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warnings and cautions
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. ( 5.7 ) Serotonin Syndrome with Concomitant Use of Serotonergic Drug s: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue Meperidine Hydrochloride Injection if serotonin syndrome is suspected. ( 5.8 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. ( 5.9 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.10 ) Severe Hypotension : Monitor during dosage initiation and titration. Avoid use of Meperidine Hydrochloride Injection in patients with circulatory shock. ( 5.11 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of Meperidine Hydrochloride Injection in patients with impaired consciousness or coma. ( 5.12 ) 5.1 Addiction, Abuse, and Misuse Meperidine Hydrochloride Injection contains meperidine, a Schedule II controlled substance. As an opioid, Meperidine Hydrochloride Injection 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 Injection. 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 Injection, and monitor all patients receiving Meperidine Hydrochloride Injection 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 Injection, but use in such patients necessitates intensive counseling about the risks and proper use of Meperidine Hydrochloride Injection along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. 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. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [ see Overdosage (10) ]. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Meperidine Hydrochloride Injection, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Meperidine Hydrochloride Injection are essential [ see Dosage and Administration (2.3) ]. Overestimating the Meperidine Hydrochloride Injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. 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 (2.1) ]. 5.3 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 Injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non- benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7) ] . If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Monitor 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 Injection 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) ] . 5.4 Neonatal Opioid Withdrawal Syndrome Use of Meperidine Hydrochloride Injection 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 management by neonatology experts will be available at delivery [ see Use in Specific Populations (8.1) ]. 5.5 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of Meperidine Hydrochloride Injection 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 [ see Warnings and Precautions (5.2) ], particularly when an inhibitor is added after a stable dose of Meperidine Hydrochloride Injection is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Meperidine Hydrochloride Injection-treated patients may increase meperidine plasma concentrations and prolong opioid adverse reactions. When using Meperidine Hydrochloride Injection with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Meperidine Hydrochloride Injection-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Meperidine Hydrochloride Injection until stable drug effects are achieved [see Drug Interactions (7) ] . Concomitant use of Meperidine Hydrochloride Injection 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 Injection 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 Fatal Interaction with Monoamine Oxidase Inhibitors Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or those who have recently received such agents. Therapeutic doses of meperidine have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear but may be related to a pre-existing hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of acute narcotic overdose. Serotonin syndrome with agitation, hyperthermia, diarrhea, tachycardia, sweating, tremors and impaired consciousness may also occur. In other reactions the predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension. Do not use Meperidine Hydrochloride Injection 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. 5.7 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) , Warnings and Precautions (5.15) ] . 5.8 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 with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), 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 MAO inhibitors, 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 Injection if serotonin syndrome is suspected. 5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Meperidine Hydrochloride Injection 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 Injection-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 Injection [ see Warnings and Precautions (5.2) ] . Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [ see Warnings and Precautions (5.2) ] . Monitor such patients closely, particularly when initiating and titrating Meperidine Hydrochloride Injection and when Meperidine Hydrochloride Injection is given concomitantly with other drugs that depress respiration [ see Warnings and Precautions (5.2) ] . Alternatively, consider the use of non-opioid analgesics in these patients. 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 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. 5.11 Severe Hypotension Meperidine Hydrochloride Injection 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 Injection. In patients with circulatory shock, Meperidine Hydrochloride Injection may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Meperidine Hydrochloride Injection 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 CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Meperidine Hydrochloride Injection may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for worsening of signs of increasing intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Meperidine Hydrochloride Injection. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Meperidine Hydrochloride Injection in patients with impaired consciousness or coma. 5.13 Risks of Use in Patients with Gastrointestinal Conditions Meperidine Hydrochloride Injection is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The meperidine in Meperidine Hydrochloride Injection 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 Injection 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. Monitor patients with a history of seizure disorders for worsened seizure control during Meperidine Hydrochloride Injection therapy. Prolonged meperidine use may increase the risk of toxicity (e.g., seizures) from the accumulation of the meperidine metabolite, normeperidine. 5.15 Withdrawal 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 Injection. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms. When discontinuing Meperidine Hydrochloride Injection, gradually taper the dosage [ see Dosage and Administration (2.4) ]. Do not abruptly discontinue Meperidine Hydrochloride Injection [ see Drug Abuse and Dependence (9.3) ]. 5.16 Risks of Driving and Operating Machinery Meperidine Hydrochloride Injection 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 Injection and know how they will react to the medication. 5.17 Risks in Patients with Pheochromocytoma In patients with pheochromocytoma, meperidine has been reported to provoke hypertension. 5.18 Risk of Use in Patients with Atrial Flutter and Other Supraventricular Tachycardias Meperidine Hydrochloride Injection 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. 5.19 Intravenous Use If necessary, meperidine may be given intravenously, but the injection should be given very slowly, preferably in the form of a diluted solution. Rapid intravenous injection of narcotic analgesics, including meperidine, increases the incidence of adverse reactions; severe respiratory depression, apnea, hypotension, peripheral circulatory collapse, and cardiac arrest have occurred. Meperidine should not be administered intravenously unless a narcotic antagonist and the facilities for assisted or controlled respiration are immediately available. When meperidine is given parenterally, especially intravenously, the patient should be lying down.