Demerol

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 ( 5.4 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.5 )] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.7 )] Serotonin Syndrome [see Warnings and Precautions ( 5.9 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.11 )] Severe Hypotension [see Warnings and Precautions ( 5.12 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.14 ) ] Seizures [see Warnings and Precautions ( 5.15 )] Withdrawal [see Warnings and Precautions ( 5.16 )] 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 ( 5.7 ) ] , syncope. Genitourinary: Urinary retention. Allergic: Pruritus, urticaria, other skin rashes, wheal and flare over the vein with intravenous injection. Hypersensitivity reactions, anaphylaxis. Histamine release leading to hypotension and/or tachycardia, flushing, sweating, and pruritus. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2 )] . To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-866-982-5438 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 Validus Pharmaceuticals LLC at 1-866-982-5438 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS DEMEROL Tablets and Oral Solution are contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.4 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.9 )] 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 ( 5.14 )] Hypersensitivity to meperidine or to any of 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 DEMEROL (meperidine hydrochloride, USP) Tablet and Oral Solution are opioid agonists. DEMEROL Tablets are available as 50 mg and 100 mg Tablets for oral administration. The chemical name is 4-Piperidinecarboxylic acid, 1-methyl-4-phenyl-, ethyl ester, hydrochloride. The molecular weight is 283,80. 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. The Tablets contain 50 mg or 100 mg of meperidine hydrochloride. The DEMEROL Oral Solution is a pleasant-tasting, nonalcoholic, banana-flavored solution containing 50 mg of meperidine hydrochloride, per 5 mL (10 mg/mL). The Inactive Ingredients in DEMEROL Tablets include: Calcium Sulfate, Dibasic Calcium Phosphate, Starch, Stearic Acid, and Talc. The Tablets are white, round and convex. The 50 mg is a scored tablet and has a stylized “W” on one side and “D” over “35” on the other side. The 100 mg is a scored tablet and has a stylized “W” on one side and “D” over “37” on the other side. The Inactive Ingredients in DEMEROL Oral Solution include: Benzoic Acid, Flavor, Liquid Glucose, Purified Water, Saccharin Sodium. The following chemical structure for DEMEROL (meperidine hydrochloride, USP) Tablet and Oral Solution are opioid agonists. DEMEROL Tablets are available as 50 mg and 100 mg Tablets for oral administration. The chemical name is 4-Piperidinecarboxylic acid, 1-methyl-4-phenyl-,ethyl ester, hydrochloride. The molecular weight is 283,80.

2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. ( 2.1 ) Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. ( 2.1 ) 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 DEMEROL Tablets and Oral Solution. Consider prescribing naloxone based in the patient’s risk factors for overdose. ( 2.2 , 5.2 , 5.4 , 5.7 ) Adult Patients: Initiate treatment in adults with 50 mg to 150 mg every 3 to 4 hours as needed for pain. ( 2.2 ) Pediatric Patients: Initiate treatment with 1.1 mg/kg to 1.8 mg/kg orally, up to the adult dose, every 3 or 4 hours as needed for pain. ( 2.2 ) Do not abruptly discontinue DEMEROL 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. ( 2.5 ) 2.1 Important Dosage and Administration Instructions Ensure accuracy when prescribing, dispensing, and administrating DEMEROL Oral Solution to avoid dosing errors due to confusion between mg and mL, and with other Meperidine Hydrochloride Oral Solutions of different concentrations, which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Do not use household teaspoons or tablespoons to measure DEMEROL Oral Solution, as using a tablespoon instead of a teaspoon could lead to overdosage. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5 ) ]. Dilute each dose of DEMEROL oral solution in one-half glass of water because the undiluted solution may exert a slight topical anesthetic effect on mucous membranes. Initiate the dosing regimen for each patient individually; taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.2 )] . Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with DEMEROL Tablets or Oral Solution and adjust the dosage accordingly [see Warnings and Precautions ( 5.4 )]. 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 DEMEROL Tablets or Oral Solution [see Warnings and Precautions ( 5.4 ), 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 , 5.4 , 5.7 )]. 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 DEMEROL Tablets or Oral Solution in a dosing range of 50 mg to 150 mg orally, every 3 or 4 hours as needed for pain. Pediatric Patients Initiate treatment with DEMEROL 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 necessary. 2. 4 Dosage Modification with Concomitant Use with Phenothiazines The dose of DEMEROL Tablets or Oral Solution should be reduced by 25 to 50% when administered concomitantly with phenothiazines and other tranquilizers. 2. 5 Titration and Maintenance of Therapy Individually titrate DEMEROL 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 DEMEROL Tablets or Oral Solution by tapering the dose and select an alternate analgesic. Continually reevaluate patients receiving DEMEROL Tablets or Oral Solution to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.2 )] . 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 DEMEROL Tablets or Oral Solution dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2. 6 Safe Reduction or Discontinuation of DEMEROL Tablets and Oral Solution Do not abruptly discontinue DEMEROL 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 DEMEROL Tablets and Oral Solution, there are a variety of factors that should be considered, including the dose of DEMEROL 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 DEMEROL 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, monitor 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 a long duration 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 ( 5.16 ), Drug Abuse and Dependence ( 9.3 )] .

1 INDICATIONS AND USAGE DEMEROL 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, even at recommended doses [see Warnings and Precautions ( 5.2 )] , reserve DEMEROL Tablets or 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. DEMEROL Tablets or Oral Solution should not be used for treatment of chronic pain. Prolonged DEMEROL Tablet or Oral Solution use may increase the risk of toxicity (e.g., seizures) from the accumulation of the meperidine metabolite, normeperidine. DEMEROL 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, even at recommended doses, reserve DEMEROL 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.

9.2 Abuse DEMEROL Tablets and Oral Solution contain meperidine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. DEMEROL Tablets and Oral Solution can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.2 )] . All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug seeking” behavior is very common in addicts and drug abusers. 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 drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. DEMEROL Tablets and Oral Solution, like other opioids, can be diverted for non-medical 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 DEMEROL Tablets and Oral Solution DEMEROL Tablets and Oral Solution are for oral use only. Abuse of DEMEROL Tablets and Oral Solution pose a risk of overdose and death. DEMEROL Tablets have been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product. The risk is increased with concurrent use of DEMEROL Tablets with alcohol and other central nervous system depressants. Due to the presence of talc as one of the excipients in tablets, parenteral abuse of crushed tablets can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart disease. In addition, parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

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

9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), 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 opioid usage. Do not abruptly discontinue DEMEROL Tablets and Oral Solution in a patient physically dependent on opioids. Rapid tapering of DEMEROL 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 DEMEROL Tablets and Oral Solution, gradually taper the dosage using a patient-specific plan that considers the following: the dose of DEMEROL 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 a long duration 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 ), Warnings and Precautions ( 5.16 )] . 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 DEMEROL Tablets and Oral Solution contain meperidine, a Schedule II controlled substance. 9.2 Abuse DEMEROL Tablets and Oral Solution contain meperidine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. DEMEROL Tablets and Oral Solution can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.2 )] . All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug seeking” behavior is very common in addicts and drug abusers. 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 drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. DEMEROL Tablets and Oral Solution, like other opioids, can be diverted for non-medical 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 DEMEROL Tablets and Oral Solution DEMEROL Tablets and Oral Solution are for oral use only. Abuse of DEMEROL Tablets and Oral Solution pose a risk of overdose and death. DEMEROL Tablets have been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product. The risk is increased with concurrent use of DEMEROL Tablets with alcohol and other central nervous system depressants. Due to the presence of talc as one of the excipients in tablets, parenteral abuse of crushed tablets can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart disease. In addition, 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 the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), 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 opioid usage. Do not abruptly discontinue DEMEROL Tablets and Oral Solution in a patient physically dependent on opioids. Rapid tapering of DEMEROL 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 DEMEROL Tablets and Oral Solution, gradually taper the dosage using a patient-specific plan that considers the following: the dose of DEMEROL 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 a long duration 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 ), Warnings and Precautions ( 5.16 )] . 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 DEMEROL Tablets and Oral Solution 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, 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 techniques. 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 DEMEROL 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 DEMEROL Tablets and Oral Solution. Table 1: Clinically Significant Drug Interactions with DEMEROL Tablets and Oral Solution Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: Meperidine is contraindicated in patients who are receiving monoamine oxidase (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 DEMEROL 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 DEMEROL Tablets or Oral Solution 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 DEMEROL Tablets or Oral Solution and CYP2B6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of DEMEROL Tablets or Oral Solution is achieved [see Warnings and Precautions ( 5.6 )] . 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 DEMEROL Tablets or Oral Solution 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 DEMEROL Tablets or Oral Solution dosage until stable drug effects are achieved. Monitor 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 DEMEROL Tablets or Oral Solution 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 ( 5.6 ) ] . 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 DEMEROL Tablets or Oral Solution dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 or CYP2B6 inducer is discontinued, consider DEMEROL Tablets or Oral Solution 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. 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. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 , 5.4 , 5.7 )]. 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, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DEMEROL 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 DEMEROL Tablets or Oral Solution 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 DEMEROL Tablets or Oral Solution and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.4 , 5.7 )]. 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 DEMEROL 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 DEMEROL Tablets or Oral Solution 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 cimetidine and DEMEROL Tablets or Oral Solution is necessary, monitor patients for respiratory depression and sedation at frequent intervals. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with DEMEROL Tablets or Oral Solution because they may reduce analgesic effect of DEMEROL Tablets or Oral Solution 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. Chronic use of opioids 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 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 ) ] . 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 post-operative 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 [ s ee Drug Interaction s ( 7 ) ] . Ritonavir Plasma concentrations of the active metabolite normeperidine may be increased by ritonavir [ s ee Drug Interactions ( 7 )]. Acyclovir Plasma concentrations of meperidine and its metabolite, normeperidine, may be increased by acyclovir [ s ee 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 [ s ee 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. Chronic use of opioids 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 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 ) ] . 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 post-operative 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 [ s ee Drug Interaction s ( 7 ) ] . Ritonavir Plasma concentrations of the active metabolite normeperidine may be increased by ritonavir [ s ee Drug Interactions ( 7 )]. Acyclovir Plasma concentrations of meperidine and its metabolite, normeperidine, may be increased by acyclovir [ s ee 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 [ s ee Drug Interactions ( 7 )].

20210301

9

3 DOSAGE FORMS AND STRENGTHS Tablets 50 mg scored tablet (white, round and convex with a stylized “W” on one side and “D” over “35” on the other side) 100 mg scored tablet (white, round and convex with a stylized “W” on one side and “D” over “37” on the other side) Oral Solution Nonalcoholic, banana-flavored 50mg per 5mL (10 mg/mL), bottles of 16 fl. oz. Tablets: 50 mg and 100 mg. ( 3 ) Oral Solution: 50mg/5mL (10 mg/mL)

Demerol Meperidine Hydrochloride MEPERIDINE HYDROCHLORIDE MEPERIDINE CALCIUM SULFATE CALCIUM PHOSPHATE, DIBASIC, ANHYDROUS STARCH, CORN STEARIC ACID TALC W;D;35 Demerol Meperidine Hydrochloride MEPERIDINE HYDROCHLORIDE MEPERIDINE CALCIUM SULFATE CALCIUM PHOSPHATE, DIBASIC, ANHYDROUS STARCH, CORN STEARIC ACID TALC W;D;37

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 to 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 to 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.

NDA005010

Demerol

Meperidine Hydrochloride

30698-337

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL NDC 30698-335-01 Demerol (meperidine hydrochloride, USP) Tablets 50 mg 100 Tablets Rx Only PRINCIPAL DISPLAY PANEL NDC 30698-335-01 Demerol (meperidine hydrochloride, USP) Tablets 50 mg 100 Tablets Rx Only

Dosage and Administration ( 2.2 ) 03/2021 Warnings and Precautions ( 5.2 , 5.4 , 5.7 ) 03/2021

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 DEMEROL 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 DEMEROL 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 DEMEROL 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 DEMEROL Oral Solution to ensure that the dose is measured and administered accurately [see Warnings and Precautions ( 5.2 ) ] . 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 DEMEROL 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 DEMEROL Tablets or Oral Solution with others and to take steps to protect DEMEROL Tablets or Oral Solution 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 DEMEROL 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 ( 5.4 )] . 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 DEMEROL 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 ( 5.4 )]. 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. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions ( 5.4 )] . Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if DEMEROL Tablets or Oral Solution are 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 ( 5.7 ), Drug Interactions ( 7 )]. MAOI Interaction Inform patients not to take DEMEROL Tablets or Oral Solution while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking DEMEROL Tablets or Oral Solution [ see Warnings and Precautions ( 5.8 ), Drug Interactions ( 7 )] . 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 )] . 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 ( 5.11 )] . Important Administration Instructions Instruct patients how to properly take DEMEROL Tablets or Oral Solution. Advise patients never to use a household teaspoon or tablespoon to measure DEMEROL Oral Solution. Advise patients not to adjust the dose of DEMEROL Tablets or Oral Solution without consulting with a physician or other healthcare professional. Advise patients to dilute each dose of DEMEROL 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 DEMEROL Tablets and Oral Solution without first discussing a tapering plan with the prescriber [see Dosage and Administration ( 2.6 )]. Hypotension Inform patients that DEMEROL Tablets or Oral Solution 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 ( 5.12 )] . Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in DEMEROL 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 prolonged use of DEMEROL Tablets or Oral Solution 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 DEMEROL Tablets and Oral Solution 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 monitor 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 chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations ( 8.3 )]. Driving or Operating Heavy Machinery Inform patients that DEMEROL 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 ( 5.17 )] . Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions ( 6 ) ] . Manufactured for and Distributed by : Validus Pharmaceuticals LLC 119 Cherry Hill Road, Suite 310 Parsippany, NJ 07054 info@validuspharma.com www.validuspharma.com 1-866-982-5438 © 2020 Validus Pharmaceuticals LLC 60037-12 March 2021

Medication Guide DEMEROL® (de-meh-rol) (meperidine hydrochloride, USP) Tablets and Oral Solution, CII DEMEROL 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 DEMEROL Tablets and Oral Solution: Get emergency help right away if you take too much DEMEROL (overdose) Tablets or Oral Solution. When you first start taking DEMEROL 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 DEMEROL 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 DEMEROL Tablets and Oral Solution. They could die from taking it. Selling or giving away DEMEROL Tablets and Oral Solution is against the law. Store DEMEROL Tablets and Oral Solution away from children and in a safe location not accessible by others, including visitors to the home. Do not take DEMEROL 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. allergy to meperidine head injury, seizures ● liver, kidney, thyroid problems problems urinating ● pancreas or gallbladder problems abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems. Before taking DEMEROL Tablets and Oral Solution, tell your healthcare provider if you have a history of: Tell your healthcare provider if you are: pregnant or planning to become pregnant. Prolonged use of DEMEROL Tablets and Oral Solution during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding. DEMEROL Tablets and Oral Solution 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 DEMEROL Tablets and Oral Solution with certain other medicines can cause serious side effects that could lead to death. When taking DEMEROL Tablets and Oral Solution: Do not change your dose. Take DEMEROL Tablets and Oral Solution exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. Always use a calibrated measuring device for DEMEROL Oral Solution to correctly measure your dose. Never use a household teaspoon or tablespoon to measure DEMEROL Oral Solution. Mix each dose of DEMEROL 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 DEMEROL Tablets and Oral Solution regularly, do not stop taking DEMEROL Tablets and Oral Solution without talking to your healthcare provider. Dispose of expired, unwanted, or unused DEMEROL 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 DEMEROL Tablets and Oral Solution DO NOT: Drive or operate heavy machinery, until you know how DEMEROL Tablets or Oral Solution affects you. DEMEROL Tablets or Oral Solution 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 DEMEROL Tablets or Oral Solution may cause you to overdose and die. The possible side effects of DEMEROL 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 DEMEROL Tablets and Oral Solution. Call your doctor 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 Manufactured for and Distributed by: Validus Pharmaceuticals LLC, Parsippany, NJ, 07054 www.validuspharma.com or call 1-866-982-5438 This Medication Guide has been approved by the U.S. Food and Drug Administration . 60071-07 Issued: March 2021

8.5 Geriatric Use Clinical studies of DEMEROL Tablets and Oral Solution 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 DEMEROL Tablets or Oral Solution slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.7 , 5.9 )] . 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 Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.5 )] . Available data with DEMEROL Tablets or Oral Solution are 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 1200 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 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics 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 or 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. DEMEROL Tablets and Oral Solution are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including DEMEROL Tablets or Oral Solution, 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 ). 8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.5 )] . Available data with DEMEROL Tablets or Oral Solution are 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 1200 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 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics 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 or 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. DEMEROL Tablets and Oral Solution are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including DEMEROL Tablets or Oral Solution, 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 DEMEROL Tablets or Oral Solution and any potential adverse effects on the breastfed infant from DEMEROL Tablets or Oral Solution or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to DEMEROL Tablets or Oral Solution 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 Chronic use of opioids 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 DEMEROL Tablets and Oral Solution 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 DEMEROL Tablets or Oral Solution slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.7 , 5.9 )] . 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 DEMEROL 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 DEMEROL 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 DEMEROL (meperidine hydrochloride) Tablets 50 mg, are white, round, convex scored tablets debossed with “W” on one side and “D” over “35” on the other, and are supplied as: HDPE plastic bottles of 100 (NDC Number 30698-335-01) DEMEROL (meperidine hydrochloride) Tablets 100 mg, are white, round, convex scored Tablets debossed with “W” on one side and “D” over “37” on the other, and are supplied as: HDPE plastic bottles of 100 (NDC Number 30698-337-01) DEMEROL (meperidine hydrochloride) Oral Solution, 50mg per 5mL (10 mg/mL) is non-alcoholic, banana-flavored syrup, and is supplied in 16 fl. oz. bottles (NDC Number 30698-332-16). Store at 77°F (25°C); excursions permitted to 59° to 86°F (15° to 30°C) [See USP Controlled Room Temperature]. Store DEMEROL Tablets and Oral Solution securely and dispose of properly [see Patient Counseling Information ( 17 )] .

WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; AND MONOAMINE OXIDASE INHIBITORS (MAOIS) INTERACTIONS Risk of Medication Errors Ensure accuracy when prescribing, dispensing, and administering DEMEROL 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 ), Warning and Precautions ( 5.1 )]. Addiction, Abuse, and Misuse DEMEROL Tablets and Oral Solution expose 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 DEMEROL Tablets or Oral Solution , and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.2 )]. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products [ see Warnings and Precautions ( 5.3 ) ] . Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are st rongly encouraged to ● complete a REMS-compliant education program, ● counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products, ● emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacists, and ● consider other toots to improve patient, household, and community safety. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of DEMEROL Tablets and Oral Solution . Monitor for respiratory depression, especially during initiation of DEMEROL Tablets or Oral Solution, or following a dose increase [see Warnings and Precautions ( 5.4 )] . Accidental Ingestion Accidental ingestion of DEMEROL Tablets and Oral Solution , especially by children, can result in a fatal overdose of meperidine [see Warnings and Precautions ( 5.4 )] . Neonatal Opioid Withdrawal Syndrome Prolonged use of DEMEROL Tablets or Oral Solution during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions ( 5.5 )] . Cytochrome P450 3A4 (CYP3A4) Interaction The concomitant use of DEMEROL Tablets or 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 cytochrome P450 3A4 (CYP3A4) inducer may result in an increase in meperidine plasma concentration. Monitor patients receiving DEMEROL Tablets or Oral Solution, and any CYP3A4 inhibitor or inducer [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7 )] . 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 [see Warnings and Precautions ( 5.7 ), Drug Interactions ( 7 )] . ● Reserve concomitant prescribing of DEMEROL Tablets or Oral Solution and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate ● Limit dosages and durations to the minimum required. ● Follow patients for signs and symptoms of respiratory depression and sedation . Concomitant use of DEMEROL Tablets and Oral Solution with Monoamine O xidase Inhibitors (MAO Is ) Concomitant use of DEMEROL Tablets or Oral Solution with monoamine oxidase inhibitors (MAO Is ) can result in coma, severe respiratory depression, cyanosis, and hypotension. Use of DEMEROL Tablets or Oral Solution with MAO Is within last 14 days is contraindicated [see Contraindications ( 4 ), Warnings and Precautions ( 5.8 ), Drug Interactions ( 7 )] . WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; AND MONOAMINE OXIDASE INHIBITORS (MAOIS) INTERACTIONS See full prescribing information for complete boxed warning. • Ensure accuracy when prescribing, dispensing, and administering DEMEROL 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 ) • DEMEROL 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 ) • 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 ) • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. ( 5.4 ) • Accidental ingestion of DEMEROL Tablets or Oral Solution, especially by children, can result in a fatal overdose of meperidine. ( 5.4 ) • Prolonged use of DEMEROL 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 ) • Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in fatal overdose of meperidine ( 5.6 , 7 ) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.7 , 7 ) • Concomitant use of DEMEROL Tablets or Oral Solution with monoamine oxidase inhibitors (MAOIs) can result in coma, severe respiratory depression, cyanosis and hypotension. Use of DEMEROL Tablets or Oral Solution with MAOIs within the last 14 days is contraindicated. ( 4 , 5.8 , 6 )