEROL Tablets and Oral Solution with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7 )].
5.000000000000000e+00 8 Fatal Interaction with Monoamine Oxidase Inhibitors (MAOIs)
Meperidine is contraindicated in patients who are receiving monoamine oxidase inhibitors (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 pre-existing hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of acute narcotic overdose. Serotonin syndrome with agitation, hyperthermia, diarrhea, tachycardia, sweating, tremors and impaired consciousness may also occur. In other reactions the predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension.
Do not use DEMEROL Tablets and Oral Solution in patients taking MAOIs or within 14 days of stopping such treatment.
Intravenous hydrocortisone or prednisolone has 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.
5.000000000000000e+00 9 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 (9.3 )]. 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 (safety switching the patient to a different opioid moiety) [see Dosage and Administration (2.6 ); Warnings and Precautions (5.17 )].
5.000000000000000e+00 10 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of DEMEROL Tablets or Oral Solution with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), St John’s wort, tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7 )] . This may occur within the recommended dosage range.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue DEMEROL Tablets or Oral Solution if serotonin syndrome is suspected.
5.11 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of DEMEROL Tablets or Oral Solution 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 : DEMEROL Tablets or Oral Solution-treated 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 including apnea, even at recommended dosages of DEMEROL Tablets or Oral Solution [see Warnings and Precautions (5.2 )].
Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2 )] .
Regularly evaluate patients, particularly when initiating and titrating DEMEROL Tablets and Oral Solution and when DEMEROL Tablets and Oral Solution are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3 )], Drug Interactions (7 )] . Alternatively, consider the use of non-opioid analgesics in these patients.
5.000000000000000e+00 1 2 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.
5.000000000000000e+00 1 3 Severe Hypotension
DEMEROL Tablets and Oral Solution 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) [see Drug Interactions (7 )]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of DEMEROL Tablets or Oral Solution. In patients with circulatory shock, DEMEROL Tablets and Oral Solution may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of DEMEROL Tablets or Oral Solution in patients with circulatory shock.
5.000000000000000e+00 1 4 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 CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), DEMEROL Tablets and Oral Solution may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with DEMEROL Tablets or Oral Solution.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of DEMEROL Tablets or Oral Solution in patients with impaired consciousness or coma.
5.000000000000000e+00 1 5 Risks of Use in Patients with Gastrointestinal Conditions
DEMEROL Tablets and Oral Solution are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The meperidine in DEMEROL Tablets and Oral Solution may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
5.000000000000000e+00 1 6 Increased Risk of Seizures in Patients with Seizure Disorders
The meperidine in DEMEROL Tablets and Oral Solution may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. If dosage is escalated substantially above recommended levels because of tolerance development, seizures may occur in individuals without a history of seizures disorders. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during DEMEROL Tablets and Oral Solution therapy. Use of DEMEROL Tablets and Oral Solution for an extended period of time may increase the risk of toxicity (e.g., seizures) from the accumulation of the meperidine metabolite, normeperidine.
5.000000000000000e+00 1 7 Withdrawal
Do not abruptly discontinue DEMEROL Tablets or Oral Solution in a patient physically dependent on opioids. When discontinuing DEMEROL Tablets or Oral Solution in a physically dependent patient, gradually taper the dosage. Rapid tapering of meperidine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [ see Dosage and Administration (2.6 ), Drug Abuse and Dependence (9 )] .
Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including DEMEROL Tablets and Oral Solution. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [ see Drug Interactions (7 )] .
5.000000000000000e+00 1 8 Risks of Driving and Operating Machinery
DEMEROL Tablets and Oral Solution 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 DEMEROL Tablets or Oral Solution and know how they will react to the medication.
5.000000000000000e+00 1 9 Risks in Patients with Pheochromocytoma
In patients with pheochromocytoma, DEMEROL Tablets and Oral Solution has been reported to provoke hypertension.
5.000000000000000e+00 20 Risk of Use in Patients with Atrial Flutter and Other Supraventricular Tachycardias
Meperidine should be used with caution in patients with atrial flutter and other supraventricular tachycardias because of a possible vagolytic action which may produce a significant increase in the ventricular response rate.
6 ADVERSE REACTIONS
The following serious adverse reactions are described, or described in greater detail, in other sections:
- Addiction, Abuse, and Misuse [see Warnings and Precautions (5.2 )]
- Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3 )]
- Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.4 )]
- Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5 )]
- Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.9 )]
- Serotonin Syndrome [see Warnings and Precautions (5.10 )]
- Adrenal Insufficiency [see Warnings and Precautions (5.12 )]
- Severe Hypotension [see Warnings and Precautions (5.13 )]
- Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.15 )]
- Seizures [see Warnings and Precautions (5.16 )]
- Withdrawal [see Warnings and Precautions (5.17 )]
The following adverse reactions associated with the use of meperidine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The major hazards of meperidine, as with other opioid analgesics, are respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest.
The most frequently observed adverse reactions included lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not experiencing severe pain. In such individuals, lower doses are advisable. Some adverse reactions in ambulatory patients may be alleviated if the patient lies down.
Other adverse reactions include:
Nervous System: Mood changes (e.g., euphoria, dysphoria), weakness, headache, agitation, tremor, involuntary muscle movements (e.g., muscle twitches, myoclonus), severe convulsions, transient hallucinations and disorientation, confusion, delirium, visual disturbances.
Gastrointestinal: Dry mouth, constipation, biliary tract spasm.
Cardiovascular: Flushing of the face, tachycardia, bradycardia, palpitation, hypotension [ see Warnings and Precautions (5.7 ) ] , syncope.
Genitourinary: Urinary retention.
Allergic: Pruritus, urticaria, other skin rashes, wheal and flare over the vein with intravenous injection. Hypersensitivity reactions, anaphylaxis.
Histamine release leading to hypotension and/or tachycardia, flushing, sweating, and pruritus.
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 (12.2 )] .
Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [ see Warnings and Precautions (5.9 ) ].
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).
To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-866-982-5438 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
7 DRUG INTERACTIONS
Table 1 includes clinically significant drug interactions with DEMEROL Tablets and Oral Solution.
| Monoamine Oxidase Inhibitors (MAOIs) | |
| Clinical Impact: | 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. Serotonin syndrome with agitation, hyperthermia, diarrhea, tachycardia, sweating, tremors and impaired consciousness may also occur. In other reactions the predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension. |
| Intervention: | 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.) |
| Examples: | phenelzine, tranylcypromine, linezolid |
| Inhibitors of CYP3A4 and CYP2B6 | |
| Clinical Impact: | 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 [see Warnings and Precautions (5.6 )] . After stopping a CYP3A4 or CYP2B6 inhibitor, as the effects of the inhibitor decline, the meperidine plasma concentration will decrease [ see Clinical Pharmacology (12.3 ) ] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to meperidine. |
| Intervention: | If concomitant use is necessary, consider dosage reduction of DEMEROL Tablets and Oral Solution until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 or CYP2B6 inhibitor is discontinued, consider increasing the DEMEROL Tablets and Oral Solution dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. |
| Examples | Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) |
| CYP3A4 and CYP2B6 Inducers | |
| Clinical Impact: | The concomitant use of DEMEROL Tablets or Oral Solution and CYP3A4 or CYP2B6 inducers can decrease the plasma concentration of meperidine [ see Clinical Pharmacology (12.3 ) ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to meperidine [ see Warnings and Precautions (5.6 ) ] . After stopping a CYP3A4 or CYP2B6 inducer, as the effects of the inducer decline, the meperidine plasma concentration will increase [ see Clinical Pharmacology (12.3 ) ] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. |
| Intervention: | If concomitant use is necessary, consider increasing the DEMEROL Tablets and Oral Solution dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. If a CYP3A4 or CYP2B6 inducer is discontinued, consider DEMEROL Tablets and Oral Solution dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. |
| Examples: | Rifampin, carbamazepine, phenytoin |
| Benzodiazepines and Other Central Nervous System (CNS) Depressants | |
| Clinical Impact: | 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. |
| Intervention: | 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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2 ), Warnings and Precautions (5.2 , 5.4 , 5.7 )]. |
| Examples: | Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol |
| Serotonergic Drugs | |
| Clinical Impact: | The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.10 ]. |
| Intervention: | If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue DEMEROL Tablets and Oral Solution if serotonin syndrome is suspected. |
| Examples: | 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 | |
| Clinical Impact: | May reduce the analgesic effect of DEMEROL Tablets or Oral Solution and/or precipitate withdrawal symptoms. |
| Intervention: | Avoid concomitant use. |
| Examples: | butorphanol, nalbuphine, pentazocine, buprenorphine |
| Muscle Relaxants | |
| Clinical Impact: | Meperidine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
| Intervention: | Because respiratory depression that may be greater than otherwise expected, decrease the dosage of DEMEROL Tablets and 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 [see Dosage and Administration (2.2 ), Warnings and Precautions (5.4 , 5.7 )]. |
| Diuretics | |
| Clinical Impact: | Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
| Intervention: | Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
| Anticholinergic Drugs | |
| Clinical Impact: | The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
| Intervention: | Evaluate patients for signs of urinary retention or reduced gastric motility when DEMEROL Tablets and Oral Solution is used concomitantly with anticholinergic drugs. |
| Acyclovir | |
| Clinical Impact: | The concomitant use of acyclovir may increase the plasma concentrations of meperidine and its metabolite, normeperidine. |
| Intervention: | If concomitant use of acyclovir and DEMEROL Tablets and Oral Solution is necessary, evaluate patients for respiratory depression and sedation at frequent intervals. |
| Cimetidine | |
| Clinical Impact: | The concomitant use of cimetidine may reduce the clearance and volume of distribution of meperidine also the formation of the metabolite, normeperidine, in healthy subjects. |
| Intervention: | If concomitant use of cimetidine and DEMEROL Tablets and Oral Solution is necessary, evaluate patients for respiratory depression and sedation at frequent intervals. |
11 DESCRIPTION
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 C 15 H 21 NO 2 ·HCl, and it has the following chemical structure.
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.
12 CLINICAL PHARMACOLOGY
12.1 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.
12.2 Pharmacodynamics
Effects on the Central Nervous System
Meperidine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.
Meperidine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Effects on the Gastrointestinal Tract and Other Smooth Muscle
Meperidine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Effects on the Cardiovascular System
Meperidine produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6 )] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6 )] .
Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
Concentration–Efficacy Relationships
The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioids agonist opioids. The minimum effective analgesic concentration of meperidine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1 ) ] .
Concentration–Adverse Reaction Relationships
There is a relationship between increasing meperidine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 )] .
12.3 Pharmacokinetics
Absorption
Oral bioavailability of meperidine is approximately 50%.
Elimination
The elimination half-life is 3 to 8 hours in healthy volunteers. The only bioactive metabolite is normeperidine which has an average elimination half-life of 20.6 hours.
Metabolism
Meperidine is metabolized through biotransformation. In vitro data show meperidine is metabolized to normeperidine in liver mainly by CYP3A4 and CYP2B6.
Excretion
Meperidine and normeperidine are excreted by kidneys.
Age
In clinical studies reported in the literature, changes in several pharmacokinetic parameters with increasing age have been observed. The initial volume of distribution and steady-state volume of distribution may be higher in elderly patients than in younger patients. The free fraction of meperidine in plasma may be higher in patients over 45 years of age than in younger patients.
Hepatic impairment
The elimination half-life is 3 to 8 hours in healthy volunteers and is 1.3 to 2 times greater in post-operative or cirrhotic patients.
Drug Interactions Studies
Phenytoin
The hepatic metabolism of meperidine may be enhanced by phenytoin. Concomitant administration resulted in reduced half-life and bioavailability with increased clearance of meperidine in healthy subjects; however, blood concentrations of normeperidine were increased [ s ee Drug Interaction s (7 ) ] .
Ritonavir
Plasma concentrations of the active metabolite normeperidine may be increased by ritonavir [ s ee Drug Interactions (7 )].
Acyclovir
Plasma concentrations of meperidine and its metabolite, normeperidine, may be increased by acyclovir [ s ee Drug Interactions (7 )].
Cimetidine
Cimetidine reduced the clearance and volume of distribution of meperidine and also the formation of the metabolite, normeperidine, in healthy subjects [ s ee Drug Interactions (7 )].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis , Impairment of Fertility
Carcinogenesis
Long-term studies in animals to evaluate the carcinogenic potential of meperidine have not been conducted.
Mutagenesis
Studies to in animals to evaluate the mutagenic potential of meperidine have not been conducted.
Impairment of Fertility
Studies to determine the effect of meperidine on fertility have not been conducted.
16 HOW SUPPLIED/STORAGE AND HANDLING
DEMEROL (meperidine hydrochloride) Tablets 50 mg, are white, round, convex scored tablets debossed with “W” on one side and “D” over “35” on the other, and are supplied as: HDPE plastic bottles of 100 (NDC Number 30698-335-01)
DEMEROL (meperidine hydrochloride) Tablets 100 mg, are white, round, convex scored Tablets debossed with “W” on one side and “D” over “37” on the other, and are supplied as: HDPE plastic bottles of 100 (NDC Number 30698-337-01)
DEMEROL (meperidine hydrochloride) Oral Solution, 50mg per 5mL (10 mg/mL) is non-alcoholic, banana-flavored syrup, and is supplied in 16 fl. oz. bottles (NDC Number 30698-332-16).
Store at 77°F (25°C); excursions permitted to 59° to 86°F (15° to 30°C) [See USP Controlled Room Temperature].
Store DEMEROL Tablets and Oral Solution securely and dispose of properly.
12.1 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.
