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 (5.1) ] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2) ] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4) ] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.7) ] Serotonin Syndrome with Concomitant Use of Serotonergic Drugs [see Warnings and Precautions (5.8) ] Adrenal Insufficiency [see Warnings and Precautions (5.10) ] Severe Hypotension [see Warnings and Precautions (5.11) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.13) ] Seizures [see Warnings and Precautions (5.14) ] Withdrawal [see Warnings and Precautions (5.15) ] The following adverse reactions associated with the use of meperidine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The major hazards of meperidine, as with other opioid analgesics, are respiratory depression and, to a lesser degree, circulatory depression; respiratory arrest, shock, and cardiac arrest have occurred. The most frequently observed adverse reactions include 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. Inadvertent injection about a nerve trunk may result in sensory-motor paralysis which is usually, though not always, transitory. Gastrointestinal: Dry mouth, constipation, biliary tract spasm. Cardiovascular : Flushing of the face, tachycardia, bradycardia, palpitation, hypotension [ see Warnings and Precautions (5.18 ) ], syncope, phlebitis following intravenous injection. 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. Other : Pain at injection site; local tissue irritation and induration following subcutaneous injection, particularly when repeated; antidiuretic effect. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids for an extended period of time [ see Clinical Pharmacology (12.2) ] . Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.7) ]. Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Most common adverse reactions were lightheadedness, dizziness, sedation, nausea, vomiting and sweating. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

4 CONTRAINDICATIONS Meperidine Hydrochloride Injection is contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.2) ] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.2) ] Concomitant use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.6 ) , Drug Interactions (7) ] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.13) ] Hypersensitivity to meperidine (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 ) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAIOs within the last 14 days. ( 7 ) 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 Injection, USP is an opioid agonist, available as a sterile aqueous solution, for intramuscular, subcutaneous or slow intravenous administration. Each mL contains meperidine hydrochloride, either 25 mg, 50 mg or 100 mg in Water for Injection. Buffered with acetic acid-sodium acetate. pH 3.5-6.0. The meperidine hydrochloride 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 is a white crystalline substance with a melting point of 186° C to 189° C. It is readily soluble in water and has a neutral reaction and a slightly bitter taste. The solution is not decomposed by a short period of boiling. Chemical Structure

2 DOSAGE AND ADMINISTRATION Meperidine Hydrochloride 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 consistent with individual patient treatment goals. Reserve titration to higher doses of Meperidine Hydrochloride Injection 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 Injection. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.2 , 5.3 ) For Relief of Pain: Titrate the dose based upon the individual patients’ response to their initial dose of Meperidine Hydrochloride Injection ( 2.2 , 5 ) Adults: 50 mg to 150 mg intramuscularly or subcutaneously every 3 to 4 hours. ( 2.2 ) Children: 0.5 mg/lb to 0.8 mg/lb intramuscularly or subcutaneously up to the adult dose every 3 to 4 hours. ( 2.2 ) Preoperative Medication: Adults: 50 mg to 150 mg intramuscularly or subcutaneously, 30 to 90 minutes before beginning anesthesia. ( 2.3 ) Children: 0.5 mg/lb to 1 mg/lb intramuscularly or subcutaneously up to the adult dose, 30 to 90 minutes before beginning anesthesia. ( 2.3 ) Obstetrical Analgesia: 50 mg to 100 mg intramuscularly or subcutaneously; may be repeated at 1 to 3 hour intervals. ( 2.4 ) Do not abruptly discontinue Meperidine Hydrochloride Injection abruptly in a physically dependent patient. ( 2.2 ) 2.1 Important Dosage and Administration Instructions Meperidine Hydrochloride Injection 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 Injection 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 Injection. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5) ] . Inspect Meperidine Hydrochloride Injection for particulate matter and discoloration prior to administration. Do not use if color is darker than pale yellow, if it is discolored in any other way, or if it contains a precipitate. 2.2 For Management of Pain I nitial Dosage Dosage should be adjusted according to the severity of the pain and the response of the patient. While subcutaneous administration is suitable for occasional use, intramuscular administration is preferred when repeated doses are required. If intravenous administration is required, dosage should be decreased and the injection made very slowly, preferably utilizing a diluted solution. Adults: Initiate treatment in a dosing range of 50 mg to 150 mg intramuscularly or subcutaneously every 3 to 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Elderly patients should usually be given meperidine at the lower end of the dose range and observed closely. Children: Initiate treatment in a dosing range of 0.5 mg/lb to 0.8 mg/lb intramuscularly or subcutaneously up to the adult dose, every 3 to 4 hours as necessary, and at the lowest dose necessary to achieve adequate analgesia. Titration and Maintenance of Therapy Titrate the dose based upon the individual patient’s response to their initial dose of Meperidine Hydrochloride Injection. Individually titrate Meperidine Hydrochloride Injection to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Meperidine Hydrochloride Injection 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 (5.1 , 5.15 )]. Frequent communication is important among the prescriber, other members of the health and care team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Meperidine Hydrochloride Injection dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a 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. Discontinuation of Meperidine Hydrochloride Injection When a patient who has been taking Meperidine Hydrochloride Injection regularly and may be physically-dependent no longer requires therapy with Meperidine Hydrochloride Injection, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Meperidine Hydrochloride Injection in a physically-dependent patient [see Warnings and Precautions (5.15) , Drug Abuse and Dependence (9.3) ] . 2.3 For Preoperative Medication Adults: The usual dosage is 50 mg to 100 mg intramuscularly or subcutaneously, 30 to 90 minutes before the beginning of anesthesia. Elderly patients should usually be given meperidine at the lower end of the dose range and observed closely. Children: The usual dosage is 0.5 mg/lb to 1 mg/lb intramuscularly or subcutaneously up to the adult dose, 30 to 90 minutes before the beginning of anesthesia. 2.4 For Support of Anesthesia Repeated slow intravenous injections of fractional doses (e.g., 10 mg/mL) or continuous intravenous infusion of a more dilute solution (e.g., 1 mg/mL) should be used. The dose should be titrated to the needs of the patient and will depend on the premedication and type of anesthesia being employed, the characteristics of the particular patient, and the nature and duration of the operative procedure. Elderly patients should usually be given meperidine at the lower end of the dose range and observed closely. 2. 5 For Obstetrical Analgesia The usual dosage is 50 mg to 100 mg intramuscularly or subcutaneously when pain becomes regular, and may be repeated at 1- to 3-hour intervals. 2.6 Dosage Modifications with Concomitant Phenothiazines The dose of Meperidine Hydrochloride Injection should be proportionately reduced (usually by 25 to 50 percent) when administered concomitantly with phenothiazines and many other tranquilizers since they potentiate the action of Meperidine Hydrochloride Injection.

9.2 Abuse Meperidine Hydrochloride Injection contains meperidine, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1) ]. 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 its 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 Injection 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 Injection with alcohol and/or 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 Injection 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 Injection 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 health care 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 Injection, 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 re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Meperidine Hydrochloride Injection Abuse of Meperidine Hydrochloride Injection poses a risk of overdose and death. The risk is increased with concurrent abuse of Meperidine Hydrochloride Injection with alcohol and other CNS depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

9.1 Controlled Substance Meperidine Hydrochloride Injection contains meperidine, a Schedule II controlled substance.

9.3 Dependence Both tolerance and physical dependence can develop during chronic 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. Meperidine Hydrochloride Injection should not be abruptly discontinued [see Dosage and Administration (2.4) ] . If Meperidine Hydrochloride Injection is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur, typically characterized by restlessness, lacrimation, rhinorrhea, 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. 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 Injection contains meperidine, a Schedule II controlled substance. 9.2 Abuse Meperidine Hydrochloride Injection contains meperidine, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1) ]. 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 its 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 Injection 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 Injection with alcohol and/or 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 Injection 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 Injection 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 health care 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 Injection, 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 re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Meperidine Hydrochloride Injection Abuse of Meperidine Hydrochloride Injection poses a risk of overdose and death. The risk is increased with concurrent abuse of Meperidine Hydrochloride Injection with alcohol and other CNS depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is 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. Meperidine Hydrochloride Injection should not be abruptly discontinued [see Dosage and Administration (2.4) ] . If Meperidine Hydrochloride Injection is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur, typically characterized by restlessness, lacrimation, rhinorrhea, 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. Infants born to mothers physically dependent on opioids will also be physically-dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1) ] .

10 OVERDOSAGE Clinical Presentation Acute overdose with Meperidine Hydrochloride Injection 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) ] . In severe overdose, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. Accumulation of normeperidine as in chronic use or possibly following introduction of a concomitant CYP3A4 inducer presents as excitatory syndrome including hallucinations, tremors, muscle twitches, dilated pupils, hyperactive reflexes, and convulsions. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. The opioid antagonists, 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 Injection, carefully monitor the patient until spontaneous respiration is reliably re-established. 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 of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun 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 Hydrochloride Injection. Table 1: Clinically Significant Drug Interactions with Meperidine Hydrochloride Injection Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or those who have recently received such agents. Therapeutic doses of meperidine have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear, but may be related to a pre-existing hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of acute narcotic overdose. Serotonin syndrome with agitation, hyperthermia, diarrhea, tachycardia, sweating, tremors and impaired consciousness may also occur. In other reactions the predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension. [see Warnings and Precautions (5.6) ]. Intervention: Do not use Meperidine Hydrochloride Injection in patients taking MAOIs or within 14 days of stopping such treatment. Intravenous hydrocortisone or prednisolone have been used to treat severe reactions, with the addition of intravenous chlorpromazine in those cases exhibiting hypertension and hyperpyrexia. The usefulness and safety of narcotic antagonists in the treatment of these reactions is unknown. Examples: Phenelzine, tranylcypromine, linezolid Inhibitors of CYP3A4 and CYP2B6 Clinical Impact: The concomitant use of Meperidine Hydrochloride Injection and CYP3A4 or CYP2B6 inhibitors can increase the plasma concentration of meperidine, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Meperidine Hydrochloride Injection and CYP2B6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Meperidine Hydrochloride Injection is achieved [see Warnings and Precautions (5.5) ]. After stopping a CYP3A4 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 Injection until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 or CYP2B6 inhibitor is discontinued, consider increasing the Meperidine Hydrochloride Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconizole), protease inhibitors (e.g., ritonavir) CYP3A4 and CYP2B6 Inducers Clinical Impact: The concomitant use of Meperidine Hydrochloride Injection and CYP3A4 inducers, or CYP2B6 inducers can decrease the plasma concentration of meperidine [see Clinical Pharmacology (12.3) ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to meperidine [see Warnings and Precautions (5.5) ]. After stopping a CYP3A4 or CYP2B6 inducer, as the effects of the inducer decline, the meperidine plasma concentration will increase [see Clinical Pharmacology (12.3) ], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the Meperidine Hydrochloride Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 or CYP2B6 inducer is discontinued, consider Meperidine Hydrochloride Injection dosage reduction and monitor for signs of respiratory depression. 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 [see Warnings and Precautions (5.3 )]. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. 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 (5.8) ]. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Meperidine Hydrochloride Injection 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 affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Meperidine Hydrochloride Injection and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine. Muscle Relaxants Clinical Impact: Meperidine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Meperidine Hydrochloride Injection and/or the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Meperidine Hydrochloride Injection 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 Injection is necessary, monitor patients for respiratory depression and sedation at frequent intervals. Cimetidine Clinical Impact: The concomitant use of cimetidine may reduce the clearance and volume of distribution of meperidine also the formation of the metabolite, normeperidine, in healthy subjects. Intervention: If concomitant use of cimetidine and Meperidine Hydrochloride Injection is necessary, monitor patients for respiratory depression and sedation at frequent intervals. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with Meperidine Hydrochloride Injection because they may reduce analgesic effect of Meperidine Hydrochloride Injection or precipitate withdrawal symptoms. ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Meperidine hydrochloride 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 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 of 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, and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormones (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 potent agonist opioids. The minimum effective analgesic concentration of meperidine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.2) ] . Meperidine, in 60 mg to 80 mg parenteral doses, is approximately equivalent in analgesic effect to 10 mg of morphine. The onset of action is slightly more rapid than with morphine, and the duration of action is slightly shorter. Meperidine is significantly less effective by the oral than by the parenteral route, but the exact ratio of oral to parenteral effectiveness is unknown. 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 , 2.2) ] . 12.3 Pharmacokinetics Elimination The half-life of meperidine is 2 to 5 hours, and the half-life of normeperidine is 15 to 30 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. Hepatic Impairment The elimination half-life is 3 to 8 hours in healthy volunteers and is 1.3 to 2 times greater in post-operative or cirrhotic patients. 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. 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 hydrochloride 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 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 of 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, and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormones (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 potent agonist opioids. The minimum effective analgesic concentration of meperidine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.2) ] . Meperidine, in 60 mg to 80 mg parenteral doses, is approximately equivalent in analgesic effect to 10 mg of morphine. The onset of action is slightly more rapid than with morphine, and the duration of action is slightly shorter. Meperidine is significantly less effective by the oral than by the parenteral route, but the exact ratio of oral to parenteral effectiveness is unknown. 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 , 2.2) ] .

12.3 Pharmacokinetics Elimination The half-life of meperidine is 2 to 5 hours, and the half-life of normeperidine is 15 to 30 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. Hepatic Impairment The elimination half-life is 3 to 8 hours in healthy volunteers and is 1.3 to 2 times greater in post-operative or cirrhotic patients. 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. 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 )].

20240409

11

3 DOSAGE FORMS AND STRENGTHS Single Dose vials: 25 mg/mL, 50 mg/mL and 100 mg/mL. Single Dose vials: 25 mg/mL, 50 mg/mL and 100 mg/mL. ( 3 )

MEPERIDINE HYDROCHLORIDE MEPERIDINE HYDROCHLORIDE MEPERIDINE HYDROCHLORIDE MEPERIDINE ACETIC ACID SODIUM ACETATE WATER MEPERIDINE HYDROCHLORIDE MEPERIDINE HYDROCHLORIDE MEPERIDINE HYDROCHLORIDE MEPERIDINE ACETIC ACID SODIUM ACETATE WATER MEPERIDINE HYDROCHLORIDE MEPERIDINE HYDROCHLORIDE MEPERIDINE HYDROCHLORIDE MEPERIDINE ACETIC ACID SODIUM ACETATE 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.

ANDA080445

MEPERIDINE HYDROCHLORIDE

MEPERIDINE HYDROCHLORIDE

0641-6052

HUMAN PRESCRIPTION DRUG

INTRAMUSCULAR,INTRAVENOUS,SUBCUTANEOUS

PRINCIPAL DISPLAY PANEL NDC 0641- 6052 -01 Rx only Meperidine HCl Injection, USP 25 mg/mL CII For IM, SC or slow IV use Do not use if precipitated 1 mL Vial NDC 0641- 6052 -25 Rx only Meperidine HCl Injection, USP 25 mg/mL CII For Intramuscular, Subcutaneous or slow Intravenous use 25 x 1 mL Single Dose Vials vial sp

RECENT MAJOR CHANGES Boxed Warning 12/2023 Indications and Usage ( 1 ) 12/2023 Dosage and Administration ( 2.1 , 2.2 ) 12/2023 Warnings and Precautions ( 5.8 ) 12/2023 Boxed Warning 12/2023 Indications and Usage ( 1 ) 12/2023 Dosage and Administration ( 2.1 , 2.2 ) 12/2023 Warnings and Precautions ( 5.8 ) 12/2023

17 PATIENT COUNSELING INFORMATION Addiction, Abuse, and Misuse Inform patients that the use of Meperidine Hydrochloride Injection, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1) ]. Instruct patients not to share Meperidine Hydrochloride Injection with others and to take steps to protect Meperidine Hydrochloride Injection 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 Meperidine Hydrochloride Injection or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.2 )]. Hyperalgesia and Allodynia Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.7) , 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 health care provider if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.7) , Drug Interactions (7) ] . Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6) , Clinical Pharmacology (12.1) ] . Manufactured by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 Revised January 2024 462-093-07

8.5 Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to meperidine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. 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 Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.2) ] . 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 efficacy of Meperidine Hydrochloride Injection in patients less than 18 years of age have not been established. 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 Prolonged use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4) ]. Available data with Meperidine Hydrochloride Injection are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics (see Clinical Considerations ). Formal animal reproduction studies have not been conducted with meperidine. Neural tube defects (exencephaly and cranioschisis) have been reported in hamsters administered a single bolus dose of meperidine during a critical period of organogenesis at 0.85 and 1.5 times the total human daily dose of 1200 mg. [see Data ] The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, 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 (5.4) ] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Meperidine Hydrochloride Injection 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 Hydrochloride Injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data Formal reproductive and developmental toxicology studies for meperidine have not been completed. In a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of meperidine hydrochloride (127 and 218 mg/kg, respectively) on Gestation Day 8 to pregnant hamsters (0.85 and 1.5 times the total daily dose of 1200 mg/day based on body surface area). The findings cannot be clearly attributed to maternal toxicity.

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) Geriatric Patients : Use caution during dose selection, starting at the low end of the dosing range while carefully monitoring for side effects. ( 8.5 ) 8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4) ]. Available data with Meperidine Hydrochloride Injection are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics (see Clinical Considerations ). Formal animal reproduction studies have not been conducted with meperidine. Neural tube defects (exencephaly and cranioschisis) have been reported in hamsters administered a single bolus dose of meperidine during a critical period of organogenesis at 0.85 and 1.5 times the total human daily dose of 1200 mg. [see Data ] The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, 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 (5.4) ] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Meperidine Hydrochloride Injection 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 Hydrochloride Injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data Formal reproductive and developmental toxicology studies for meperidine have not been completed. In a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of meperidine hydrochloride (127 and 218 mg/kg, respectively) on Gestation Day 8 to pregnant hamsters (0.85 and 1.5 times the total daily dose of 1200 mg/day based on body surface area). The findings cannot be clearly attributed to maternal toxicity. 8.2 Lactation Risk Summary Meperidine appears in the milk of nursing mothers receiving the drug. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Meperidine Hydrochloride Injection and any potential adverse effects on the breastfed infant from Meperidine Hydrochloride Injection or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to Meperidine Hydrochloride Injection 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 Pharmacology (13.1) ]. 8.4 Pediatric Use The safety and efficacy of Meperidine Hydrochloride Injection in patients less than 18 years of age have not been established. 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 Elderly patients (aged 65 years or older) may have increased sensitivity to meperidine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. 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 Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.2) ] . 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 also 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 Injection 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 occur in patients with renal impairment. Meperidine should therefore be used with caution in patients with renal impairment. Titrate the dosage of Meperidine Hydrochloride Injection slowly in patients with renal impairment and monitor closely for signs of central nervous system and respiratory depression.

16 HOW SUPPLIED/STORAGE AND HANDLING For Parenteral Use Meperidine Hydrochloride Injection, USP is clear and colorless and is available in the following packages: 25 mg/mL 1 mL Single Dose vials packaged in 25s ( NDC 0641-6052-25) 50 mg/mL 1 mL Single Dose vials packaged in 25s ( NDC 0641-6053-25) 100 mg/mL 1 mL Single Dose vials packaged in 25s ( NDC 0641-6054-25) Store at 20 ° to 25 °C (68 ° to 77 °F), excursions permitted to 15 ° to 30 °C (59 ° to 86 °F) [See USP Controlled Room Temperature].

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF MEPERIDINE HYDROCHLORIDE INJECTION WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF MEPERIDINE HYDROCHLORIDE INJECTION See full prescribing information for complete boxed warning. Meperidine Hydrochloride Injection exposes users to risks of addiction, abuse, and misuse, which can also lead to overdose and death. Assess patient's risk before prescribing and reassess regularly for these behaviors and conditions. ( 5.1 ) Serious, life-threatening, or fatal respiratory depression may occur with the use of Meperidine Hydrochloride Injection, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Meperidine Hydrochloride are essential ( 5.2 ) 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. ( 5.3 , 7 ). If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. ( 5.4 ) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in fatal overdose of meperidine. ( 5.5 , 7 ) Concomitant use of Meperidine Hydrochloride Injection with Monoamine oxidase (MAO) inhibitors can result in coma, severe respiratory depression, cyanosis and hypotension. Use of Meperidine Hydrochloride Injection with MAO inhibitors is contraindicated. ( 4 , 5.6 , 7 ) Addiction, Abuse, and Misuse Because the use of Meperidine Hydrochloride Injection 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 (5.1) ]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Meperidine Hydrochloride Injection, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of Meperidine Hydrochloride Injection are essential. [ see Warnings and Precautions (5.2) ] . 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 Injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. [ see Warnings and Precautions (5.3) , 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 Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. [ see Warnings and Precautions (5.4) ]. Cytochrome P450 3A4 Interaction The concomitant use of Meperidine Hydrochloride Injection with all cytochrome P450 3A4 inhibitors may result in an increase in meperidine plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in meperidine plasma concentration. Monitor patients receiving Meperidine Hydrochloride Injection and any CYP3A4 inhibitor or inducer. [ see Warnings and Precautions (5.5) , Drug Interactions (7) ]. Concomitant Use of Meperidine Hydrochloride Injection with Monoamine Oxidase (MAO) Inhibitors Concomitant use of Meperidine Hydrochloride Injection with monoamine oxidase (MAO) inhibitors can result in coma, severe respiratory depression, cyanosis, and hypotension. Use of Meperidine Hydrochloride Injection with MAO inhibitors within last 14 days is contraindicated [see Contraindications (4) , Warnings and Precautions (5.6) , Drug Interactions (7) ].