MEPERIDINE HYDROCHLORIDE tablet

Meperidine Hydrochloride by

Drug Labeling and Warnings

Meperidine Hydrochloride by is a Prescription medication manufactured, distributed, or labeled by EPIC PHARMA, LLC. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • BOXED WARNING (What is this?)

    WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION

    STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL

    INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450

    3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES

    OR OTHER CNS DEPRESSANTS; and MONOAMINE OXIDASE INHIBITORS (MAOIs)

    INTERACTIONS

    Addiction, Abuse, and Misuse

    Meperidine hydrochloride tablets exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing meperidine hydrochloride tablets, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

    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 REMS for these products [see Warnings and Precautions (5.2)]. 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

    • complete a REMS-compliant education program,
    • counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
    • emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
    • consider other tools to improve patient, household, and community safety.

    Life-Threatening Respiratory Depression

    Serious, life-threatening, or fatal respiratory depression may occur with use of meperidine hydrochloride tablets. Monitor for respiratory depression, especially during initiation of meperidine hydrochloride tablets or following a dose increase [see Warnings and Precautions (5.3)].

    Accidental Ingestion

    Accidental ingestion of meperidine hydrochloride tablets, especially by children, can result in a fatal overdose of meperidine [see Warnings and Precautions (5.3)].

    Neonatal Opioid Withdrawal Syndrome

    Prolonged use of meperidine hydrochloride tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.4)].

    Cytochrome P450 3A4 (CYP3A4) Interaction

    The concomitant use of meperidine hydrochloride tablets 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 meperidine hydrochloride tablets and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.5), Drug Interactions (7)].

    Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

    Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.6), Drug Interactions (7)].

    • Reserve concomitant prescribing of meperidine hydrochloride tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate
    • Limit dosages and durations to the minimum required.
    • Follow patients for signs and symptoms of respiratory depression and sedation.

    Concomitant use of Meperidine Hydrochloride Tablets with Monoamine Oxidase Inhibitors (MAOIs)

    Concomitant use of meperidine hydrochloride tablets with monoamine oxidase inhibitors (MAOIs) can result in coma, severe respiratory depression, cyanosis, and hypotension. Use of meperidine hydrochloride tablets with MAOIs within last 14 days is contraindicated [see Contraindications (4), Warnings and Precautions (5.7), Drug Interactions (7)].

  • 1 INDICATIONS AND USAGE

    Meperidine hydrochloride tablets 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, even at recommended doses [see Warnings and Precautions (5.1)], reserve meperidine hydrochloride tablets 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.

    Meperidine hydrochloride tablets should not be used for treatment of chronic pain. Prolonged meperidine hydrochloride tablets use may increase the risk of toxicity (e.g. seizures) from the accumulation of the meperidine metabolite, normeperidine.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Important Dosage and Administration Instructions

    Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

    Initiate the dosing regimen for each patient individually, taking into account the patient’s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].

    Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with meperidine hydrochloride tablets and adjust the dosage accordingly [see Warnings and Precautions (5.3)].

    2.2 Initial Dosage

    Adults

    Initiate treatment with meperidine hydrochloride tablets in a dosing range of 50 mg to 150 mg orally, every 3 or 4 hours as needed for pain.

    Pediatric Patients

    Initiate treatment with meperidine hydrochloride tablets 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 necessary.

    2.3 Dosage Modification with Concomitant Use with Phenothiazines

    The dose of meperidine should be reduced by 25 to 50% when administered concomitantly with phenothiazines and other tranquilizers.

    2.4 Titration and Maintenance of Therapy

    Individually titrate meperidine hydrochloride tablets 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 meperidine by tapering the dose and select an alternate analgesic.

    Continually reevaluate patients receiving meperidine to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)]. 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 meperidine hydrochloride tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

    2.5 Safe Reduction or Discontinuation of Meperidine Hydrochloride Tablets

    Do not abruptly discontinue meperidine hydrochloride tablets 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 meperidine hydrochloride tablets, there are a variety of factors that should be considered, including the dose of meperidine hydrochloride tablets 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 meperidine hydrochloride tablets 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, monitor 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 a long duration 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 [see Warnings and Precautions (5.15), Drug Abuse and Dependence (9)].

  • 3 DOSAGE FORMS AND STRENGTHS

    • 50 mg tablet (white, round biconvex tablets, debossed “Є” above bisect and “50” below bisect on one side, plain on the other side)
    • 100 mg tablet (white, round biconvex tablets, debossed “Є51” on one side and bisected on the other side)
  • 4 CONTRAINDICATIONS

    Meperidine hydrochloride tablets are contraindicated in patients with:

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Addiction, Abuse, and Misuse

    Meperidine hydrochloride tablets contain meperidine, a Schedule II controlled substance. As an opioid, meperidine hydrochloride tablets exposes 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 meperidine hydrochloride tablets. 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 meperidine hydrochloride tablets, and monitor all patients receiving meperidine hydrochloride tablets 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 meperidine hydrochloride tablets, but use in such patients necessitates intensive counseling about the risks and proper use of meperidine hydrochloride tablets along with intensive monitoring for signs of addiction, abuse, and misuse.

    Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing meperidine hydrochloride tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. 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.

    Meperidine hydrochloride 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.

    5.2 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 medicines 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.

    5.3 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 (CO2) 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 meperidine hydrochloride tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of meperidine hydrochloride tablets.

    To reduce the risk of respiratory depression, proper dosing and titration of meperidine hydrochloride tablets are essential [see Dosage and Administration (2)]. Overestimating the meperidine hydrochloride tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

    Accidental ingestion of meperidine hydrochloride tablets, especially by children, can result in respiratory depression and death due to an overdose of meperidine.

    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 (2.5)].

    5.4 Neonatal Opioid Withdrawal Syndrome

    Prolonged use of meperidine hydrochloride tablets 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 a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

    5.5 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 (CYP3A4) Inhibitors and Inducers

    Concomitant use of meperidine hydrochloride tablets 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 meperidine hydrochloride tablets is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in meperidine hydrochloride tablets-treated patients may increase meperidine plasma concentrations and prolong opioid adverse reactions. When using meperidine with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in meperidine hydrochloride tablets-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of meperidine hydrochloride tablets until stable drug effects are achieved [see Drug Interactions (7)].

    Concomitant use of meperidine hydrochloride tablets 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 meperidine hydrochloride tablets with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor 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)].

    5.6 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

    Profound sedation, respiratory depression, coma, and death may result from the concomitant use of meperidine hydrochloride tablets with benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). 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. Follow patients closely for signs and symptoms of respiratory depression and sedation.

    Advise both patients and caregivers about the risks of respiratory depression and sedation when meperidine hydrochloride tablets are 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), Patient Counseling Information (17)].

    5.7 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 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.

    Do not use meperidine hydrochloride tablets 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.

    5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

    The use of meperidine hydrochloride tablets 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: Meperidine hydrochloride tablets-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of meperidine hydrochloride tablets [see Warnings and Precautions (5.3)].

    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 (5.3)].

    Monitor such patients closely, particularly when initiating and titrating meperidine hydrochloride tablets and when meperidine hydrochloride tablets are given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

    5.9 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

    Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of meperidine hydrochloride tablets 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 meperidine hydrochloride tablets if serotonin syndrome is suspected.

    5.10 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 nonspecific 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.

    5.11 Severe Hypotension

    Meperidine hydrochloride tablets 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)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of meperidine hydrochloride tablets. In patients with circulatory shock, meperidine hydrochloride tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of meperidine hydrochloride tablets in patients with circulatory shock.

    5.12 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 CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), meperidine may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with meperidine hydrochloride tablets.

    Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of meperidine hydrochloride tablets in patients with impaired consciousness or coma.

    5.13 Risks of Use in Patients with Gastrointestinal Conditions

    Meperidine hydrochloride tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

    The meperidine in meperidine hydrochloride tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

    5.14 Increased Risk of Seizures in Patients with Seizure Disorders

    The meperidine in meperidine hydrochloride tablets 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. Monitor patients with a history of seizure disorders for worsened seizure control during meperidine hydrochloride tablets therapy. Prolonged meperidine use may increase the risk of toxicity (e.g., seizures) from the accumulation of the meperidine metabolite, normeperidine.

    5.15 Withdrawal

    Do not abruptly discontinue meperidine hydrochloride tablets in a patient physically dependent on opioids. When discontinuing meperidine hydrochloride tablets 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 (2.5), 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 meperidine hydrochloride tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].

    5.16 Risks of Driving and Operating Machinery

    Meperidine hydrochloride tablets 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 meperidine hydrochloride tablets and know how they will react to the medication [see Patient Counseling Information (17)].

    5.17 Risks in Patients with Pheochromocytoma

    In patients with pheochromocytoma, meperidine hydrochloride tablets has been reported to provoke hypertension.

    5.18 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:

    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 chronic use of opioids [see Clinical Pharmacology (12.2)].

    To report SUSPECTED ADVERSE REACTIONS, contact Epic Pharma, LLC at 1-888-374-2791 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

  • 7 DRUG INTERACTIONS

    Table 1 includes clinically significant drug interactions with meperidine hydrochloride tablets.

    Table 1: Clinically Significant Drug Interactions with Meperidine Hydrochloride Tablets

    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 meperidine hydrochloride tablets 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 meperidine hydrochloride tablets 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 meperidine hydrochloride tablets and CYP2B6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of meperidine hydrochloride tablets is achieved [see Warnings and Precautions (5.5)].

    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 meperidine hydrochloride tablets 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 meperidine hydrochloride tablets dosage until stable drug effects are achieved. Monitor 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 meperidine hydrochloride tablets 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 (5.5)].

    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 meperidine hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 or CYP2B6 inducer is discontinued, consider meperidine hydrochloride tablets dosage reduction and monitor for signs of respiratory depression.

    Examples:

    Rifampin, carbamazepine, phenytoin

    Benzodiazepines and Other Central Nervous System (CNS) Depress

    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. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].

    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 (5.9)].

    Intervention:

    If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue meperidine hydrochloride tablets 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 meperidine hydrochloride tablets 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:

    Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of meperidine hydrochloride tablets and/or the muscle relaxant as necessary.

    Diuretics

    Clinical Impact:

    Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

    Intervention:

    Monitor 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:

    Monitor patients for signs of urinary retention or reduced gastric motility when meperidine hydrochloride tablets 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 meperidine hydrochloride tablets is necessary, monitor 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 meperidine hydrochloride tablets is necessary, monitor patients for respiratory depression and sedation at frequent intervals.
  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)]. Available data with meperidine hydrochloride tablets are insufficient to inform a drug-associated risk for major birth defects and miscarriage. 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].

    Adverse outcomes in pregnancy can occur regardless of the health of the mother or the use of medications. 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

    Prolonged use of opioid analgesics 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 (5.4)].

    Labor and Delivery

    Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. Resuscitation may be required [see Overdosage (10)]. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Meperidine hydrochloride tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including meperidine hydrochloride tablets, 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 meperidine hydrochloride tablets and any potential adverse effects on the breastfed infant from meperidine hydrochloride tablets or from the underlying maternal condition.

    Clinical Considerations

    Monitor infants exposed to meperidine hydrochloride tablets 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.

    8.3 Females and Males of Reproductive Potential

    Infertility

    Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

    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 meperidine hydrochloride tablets 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 meperidine hydrochloride tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6, 5.8)].

    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 monitor 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 meperidine hydrochloride tablets slowly in patients with hepatic impairment and monitor closely 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 meperidine hydrochloride tablets slowly in patients with renal impairment and monitor closely for signs of central nervous system and respiratory depression.

  • 9 DRUG ABUSE AND DEPENDENCE

    9.1 Controlled Substance

    Meperidine hydrochloride tablets contain meperidine, a Schedule II controlled substance.

    9.2 Abuse

    Meperidine hydrochloride tablets contain meperidine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Meperidine hydrochloride tablets can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

    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.

    Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

    Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

    “Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

    Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

    Meperidine hydrochloride tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

    Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

    Risks Specific to Abuse of Meperidine Hydrochloride Tablets

    Meperidine hydrochloride tablets are for oral use only. Abuse of meperidine hydrochloride tablets poses a risk of overdose and death. Meperidine hydrochloride tablets have been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product. The risk is increased with concurrent use of meperidine hydrochloride tablets with alcohol and other central nervous system depressants. In addition, parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

    9.3 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.

    Do not abruptly discontinue meperidine hydrochloride tablets in a patient physically dependent on opioids. Rapid tapering of meperidine hydrochloride tablets in a patient physically dependent on opioids may lead to 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.

    When discontinuing meperidine hydrochloride tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of meperidine hydrochloride tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5), Warnings and Precautions (5.15)].

    Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

  • 10 OVERDOSAGE

    Clinical Presentation

    Acute overdose with meperidine hydrochloride tablets 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 [see Clinical Pharmacology (12.2)].

    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.

    The opioid antagonists, naloxone or nalmefene, 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. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to meperidine overdose.

    Because the duration of opioid reversal is expected to be less than the duration of action of meperidine in meperidine hydrochloride tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

    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.

  • 11 DESCRIPTION

    Meperidine hydrochloride tablet is an opioid agonist, 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 C15H21NO2HCl, and it has the following chemical structure.

    chemistry structure.jpg

    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 inactive ingredients in meperidine hydrochloride tablets include: pregelatinized starch, microcrystalline cellulose, lactose monohydrate, silicon dioxide and stearic acid.

  • 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.

    Chronic use of opioids 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 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 potent 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 postoperative 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 [see Drug Interactions (7)].

    Ritonavir

    Plasma concentrations of the active metabolite normeperidine may be increased by ritonavir [see Drug Interactions (7)].

    Acyclovir

    Plasma concentrations of meperidine and its metabolite, normeperidine, may be increased by acyclovir [see 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 [see 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 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

    Meperidine Hydrochloride Tablets USP, 50 mg are white, round biconvex tablets, debossed “Є” above bisect and “50” below bisect on one side, plain on the other side, available in bottles of 30, NDC: 42806-050-30 and in bottles of 100, NDC: 42806-050-01.

    Meperidine Hydrochloride Tablets USP, 100 mg are white, round biconvex tablets, debossed “Є51” on one side and bisected on the other side, available in bottles of 100, NDC: 42806-051-01.

    Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

    Store at 20° to 25° C (68° to 77° F) [See USP Controlled Room Temperature].

    Store meperidine hydrochloride tablets securely and dispose of properly [see Patient Counseling Information (17)].

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling (Medication Guide).

    Storage and Disposal

    Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store meperidine hydrochloride tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9)]. Inform patients that leaving meperidine hydrochloride tablets unsecured can pose a deadly risk to others in the home.

    Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused meperidine hydrochloride tablets should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

    Addiction, Abuse, and Misuse

    Inform patients that the use of meperidine hydrochloride tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share meperidine hydrochloride tablets with others and to take steps to protect meperidine hydrochloride tablets from theft or misuse.

    Life-Threatening Respiratory Depression

    Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting meperidine hydrochloride tablets or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.3)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

    Accidental Ingestion

    Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3)].

    Interactions with Benzodiazepines and Other CNS Depressants

    Inform patients and caregivers that potentially fatal additive effects may occur if meperidine hydrochloride tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.6), Drug Interactions (7)]

    MAOI Interaction

    Inform patients not to take meperidine hydrochloride tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking meperidine hydrochloride tablets [see Warnings and Precautions (5.7), Drug Interactions (7)].

    Serotonin Syndrome

    Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.9), Drug Interactions (7)].

    Adrenal Insufficiency

    Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.10)].

    Important Administration Instructions

    Instruct patients how to properly take meperidine hydrochloride tablets.

    • Advise patients not to adjust the dose of meperidine hydrochloride tablets without consulting with a physician or other healthcare professional.
    • If patients have been receiving treatment with meperidine hydrochloride tablets for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose as abrupt discontinuation of the medication could precipitate withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the medication [see Dosage and Administration (2.5)].

    Hypotension

    Inform patients that meperidine hydrochloride tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.11)].

    Anaphylaxis

    Inform patients that anaphylaxis has been reported with ingredients contained in meperidine hydrochloride tablets. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

    Pregnancy

    Neonatal Opioid Withdrawal Syndrome

    Inform female patients of reproductive potential that prolonged use of meperidine hydrochloride tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

    Embryo-Fetal Toxicity

    Inform female patients of reproductive potential that meperidine hydrochloride tablets can cause fetal harm and to inform healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

    Lactation

    Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2)].

    Infertility

    Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

    Driving or Operating Heavy Machinery

    Inform patients that meperidine hydrochloride tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.16)].

    Constipation

    Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6)].

    Distributed by:

    Epic Pharma, LLC

    Laurelton, NY 11413

    Rev. 10-2019-01

    MF050REV10/19

    OE1119

  • Medication Guide

    Medication Guide

    Meperidine Hydrochloride

    (me-PER-ih-deen HYE-droe-KLOR-ide)

    Tablets USP, CII

    Meperidine hydrochloride tablets are:

    • A strong prescription pain medicine that contain an opioid (narcotic) that is used to manage the relief short-term (acute) pain, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.
    • An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.

    Important information about meperidine hydrochloride tablets:

    • Get emergency help right away if you take too many meperidine hydrochloride tablets (overdose). When you first start taking meperidine hydrochloride tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
    • Taking meperidine hydrochloride tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
    • Never give anyone else your meperidine hydrochloride tablets. They could die from taking it. Selling or giving away meperidine hydrochloride tablets is against the law.
    • Store meperidine hydrochloride tablets away from children and in a safe location not accessible by others, including visitors to the home.

    Do not take meperidine hydrochloride tablets if you have:

    • severe asthma, trouble breathing, or other lung problems.
    • a bowel blockage or have narrowing of the stomach or intestines.
    • allergy to meperidine

    Before taking meperidine hydrochloride tablets, tell your healthcare provider if you have a history of:

    • head injury, seizures
    • liver, kidney, thyroid problems
    • pancreas or gallbladder problems
    • problems urinating
    • abuse of street or prescription drugs, alcohol addiction, or mental health problems.

    Tell your healthcare provider if you are:

    • pregnant or planning to become pregnant. Prolonged use of meperidine hydrochloride tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
    • breastfeeding. Meperidine passes into breast milk and may harm your baby.
    • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking meperidine hydrochloride tablets with certain other medicines can cause serious side effects that could lead to death.

    When taking meperidine hydrochloride tablets:

    • Do not change your dose. Take meperidine hydrochloride tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
    • Take your prescribed dose every 3 or 4 hours as necessary. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.
    • Call your healthcare provider if the dose you are taking does not control your pain.
    • If you have been taking meperidine hydrochloride tablets regularly, do not stop taking meperidine hydrochloride tablets without talking to your healthcare provider.
    • Dispose of expired, unwanted, or unused meperidine hydrochloride tablets by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.

    While taking meperidine hydrochloride tablets DO NOT:

    • Drive or operate heavy machinery, until you know how meperidine hydrochloride tablets affect you. Meperidine can make you sleepy, dizzy, or lightheaded.
    • Drink alcohol or use prescription or over-thecounter medicines that contain alcohol. Using products containing alcohol during treatment with meperidine hydrochloride tablets may cause you to overdose and die.

    The possible side effects of meperidine:

    • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.

    Get emergency medical help if you have:

    • trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

    These are not all the possible side effects of meperidine. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to fda.report

    Distributed by: Epic Pharma LLC, Laurelton, NY 11413, call Epic Pharma, LLC at 1-888-374-2791

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

    Rev. 10-2019-01

    OE2687

  • PACKAGE/LABEL PRINCIPAL DISPLAY PANEL – Meperidine 50 mg 30ct

    meperidine-50mg-30ct.jpg
  • PACKAGE/LABEL PRINCIPAL DISPLAY PANEL – Meperidine 100 mg 100ct

    meperidine-100mg-100ct.jpg
  • INGREDIENTS AND APPEARANCE
    MEPERIDINE HYDROCHLORIDE 
    meperidine hydrochloride tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 42806-050
    Route of AdministrationORALDEA ScheduleCII    
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    MEPERIDINE HYDROCHLORIDE (UNII: N8E7F7Q170) (MEPERIDINE - UNII:9E338QE28F) MEPERIDINE HYDROCHLORIDE50 mg
    Inactive Ingredients
    Ingredient NameStrength
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    STARCH, CORN (UNII: O8232NY3SJ)  
    STEARIC ACID (UNII: 4ELV7Z65AP)  
    Product Characteristics
    ColorWHITEScore2 pieces
    ShapeROUNDSize6mm
    FlavorImprint Code E50
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 42806-050-01100 in 1 BOTTLE; Type 0: Not a Combination Product05/05/2011
    2NDC: 42806-050-3030 in 1 BOTTLE; Type 0: Not a Combination Product01/01/2020
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA04033105/05/2011
    MEPERIDINE HYDROCHLORIDE 
    meperidine hydrochloride tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 42806-051
    Route of AdministrationORALDEA ScheduleCII    
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    MEPERIDINE HYDROCHLORIDE (UNII: N8E7F7Q170) (MEPERIDINE - UNII:9E338QE28F) MEPERIDINE HYDROCHLORIDE100 mg
    Inactive Ingredients
    Ingredient NameStrength
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    STARCH, CORN (UNII: O8232NY3SJ)  
    STEARIC ACID (UNII: 4ELV7Z65AP)  
    Product Characteristics
    ColorWHITEScore2 pieces
    ShapeROUNDSize8mm
    FlavorImprint Code E51
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 42806-051-01100 in 1 BOTTLE; Type 0: Not a Combination Product05/05/2011
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA04033105/05/2011
    Labeler - EPIC PHARMA, LLC (827915443)
    Registrant - EPIC PHARMA, LLC (827915443)
    Establishment
    NameAddressID/FEIBusiness Operations
    EPIC PHARMA, LLC827915443MANUFACTURE(42806-050, 42806-051)
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