Meperidine Hydrochloride

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 ( 5.5 )] • Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.4 )] • Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.9 )] • Serotonin Syndrome [see Warnings and Precautions ( 5.10 )] • Adrenal Insufficiency [see Warnings and Precautions ( 5.12 )] • Severe Hypotension [see Warnings and Precautions ( 5.13 )] • Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.15 )] • Seizures [see Warnings and Precautions ( 5.16 )] • Withdrawal [see Warnings and Precautions ( 5.17 )] The following adverse reactions associated with the use of meperidine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The major hazards of meperidine, as with other opioid analgesics, are respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. The most frequently observed adverse reactions included lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not experiencing severe pain. In such individuals, lower doses are advisable. Some adverse reactions in ambulatory patients may be alleviated if the patient lies down. Other adverse reactions include: Nervous System : Mood changes (e.g., euphoria, dysphoria), weakness, headache, agitation, tremor, involuntary muscle movements (e.g., muscle twitches, myoclonus), severe convulsions, transient hallucinations and disorientation, confusion, delirium, visual disturbances. Gastrointestinal: Dry mouth, constipation, biliary tract spasm. Cardiovascular: Flushing of the face, tachycardia, bradycardia, palpitation, hypotension [see Warnings and Precautions ( 5.4 )], syncope. Genitourinary: Urinary retention. Allergic: Pruritus, urticaria, other skin rashes, wheal and flare over the vein with intravenous injection. Hypersensitivity reactions, anaphylaxis. Histamine release leading to hypotension and/or tachycardia, flushing, sweating, and pruritus. Serotonin Syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Androgen Deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time. Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.9 )]. Hypoglycemia: Case of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 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 Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS Meperidine Hydrochloride Tablets and Oral Solution are contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions ( 5.3 )]. • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.11 )]. • Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days of having taken an MAOI [see Drug Interactions ( 7 )]. • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.15 )]. • Hypersensitivity to meperidine or to any of the other ingredients of the product (e.g., anaphylaxis) [see Adverse Reactions ( 6 )]. • Significant respiratory depression. ( 4 ) • Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ) • Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days of having taken an MAOI. ( 4 ) • Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) • Hypersensitivity to meperidine or to any other ingredients of the product. ( 4 )

11 DESCRIPTION Meperidine hydrochloride is an opioid agonist, available as 50 mg and 100 mg tablets or 50 mg per 5 mL solution for oral administration. The chemical name is 4-Piperidinecarboxylic acid, 1-methyl-4-phenyl-,ethyl ester, hydrochloride. The molecular weight is 283.79. Its molecular formula is C 15 H 21 NO 2 • HCl, and it has the following chemical structure: Meperidine hydrochloride, USP is a fine, white powder with a melting point of 186° C to 189° C. It is very soluble in water and has a neutral reaction. The solution is not decomposed by a short period of boiling. Each Meperidine Hydrochloride Tablet, USP for oral administration contains either 50 mg or 100 mg meperidine hydrochloride, USP and the following inactive ingredients: corn starch, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and pregelatinized starch. Each 5 mL of Meperidine Hydrochloride Oral Solution, USP for oral administration contains 50 mg meperidine hydrochloride, USP and the following inactive ingredients: glycerin, hydrochloric acid, maltol, sodium benzoate, sorbitol solution and purified water. chem-meperidine.jpg

2 DOSAGE AND ADMINISTRATION • Meperidine Hydrochloride Tablets and Oral Solution should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of Meperidine Hydrochloride Tablets and Oral Solution for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.1 ) • Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.2 ) • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Meperidine Hydrochloride Tablets and Oral Solution. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.3 ) • Adult Patients : Initiate treatment in adults with 50 mg to 150 mg orally, every 3 to 4 hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia ( 2.3 ). Titrate the dose based upon the individual patient’s response to their initial dose of Meperidine Hydrochloride Tablets and Oral Solution. • Pediatric Patients : Initiate treatment in pediatric patients with 1.1 mg/kg to 1.8 mg/kg orally, up to the adult dose, every 3 to 4 hours as needed, at the lowest dose necessary to achieve adequate analgesia ( 2.3 ). Titrate the dose based upon the individual patient’s response to their initial dose of Meperidine Hydrochloride Tablets and Oral Solution. • Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with Meperidine Hydrochloride Tablets and Oral Solution. Consider prescribing naloxone based on the patient’s risk factors for overdose. ( 2.2 , 5.2 , 5.3 , 5.4 ) • Do not abruptly discontinue Meperidine Hydrochloride Tablets and Oral Solution in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.6 ) 2.1 Important Dosage and Administration Instructions Meperidine Hydrochloride Tablets and Oral Solution should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Meperidine Hydrochloride Tablets and Oral Solution for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Meperidine Hydrochloride Tablets and Oral Solution. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 )]. 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Meperidine Hydrochloride Tablets or Oral Solution [see Warnings and Precautions ( 5.3 ), Patient Counseling Information ( 17 )]. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 )]. Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. 2.3 Initial Dosage Adults Initiate treatment with Meperidine Hydrochloride Tablets or Oral Solution in a dosing range of 50 mg to 150 mg (5 mL to 15 mL) orally, every 3 or 4 hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Meperidine Hydrochloride Tablets or Oral Soluti on. Pediatric Patients Initiate treatment with Meperidine Hydrochloride Tablets or Oral Solution in a dosing range of 1.1 mg/kg to 1.8 mg/kg orally, up to the adult dose, every 3 or 4 hours as needed, at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Meperidine Hydrochloride Tablets or Oral Solution . 2.4 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. 2.5 Titration and Maintenance of Therapy Individually titrate Meperidine Hydrochloride Tablets and Oral Solution to a dose that provides adequate analgesia and minimizes adverse reactions. If adequate pain management cannot be achieved with a total daily dosage of 600 mg or less, discontinue treatment with meperidine by tapering the dose and select an alternate analgesic. Continually reevaluate patients receiving meperidine to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.2 , 5.17 )] . 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 dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5 )]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.6 Safe Reduction or Discontinuation of Meperidine Hydrochloride Tablets and Oral Solution Do not abruptly discontinue Meperidine Hydrochloride Tablets and Oral Solution in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Meperidine Hydrochloride Tablets and Oral Solution, there are a variety of factors that should be considered, including the total daily dose of opioid (including Meperidine Hydrochloride Tablets and Oral Solution) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Meperidine Hydrochloride Tablets and Oral Solution who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.17 ), Drug Abuse and Dependence ( 9.3 )].

1 INDICATIONS AND USAGE Meperidine Hydrochloride Tablets and Oral Solution are indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions ( 5.2 )] , reserve Meperidine Hydrochloride Tablets and Oral Solution for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products] : • Have not been tolerated, or are not expected to be tolerated, • Have not provided adequate analgesia, or are not expected to provide adequate analgesia. Meperidine Hydrochloride Tablets or Oral Solution should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. Meperidine Hydrochloride Tablets or Oral Solution should not be used for the treatment of chronic pain. Use of Meperidine Hydrochloride Tablets or Oral Solution for an extended period of time may increase the risk of toxicity (e.g. seizures) from the accumulation of the meperidine metabolite, normeperidine . Meperidine Hydrochloride Tablets and Oral Solution are opioid agonists indicated for the management of pain, severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Limitations of Use ( 1 ): Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, reserve Meperidine Hydrochloride Tablets and Oral Solution for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]: • Have not been tolerated, or are not expected to be tolerated ( 1 ) • Have not provided adequate analgesia, or are not expected to provide adequate analgesia ( 1 ) Meperidine Hydrochloride Tablets and Oral Solution should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. Meperidine Hydrochloride Tablets and Oral Solution should not be used for the treatment of chronic pain. Use of Meperidine Hydrochloride Tablets and Oral Solution for an extended period of time may increase the risk of toxicity (e.g., seizures) from the accumulation of the meperidine metabolite, normeperidine.

9.2 Abuse Meperidine Hydrochloride Tablets and Oral Solution contain meperidine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions ( 5.2 )]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of Meperidine Hydrochloride Tablets and Oral Solution increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of Meperidine Hydrochloride Tablets and/or Oral Solution with alcohol and other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Meperidine Hydrochloride Tablets and Oral Solution abuse include those with a history of prolonged use of any opioid, including products containing meperidine, those with a history of drug or alcohol abuse, or those who use Meperidine Hydrochloride Tablets and Oral Solution in combination with other abused drugs. “Drug-seeking” behavior is very common in persons with substance use disorders. 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 people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Meperidine Hydrochloride Tablets and Oral Solution, like other opioids, can be diverted for nonmedical 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 reevaluation 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 and Oral Solution Abuse of Meperidine Hydrochloride Tablets and Oral Solution poses a risk of overdose and death. The risk is increased with concurrent use of Meperidine Hydrochloride Tablets and Oral Solution with alcohol and/or other CNS depressants. Meperidine Hydrochloride Tablets and Oral Solution are approved for oral use only. Meperidine Hydrochloride Tablets have been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product. Inappropriate intravenous, intramuscular, or subcutaneous use of Meperidine Hydrochloride Tablets and Oral Solution can result in death, local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, and valvular heart injury, and embolism. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

9.1 Controlled Substance Meperidine Hydrochloride Tablets and Oral Solution contain meperidine, a Schedule II controlled substance.

9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), 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 use. Do not abruptly discontinue Meperidine Hydrochloride Tablets and Oral Solution in a patient physically dependent on opioids. Rapid tapering of Meperidine Hydrochloride Tablets and Oral Solution 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, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Meperidine Hydrochloride Tablets and Oral Solution 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 an extended period of time 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 ( 2.6 ), and Warnings and Precautions ( 5.17 )]. 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 )].

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Meperidine Hydrochloride Tablets and Oral Solution contain meperidine, a Schedule II controlled substance. 9.2 Abuse Meperidine Hydrochloride Tablets and Oral Solution contain meperidine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions ( 5.2 )]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of Meperidine Hydrochloride Tablets and Oral Solution increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of Meperidine Hydrochloride Tablets and/or Oral Solution with alcohol and other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Meperidine Hydrochloride Tablets and Oral Solution abuse include those with a history of prolonged use of any opioid, including products containing meperidine, those with a history of drug or alcohol abuse, or those who use Meperidine Hydrochloride Tablets and Oral Solution in combination with other abused drugs. “Drug-seeking” behavior is very common in persons with substance use disorders. 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 people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Meperidine Hydrochloride Tablets and Oral Solution, like other opioids, can be diverted for nonmedical 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 reevaluation 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 and Oral Solution Abuse of Meperidine Hydrochloride Tablets and Oral Solution poses a risk of overdose and death. The risk is increased with concurrent use of Meperidine Hydrochloride Tablets and Oral Solution with alcohol and/or other CNS depressants. Meperidine Hydrochloride Tablets and Oral Solution are approved for oral use only. Meperidine Hydrochloride Tablets have been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product. Inappropriate intravenous, intramuscular, or subcutaneous use of Meperidine Hydrochloride Tablets and Oral Solution can result in death, local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, and valvular heart injury, and embolism. 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 use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), 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 use. Do not abruptly discontinue Meperidine Hydrochloride Tablets and Oral Solution in a patient physically dependent on opioids. Rapid tapering of Meperidine Hydrochloride Tablets and Oral Solution 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, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Meperidine Hydrochloride Tablets and Oral Solution 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 an extended period of time 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 ( 2.6 ), and Warnings and Precautions ( 5.17 )]. 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 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, hypoglycemia, 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 measure. Opioid antagonists, such as naloxone, 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. Because the duration of opioid reversal is expected to be less than the duration of action of meperidine in Meperidine Hydrochloride Tablets and Oral Solution, 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.

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with meperidine. Table 1: Clinically Significant Drug Interactions with Meperidine Hydrochloride Tablets and Oral Solution Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: 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. Intervention: 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 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 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 and CYP2B6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of meperidine is achieved [see Warnings and Precautions ( 5.7 )]. 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 or Oral Solution until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 or CYP2B6 inhibitor is discontinued, consider increasing the meperidine dosage until stable drug effects are achieved. Evaluate 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 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 ( 5.7 )]. 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 or Oral Solution dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 or CYP2B6 inducer is discontinued, consider meperidine dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin. Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions ( 5.10 )]. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Meperidine Hydrochloride Tablets or Oral Solution if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase inhibitors (MAOIs) (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of meperidine and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine. Muscle Relaxants Clinical Impact: Meperidine Hydrochloride Tablets or Oral Solution may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of Meperidine Hydrochloride Tablets or Oral Solution and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when Meperidine Hydrochloride Tablets or Oral Solution is used concomitantly with anticholinergic drugs. Acyclovir Clinical Impact: The concomitant use of acyclovir may increase the plasma concentrations of meperidine and its metabolite, normeperidine. Intervention: If concomitant use of acyclovir and Meperidine Hydrochloride Tablets or Oral Solution is necessary, evaluate patients for respiratory depression and sedation at frequent intervals. Cimetidine Clinical Impact: The concomitant use of cimetidine may reduce the clearance and volume of distribution of meperidine also the formation of the metabolite, normeperidine, in healthy subjects. Intervention: If concomitant use of cimetidine and Meperidine Hydrochloride Tablets or Oral Solution is necessary, evaluate patients for respiratory depression and sedation at frequent intervals. • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with Meperidine Hydrochloride Tablets or Oral Solution because they may reduce analgesic effect of meperidine or precipitate withdrawal symptoms. ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Meperidine is an opioid agonist with multiple actions qualitatively similar to those of morphine; the most prominent of these involve the central nervous system and organs composed of smooth muscle. The principal actions of therapeutic value are analgesia and sedation. 12.2 Pharmacodynamics Effects on the Central Nervous System Meperidine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Meperidine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Meperidine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Meperidine produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6 )]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6 )]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in 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 extended-release 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 )].

12.1 Mechanism of Action Meperidine is an opioid agonist with multiple actions qualitatively similar to those of morphine; the most prominent of these involve the central nervous system and organs composed of smooth muscle. The principal actions of therapeutic value are analgesia and sedation.

12.2 Pharmacodynamics Effects on the Central Nervous System Meperidine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Meperidine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Meperidine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Meperidine produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6 )]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6 )]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in 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 extended-release 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 )].

20231106

18

3 DOSAGE FORMS AND STRENGTHS Meperidine Hydrochloride Tablets, USP: • 50 mg tablet is supplied as a white, round tablet, scored on one side with “54 879” debossed on the other side. • 100 mg tablet is supplied as a white, round tablet, scored on one side with “54 163” debossed on the other side. Meperidine Hydrochloride Oral Solution, USP: • 50 mg/5 mL oral solution: clear, colorless, slightly viscous solution. Tablets: 50 mg and 100 mg. ( 3 ) Oral Solution: 50 mg per 5 mL. ( 3 )

Meperidine Hydrochloride Meperidine Hydrochloride MEPERIDINE HYDROCHLORIDE MEPERIDINE STARCH, CORN CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POVIDONE, UNSPECIFIED 54;879 Meperidine Hydrochloride Meperidine Hydrochloride MEPERIDINE HYDROCHLORIDE MEPERIDINE STARCH, CORN CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POVIDONE, UNSPECIFIED 54;879 Meperidine Hydrochloride Meperidine Hydrochloride MEPERIDINE HYDROCHLORIDE MEPERIDINE STARCH, CORN CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POVIDONE, UNSPECIFIED 54;163 Meperidine Hydrochloride Meperidine Hydrochloride MEPERIDINE HYDROCHLORIDE MEPERIDINE GLYCERIN HYDROCHLORIC ACID MALTOL SODIUM BENZOATE SORBITOL WATER

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.

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.

ANDA088744

Meperidine Hydrochloride

Meperidine Hydrochloride

0054-3545

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Meperidine Hydrochloride Tablets USP, 50 mg 100 Tablets NDC 0054-4595-25 Rx only meperidine-tabs-bl-50mg-100s-c50000731-01-k02

Boxed Warning 11/2023 Indications and Usage ( 1 ) 11/2023 Dosage and Administration ( 2.1 , 2.3 ) 11/2023 Warnings and Precautions ( 5.9 ) 11/2023

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 and Oral Solution 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 and Oral Solution 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 and Oral Solution 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. Medication Errors Provide detailed instructions to patients on how to measure and take the correct dose of Meperidine Hydrochloride Oral Solution to ensure that the dose is measured and administered accurately [see Warnings and Precautions ( 5.1 )] . If the prescribed dosage is changed, instruct patients on how to correctly measure the new dose to avoid errors which could result in accidental overdose and death. Addiction, Abuse, and Misuse Inform patients that the use of Meperidine Hydrochloride Tablets or Oral Solution, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions ( 5.2 )]. Instruct patients not to share Meperidine Hydrochloride Tablets or Oral Solution with others and to take steps to protect meperidine 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 Oral Solution or when the dosage is increased, and that it can occur even at recommended dosages. 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 [see Warnings and Precautions ( 5.3 )]. 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 or Oral Solution is 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 ( 5.4 ), Drug Interactions ( 7 )]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Meperidine Hydrochloride Tablets or Oral Solution. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.3 )]. Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage ( 10 )]. If naloxone is prescribed, also advise patients and caregivers: • How to treat with naloxone in the event of an opioid overdose • To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency • To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. MAOI Interaction Inform patients not to take Meperidine Hydrochloride Tablets or Oral Solution while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking meperidine [see Warnings and Precautions ( 5.8 ), Drug Interactions ( 7 )]. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions ( 5.9 ); Adverse Reactions ( 6 )]. 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 ( 5.10 ), Drug Interactions ( 7 )]. Important Administration Instructions Instruct patients how to properly take Meperidine Hydrochloride Tablets or Oral Solution. • Advise patients never to use a household teaspoon or tablespoon to measure Meperidine Hydrochloride Oral Solution. • Advise patients not to adjust the dose of Meperidine Hydrochloride Tablets or Oral Solution without consulting with a physician or other healthcare professional. • Advise patients to dilute each dose of Meperidine Hydrochloride Oral Solution in one-half glass of water because the undiluted solution may exert a slight topical anesthetic effect on mucous membranes. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Meperidine Hydrochloride Tablets and Oral Solution without first discussing a tapering plan with the prescriber [see Dosage and Administration ( 2.6 )]. Driving or Operating Heavy Machinery Inform patients that Meperidine Hydrochloride Tablets and Oral Solution 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 ( 5.18 )]. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions ( 6 )]. 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 ( 5.12 )]. Hypotension Inform patients that meperidine 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 ( 5.13 )]. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in Meperidine Hydrochloride Tablets and Oral Solution. 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 use of meperidine for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.1 )]. Embryo-Fetal Toxicity : Inform female patients of reproductive potential that meperidine 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 carefully observe 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 use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations ( 8.3 )]. Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 C50000733/02 Revised November 2023

MEDICATION GUIDE Meperidine Hydrochloride Tablets, USP CII and Meperidine Hydrochloride Oral Solution, USP CII (me per’ i deen hye” droe klor’ ide) Rx only Meperidine Hydrochloride Tablets and Oral Solution are: • A strong prescription pain medicine that contains 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 and Oral Solution: • Get emergency help or call 911 right away if you take too much (overdose) Meperidine Hydrochloride Tablets or Oral Solution. When you first start taking Meperidine Hydrochloride Tablets or Oral Solution, 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. Talk to your healthcare provider about naloxone, a medicine for the treatment of opioid overdose. • Taking Meperidine Hydrochloride Tablets and Oral Solution 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 and Oral Solution. They could die from taking it. Selling or giving away Meperidine Hydrochloride Tablets and Oral Solution is against the law. • Store Meperidine Hydrochloride Tablets and Oral Solution away from children and in a safe location not accessible to others, including visitors to the home. Do not take Meperidine Hydrochloride Tablets and Oral Solution if you have: • severe asthma, trouble breathing, or other lung problems. • a bowel blockage or have narrowing of the stomach or intestines. • an allergy to meperidine. Before taking Meperidine Hydrochloride Tablets and Oral Solution, tell your healthcare provider if you have a history of: • head injury, seizures • problems urinating • liver, kidney, thyroid problems • pancreas or gallbladder problems • abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems. Tell your healthcare provider if you are: • noticing your pain getting worse. If your pain gets worse after you take Meperidine Hydrochloride Tablets or Oral Solution, do not take more of Meperidine Hydrochloride Tablets or Oral Solution without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking Meperidine Hydrochloride Tablets or Oral Solution. • pregnant or planning to become pregnant . Use of Meperidine Hydrochloride Tablets or Oral Solution for an extended period of time 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. • living in a household where there are small children or someone who has abused street or prescription drugs. • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Meperidine Hydrochloride Tablets and Oral Solution with certain other medicines can cause serious side effects that could lead to death. When taking Meperidine Hydrochloride Tablets or Oral Solution: • Do not change your dose. Take Meperidine Hydrochloride Tablets and Oral Solution exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. • For acute (short-term) pain, you may only need to take Meperidine Hydrochloride Tablets or Oral Solution for a few days. You may have some Meperidine Hydrochloride Tablets or Oral Solution left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused Meperidine Hydrochloride Tablets and Oral Solution. • Always use a calibrated measuring device for Meperidine Hydrochloride Oral Solution to correctly measure your dose. Never use a household teaspoon or tablespoon to measure Meperidine Hydrochloride Oral Solution. • Mix each dose of Meperidine Hydrochloride Oral Solution into one-half glass of water before swallowing. • 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 and Oral Solution regularly, do not stop taking Meperidine Hydrochloride Tablets or Oral Solution without talking to your healthcare provider. • Dispose of expired, unwanted, or unused Meperidine Hydrochloride Tablets and Oral Solution 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 and Oral Solution DO NOT: • Drive or operate heavy machinery, until you know how Meperidine Hydrochloride Tablets or Oral Solution affects you. Meperidine can make you sleepy, dizzy, or lightheaded. • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Meperidine Hydrochloride Tablets or Oral Solution may cause you to overdose and die. The possible side effects of Meperidine Hydrochloride Tablets and Oral Solution: • 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 or call 911 right away 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 Hydrochloride Tablets and Oral Solution. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov . For information, please call Hikma Pharmaceuticals USA Inc. at 1-800-962-8364. This Medication Guide has been approved by the U.S. Food and Drug Administration. Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 C50000733/02 Revised November 2023

8.5 Geriatric Use Clinical studies of meperidine 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 or Oral Solution slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.4 , 5.11 )]. Meperidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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.

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.5 )]. Available data with meperidine is 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 1,200 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 : Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.5 )]. Labor and Delivery : Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. Resuscitation may be required [see Overdose ( 10 )]. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Meperidine is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including meperidine, 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 1,200 mg/day based on body surface area). The findings cannot be clearly attributed to maternal toxicity.

8 USE IN SPECIFIC POPULATIONS • Pregnancy: May cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.5 )]. Available data with meperidine is 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 1,200 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 : Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.5 )]. Labor and Delivery : Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. Resuscitation may be required [see Overdose ( 10 )]. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Meperidine is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including meperidine, 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 1,200 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 and any potential adverse effects on the breastfed infant from Meperidine Hydrochloride Tablets or Oral Solution or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to meperidine 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 Use of opioids for an extended period of time 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 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 or Oral Solution slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.4 , 5.11 )]. Meperidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to 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 or Oral Solution 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 or Oral Solution slowly in patients with renal impairment and monitor closely for signs of central nervous system and respiratory depression.

16 HOW SUPPLIED/STORAGE AND HANDLING Meperidine Hydrochloride Tablets, USP 50 mg tablet is supplied as a white, round tablet, scored on one side with “54 879” debossed on the other side. NDC 0054-8595-11: 1 x 25 Unit-Dose (Reverse Numbered) Tablets NDC 0054-4595-25: Bottle of 100 Tablets 100 mg tablet is supplied as a white, round tablet, scored on one side with “54 163” debossed on the other side. NDC 0054-4596-25: Bottle of 100 Tablets Meperidine Hydrochloride Oral Solution, USP 50 mg per 5 mL oral solution is supplied as a clear, colorless, slightly viscous (unflavored) solution. NDC 0054-3545-63: Bottle of 500 mL Dispense in a tight, light-resistant container as defined in the USP/NF. Store at 20º to 25ºC (68º to 77ºF). [See USP Controlled Room Temperature.] Store Meperidine Hydrochloride Tablets and Oral Solution securely and dispose of properly [see Patient Counseling Information ( 17 )] .

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF MEPERIDINE HYDROCHLORIDE TABLETS AND ORAL SOLUTION. Risk of Medication Errors Ensure accuracy when prescribing, dispensing, and administering Meperidine Hydrochloride Oral Solution. Dosing errors due to confusion between mg and mL, and other Meperidine Hydrochloride Oral Solutions of different concentrations can result in accidental overdose and death [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.1 )] . Addiction, Abuse, and Misuse Because the use of Meperidine Hydrochloride Tablets and Oral Solution 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 and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.2 )] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Meperidine Hydrochloride Tablets and Oral Solution, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of Meperidine Hydrochloride Tablets and Oral Solution are essential [see Warnings and Precautions ( 5.3 )]. Accidental Ingestion Accidental ingestion of Meperidine Hydrochloride Tablets and Oral Solution, especially by children, can result in a fatal overdose of meperidine [see Warnings and Precautions ( 5.3 )] . 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. Reserve concomitant prescribing of Meperidine Hydrochloride Tablets and Oral Solution and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [ see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 )] . Neonatal Opioid Withdrawal Syndrome (NOWS) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be lifethreatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions ( 5.5 )] . Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions ( 5.6 )]. Cytochrome P450 3A4 (CYP3A4) Interaction The concomitant use of Meperidine Hydrochloride Tablets and Oral Solution with all cytochrome P450 3A4 (CYP3A4) inhibitors may result in an increase in meperidine plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used CYP 3A4 inducer may result in an increase in meperidine plasma concentration. Frequently reevaluate patients receiving Meperidine Hydrochloride Tablets and Oral Solution and any CYP 3A4 inhibitor or inducer [see Warnings and Precautions ( 5.7 ), Drug Interactions (7 )]. Monoamine Oxidase Inhibitors (MAOIs) Interaction The concomitant use of Meperidine Hydrochloride Tablets and Oral Solution with monoamine oxidase inhibitors (MAOIs) can result in coma, severe respiratory depression, cyanosis, and hypotension. Use of Meperidine Hydrochloride Tablets and Oral Solution with MAOIs within the last 14 days is contraindicated [see Contraindications ( 4 ), Warnings and Precautions ( 5.8 ), Drug Interactions ( 7 )]. WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF MEPERIDINE HYDROCHLORIDE TABLETS AND ORAL SOLUTION See full prescribing information for complete boxed warning. • Ensure accuracy when prescribing, dispensing, and administering Meperidine Hydrochloride Oral Solution. Dosing errors due to confusion between mg and mL, and other Meperidine Hydrochloride Oral Solutions of different concentrations can result in accidental overdose and death. ( 2.1, 5.1 ) • Meperidine Hydrochloride Tablets and Oral Solution 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 or Oral Solution, especially by children, can result in a fatal overdose of meperidine. ( 5.3 ) • 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. ( 5.7 , 7 ) • Prolonged use of Meperidine Hydrochloride Tablets or Oral Solution 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. ( 5.5 ) • 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. ( 5.3 ) • Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in fatal overdose of meperidine. ( 5.6 , 7 ) • Concomitant use of Meperidine Hydrochloride Tablets or Oral Solution with monoamine oxidase inhibitors (MAOIs) can result in coma, severe respiratory depression, cyanosis and hypotension. Use of Meperidine Hydrochloride Tablets or Oral Solution with MAOIs within the last 14 days is contraindicated. ( 4 , 5.8 , 6 )