DEMEROL

1 INDICATIONS AND USAGE DEMEROL Injection is indicated for preoperative medication, support of anesthesia, and obstetrical analgesia. DEMEROL Injection is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. DEMEROL Injection is indicated for preoperative medication, support of anesthesia, for obstetrical analgesia, and for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including DEMEROL Injection, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Use of ‎DEMEROL Injection for an extended period of time may increase the risk of ‎toxicity (e.g., seizures) from the accumulation of the meperidine metabolite, ‎normeperidine. ( 1 , 5.1 )‎ Limitations of Use: Because of the risks of addiction, abuse, misuse , overdose, and death , which can occur at any dosage or duration and persist over the course of therapy, [see Warnings and Precautions (5.1) ] , reserve opioid analgesics, including DEMEROL Injection, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Use of DEMEROL Injection for an extended period of time may increase the risk of toxicity (e.g., seizures) from the accumulation of the meperidine metabolite, normeperidine.

2 DOSAGE AND ADMINISTRATION • DEMEROL Injection should be prescribed only by healthcare ‎professionals who are knowledgeable about the use of ‎opioids and how to mitigate the associated risks. ( 2.1 )‎ • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. ‎Reserve titration to higher doses of DEMEROL ‎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 DEMEROL Injection. Consider this risk ‎when selecting an initial dose and when making dose ‎adjustments. ( 2.2 , 5.3 )‎ • Periodically reassess patients receiving DEMEROL Injection to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.2 ) • For Relief of Pain: Titrate the dose based upon the individual patient’s response to their ‎initial dose of DEMEROL 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 100 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 rapidly reduce or abruptly discontinue DEMEROL Injection in a physically‑dependent patient. ( 2.2 , 5.15 ) 2.1 Important Dosage and Administration Instructions • DEMEROL 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 DEMEROL 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 DEMEROL Injection.‎ Consider t…

5 WARNINGS AND PRECAUTIONS • Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced ‎Hyperalgesia (OIH) occurs when an opioid analgesic ‎paradoxically causes an increase in pain, or an increase in ‎sensitivity to pain. If OIH is suspected, carefully consider appropriately ‎decreasing the dose of the current opioid analgesic or ‎opioid rotation. ( 5.7 )‎ • Serotonin Syndrome with Concomitant Use of Serotonergic Drugs : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue DEMEROL Injection if serotonin syndrome is suspected. ( 5.8 ) • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration. ( 5.9 ) • Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.10 ) • Severe Hypotension : Monitor during dosage initiation and titration. Avoid use of DEMEROL Injection in patients with circulatory shock. ( 5.11 ) • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of DEMEROL Injection in patients with impaired consciousness or coma. ( 5.12 ) 5.1 Addiction, Abuse, and Misuse DEMEROL Injection contains meperidine, a Schedule II controlled substance. As an opioid, DEMEROL Injection exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed DEMEROL Injection. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6) ] . Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing DEMEROL Injection, and monitor all patients receiving DEMEROL Injection for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as DEMEROL Injection but use in such patients necessitates intensive counseling about the risks and proper use of DEMEROL Injection along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought for nonmedical use and are subject to diversion from ‎legitimate prescribed use. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents (e.g., naloxone, nalmefene), depending on the patient's clinical status [see Overdosage (10) ] . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during…

4 CONTRAINDICATIONS DEMEROL 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 (5.9) ] • Concurrent 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 MAOIs 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 )

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with DEMEROL Injection. Table 1: Clinically Significant Drug Interactions with DEMEROL 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 preexisting hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of acute opioid 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 DEMEROL 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 opioid overdose reversal agents in the treatment of these reactions are unknown. Examples: Phenelzine, tranylcypromine, linezolid Inhibitors of CYP3A4 and CYP2B6 Clinical Impact: The concomitant use of DEMEROL 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 DEMEROL Injection and CYP2B6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of DEMEROL 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) ] , potentially 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 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 DEMEROL 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 DEMEROL 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 DEMEROL Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 or CYP2B6 inducer is discontinued, consider DEMEROL Injection dosage reduction and monitor for signs of respiratory depression. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressan…

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4) ] . Available data with DEMEROL 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 adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4) ] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agents, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. DEMEROL 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 DEMEROL 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.

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, seizures, 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 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).‎ Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking op…