Meperidine Hydrochloride

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 OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. ( 5.9 ) • Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue Meperidine Hydrochloride 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: 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 Meperidine Hydrochloride 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: Regularly evaluate for sedation and respiratory depression. Avoid use of Meperidine Hydrochloride 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 Meperidine 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 Meperidine 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 )]. 5.2 Addiction, Abuse, and Misuse Meperidine Hydrochloride Tablets and Oral Solution contain meperidine, a Schedule II controlled substance. As an opioid, Meperidine Hydrochloride 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 Meperidine Hydrochloride Tablets or Oral Solution. Addiction can occur at recommended doses and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and the risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions ( 6 )]. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Meperidine Hydrochloride Tablets and Oral Solution, and reassess all patients receiving Meperidine Hydrochloride 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 Meperidine Hydrochloride Tablets or Oral Solution, but use in such patients necessitates intensive counseling about the risks and proper use of Meperidine Hydrochloride Tablets and Oral Solution along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.4 )] . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Meperidine Hydrochloride 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. 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. 5.3 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 overdose reversal agents , 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 Meperidine Hydrochloride Tablets or Oral Solution, the risk is greatest during the initiation of therapy or following a dosage increase of Meperidine Hydrochloride Tablets or Oral Solution. To reduce the risk of respiratory depression, proper dosing and titration of Meperidine Hydrochloride Tablets and Oral Solution are essential [see Dosage and Administration ( 2 )]. Overestimating the meperidine dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of Meperidine Hydrochloride 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 an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.2 , 5.4 )]. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [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 Meperidine Hydrochloride Tablets or Oral Solution with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin] , and 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 recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.3 ), Overdosage ( 10 )]. Advise both patients and caregivers about the risks of respiratory depression and sedation when Meperidine Hydrochloride 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 Meperidine Hydrochloride Tablets or 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 )]. 5.6 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 . 5.7 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 (CYP3A4) Inhibitors and Inducers Concomitant use of Meperidine Hydrochloride 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 Meperidine Hydrochloride Tablets or Oral Solution is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Meperidine Hydrochloride Tablets or Oral Solution-treated patients may increase meperidine plasma concentrations and prolong opioid adverse reactions. When using Meperidine Hydrochloride Tablets and Oral Solution with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in meperidine-treated patients, evaluate patients at frequent intervals and consider dosage reduction of Meperidine Hydrochloride Tablets or Oral Solution until stable drug effects are achieved . Concomitant use of Meperidine Hydrochloride 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 Meperidine Hydrochloride Tablets or 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 )]. 5.8 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 opioid 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 or 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 opioid overdose reversal agents in the treatment of these reactions is unknown. 5.9 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 (safely switching the patient to a different opioid moiety) [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.17 )] . 5.10 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of meperidine hydrochloride 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) and can be fatal. 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 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 Meperidine Hydrochloride 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 Meperidine-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 Meperidine Hydrochloride Tablets or Oral Solution [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 )]. Regularly evaluate patients, particularly when initiating and titrating Meperidine Hydrochloride Tablets or Oral Solution and when Meperidine Hydrochloride 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. 5.12 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. 5.13 Severe Hypotension Meperidine Hydrochloride 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 Meperidine Hydrochloride Tablets or Oral Solution. In patients with circulatory shock, Meperidine Hydrochloride Tablets and Oral Solution may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Meperidine Hydrochloride Tablets or Oral Solution in patients with circulatory shock. 5.14 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), Meperidine Hydrochloride 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 Meperidine Hydrochloride Tablets or Oral Solution. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of meperidine in patients with impaired consciousness or coma. 5.15 Risks of Gastrointestinal Complications Meperidine Hydrochloride Tablets and Oral Solution are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The meperidine in Meperidine Hydrochloride 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 pancreatitis, for worsening symptoms. Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appro priate . 5.16 Seizures Meperidine may increase the risk of having a seizure in patients with or without a pre-existing seizure disorder. Prolonged use of meperidine may also increase the risk of seizure due to the accumulation of the meperidine metabolite, normeperidine. Frequently evaluate patients with a history of seizure disorder for worsening seizure control and advise patients and caregivers to get emergency medical help right away in the event of a known or suspected seizure. 5.17 Withdrawal Do not rapidly reduce or abruptly discontinue Meperidine Hydrochloride Tablets or Oral Solution in a patient physically dependent on opioids. When discontinuing Meperidine Hydrochloride 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 Meperidine Hydrochloride 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 )]. 5.18 Risks of Driving and Operating Machinery Meperidine Hydrochloride 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 Meperidine Hydrochloride Tablets or Oral Solution and know how they will react to the medication. 5.19 Risks in Patients with Pheochromocytoma In patients with pheochromocytoma, meperidine has been reported to provoke hypertension. 5.20 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.