FDA label 9c56afa2-bfa0-fa03-e053-2995a90a7437

WARNING: ADDICTION, ABUSE, AND MISUSE; 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 Meperidine hydrochloride tablets expose users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and monitor regularly for these behaviors and conditions. ( 5.2 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. ( 5.3 ) Accidental ingestion of meperidine hydrochloride tablets, especially by children, can result in a fatal overdose of meperidine. ( 5.3 ) 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. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. ( 5.4 ) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in fatal overdose of meperidine ( 5.5 , 7 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.6 , 7 ) 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 the last 14 days is contraindicated. ( 4 , 5.7 , 6 ) WARNING: ADDICTION, ABUSE, AND MISUSE; 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 See full prescribing information for complete boxed warning.

5 WARNINGS AND PRECAUTIONS Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration. ( 5.8 ) Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue meperidine hydrochloride tabletsif serotonin syndrome is suspected. ( 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 tabletsin 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 tabletsin patients with impaired consciousness or coma. ( 5.12 ) 5.2 Addiction, Abuse, and Misuse Meperidine hydrochloride tablets contain meperidine, a Schedule II controlled substance. As an opioid, meperidine hydrochloride tablets 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. 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. 5.3 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage ( 10 )] . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of 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 24-72 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. 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 hydrochloride tablets 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., non-benzodiazepine 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 has been used to treat severe reactions, with the addition of intravenous chlorpromazine in those cases exhibiting hypertension and hyperpyrexia. The usefulness and safety of narcotic antagonists in the treatment of these reactions is unknown. 5.8 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: M eperidine hydrochloride tablets -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 [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 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. 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), 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 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 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 CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), meperidine hydrochloride tablets 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. 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 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 due to competitive blocking of receptors. When discontinuing meperidine hydrochloride tablets in a physically-dependent patient, gradually taper the dosage [see Dosage and Administration ( 2.5 )] . Do not abruptly discontinue meperidine hydrochloride tablets in these patients [see Drug Abuse and Dependence ( 9 )] . 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 )] . In patients with pheochromocytoma, meperidine hydrochloride tablets have 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: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.2 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.3 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.6 )] Serotonin Syndrome [see Warnings and Precautions ( 5.8 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.10 )] Severe Hypotension [see Warnings and Precautions ( 5.11 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.13 )] Seizures [see Warnings and Precautions ( 5.14 )] Withdrawal [see Warnings and Precautions ( 5.15 )] 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 ( 5.6 )] , 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 Mikart, Inc. at 1-404-351-4510 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Most common adverse reactions were lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mikart, Inc. or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.