Drug Safety-related Labeling Changes (SrLC)

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DEMEROL (NDA-005010)

(MEPERIDINE HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/22/2025 (SUPPL-62)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

. . .

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed DEMEROL Tablets or Oral Solution. Addiction can occur at recommended doses 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 the 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 (6.2)].

. . .

Patients at increased risk may be prescribed opioids such as DEMEROL Tablets and Oral Solution, but use in such patients necessitates intensive counseling about the risks and proper use of DEMEROL Tablets and Oral Solution along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].

. . .

5.3 Life-Threatening Respiratory Depression

Additions and/or revisions underlined:

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, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

. . .

Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.2, 5.4)].

Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.4), Overdosage (10)].

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of DEMEROL Tablets or Oral Solution with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

. . .

If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.3), Overdosage (10)].

. . .

5.8 Fatal Interaction with Monoamine Oxidase Inhibitors (MAOIs)

Additions and/or revisions underlined:

Meperidine is contraindicated in patients who are receiving monoamine oxidase inhibitors (MAOIs) or those who have recently received such agents. Therapeutic doses of meperidine have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear, but may be related to a pre-existing 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.

Do not use DEMEROL Tablets or and Oral Solution in patients taking MAOIs or within 14 days of stopping such treatment.

Intravenous hydrocortisone or prednisolone has been used to treat severe reactions, with the addition of intravenous chlorpromazine in those cases exhibiting hypertension and hyperpyrexia. The usefulness and safety of opioid overdose reversal agents in the treatment of these reactions is unknown.

5.15 Risks of Gastrointestinal Complications

Subsection title revised.

Additions and/or revisions underlined:

. . .

Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate.

5.16 Seizures

Newly added subsection:

Meperidine may increase the risk of having a seizure in patients with or without a pre-existing seizure disorder. Prolonged use of meperidine may also increase the risk of seizure due to the accumulation of the meperidine metabolite, normeperidine.

Frequently evaluate patients with a history of seizure disorder for worsening seizure control and advise patients and caregivers to get emergency medical help right away in the event of a known or suspected seizure.

5.17 Withdrawal

Additions and/or revisions underlined:

Do not rapidly reduce or abruptly discontinue DEMEROL Tablets or Oral Solution in a patient physically dependent on opioids. When discontinuing DEMEROL Tablets or Oral Solution in a physically dependent patient, gradually taper the dosage. Rapid tapering of meperidine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.6), Drug Abuse and Dependence (9)].

. . .

6 Adverse Reactions

Additions and/or revisions underlined:

. . .

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.

. . .

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 opioids longer term [see Warnings and Precautions (5.15)].

Adverse Reactions from Observational Studies

A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months.

Over 12 months:

• approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and
• approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence (9.2)], respectively, as measured with a validated self-reported instrument.

A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.

The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

7 Drug Interactions

Additions and/or revisions underlined for Clinical Impact section of Monoamine Oxidase Inhibitors (MAOIs) of table; please refer to table for complete information:

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 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.

Additions and/or revisions underlined for Intervention section of Monoamine Oxidase Inhibitors (MAOIs) of table; please refer to table for complete information:

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 opioid overdose reversal agents in the treatment of these reactions is unknown.)

Additions and/or revisions underlined for Intervention section of Benzodiazepines and Other Central Nervous System (CNS) Depressants of table; please refer to table for complete information:

Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.4, 5.7)].

Additions and/or revisions underlined for Examples section of Benzodiazepines and Other Central Nervous System (CNS) Depressants of table; please refer to table for complete information:

Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol.

Additions and/or revisions underlined for Intervention section of Muscle Relaxants of table; please refer to table for complete information:

Because respiratory depression may be greater than otherwise expected, decrease the dosage of DEMEROL Tablets and 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 recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.4, 5.7)].

Newly added Examples section of Muscle Relaxants of table; please refer to table for complete information:

Cyclobenzaprine, metaxalone

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

. . .

Clinical Considerations

. . .

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 overdose reversal agent, such as naloxone or nalmefene, 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.

. . .

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

Important information about DEMEROL Tablets and Oral Solution:

• Get emergency help or call 911 right away if you take too much DEMEROL (overdose). 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. Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose.
• Taking DEMEROL Tablets and Oral Solution with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.

. . .

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

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 (e.g., non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids), and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.7), Drug Interactions (7)].

Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over- the-counter, or as part of a community-based program) [see Dosage and Administration (2.2), Warning 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 effects of opioid overdose reversal agents like naloxone and nalmefene 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 an opioid overdose reversal agent is administered [see Overdosage (10)].

Advise patients and caregivers:

• how to treat with the overdose reversal agent in the event of an opioid overdose.
• to tell family and friends about the opioid overdose reversal agent, 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 opioid overdose reversal agent. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

. . .

12/15/2023 (SUPPL-60)

Approved Drug Label (PDF)

Boxed Warning

Extensive changes; please refer to label for complete information

5 Warnings and Precautions

5.1 Risks of Accidental Overdose and Death Due to Medication Errors

Additions and/or revisions underlined:

…

Instruct patients and caregivers on how to measure and take or administer the correct dose of DEMEROL Oral Solution and to use extreme caution when measuring the dose. Strongly advise patients to obtain and always use a graduated device that can measure and deliver the prescribed dose accurately, and to never use household teaspoons or tablespoons to measure a dose because these are not accurate measuring devices [see Dosage and Administration (2.1)].

5.2 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

…

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing DEMEROL Tablets and Oral Solution, and reassess all patients receiving DEMEROL Tablets or Oral Solution 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 Tablets and Oral Solution, but use in such patients necessitates intensive counseling about the risks and proper use of DEMEROL Tablets and Oral Solution along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing DEMEROL Tablets and Oral Solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. 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.

…

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

…

Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

5.5 Neonatal Opioid Withdrawal Syndrome

Additions and/or revisions underlined:

Use of DEMEROL Tablets and Oral Solution for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), ].

5.7 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 (CYP3A4) Inhibitors and Inducers

Additions and/or revisions underlined:

…

When using DEMEROL and Oral Solution with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in DEMEROL Tablets and Oral Solution-treated patients, evaluate patients at frequent intervals and consider dosage reduction of DEMEROL Tablets and Oral Solution until stable drug effects are achieved.

…

When using DEMEROL Tablets and Oral Solution with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7)].

5.9 Opioid-Induced Hyperalgesia and Allodynia

Newly added section:

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.6); Warnings and Precautions (5.17)].

5.11 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

Additions and/or revisions underlined:

…

Regularly evaluate patients, particularly when initiating and titrating DEMEROL Tablets and Oral Solution and when DEMEROL Tablets and Oral Solution are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3), Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients.

5.13 Severe Hypotension

Additions and/or revisions underlined:

…

Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of DEMEROL Tablets or Oral Solution.

…

5.15 Risks of Use in Patients with Gastrointestinal Conditions

Additions and/or revisions underlined:

…

Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.16 Increased Risk of Seizures in Patients with Seizure Disorders

Additions and/or revisions underlined:

…

Regularly evaluate patients with a history of seizure disorders for worsened seizure control during DEMEROL Tablets and Oral Solution therapy. Use of DEMEROL Tablets and Oral Solution for an extended period of time may increase the risk of toxicity (e.g., seizures) from the accumulation of the meperidine metabolite, normeperidine.

6 Adverse Reactions

Additions and/or revisions underlined:

• Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.9)]

…

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 (5.9)].

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).

7 Drug Interactions

Extensive changes to Table 1; please refer to label for complete information

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.5)]. Available data with DEMEROL Tablets or Oral Solution are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. 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.

…

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.

…

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Infertility

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6), Clinical Pharmacology (12.2)], Nonclinical Toxicology (13.1)].

8.5 Geriatric Use

Additions and/or revisions underlined:

…

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 slowly in geriatric patients and frequent reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.11)].

Meperidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

8.6 Hepatic Impairment

Additions and/or revisions underlined:

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 regularly evaluate for signs of central nervous system and respiratory depression.

8.7 Renal Impairment

Additions and/or revisions underlined:

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 regularly evaluate for signs of central nervous system and respiratory depression.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Medication Errors

Strongly advise patients and caregivers to always use a graduated oral syringe or measuring cup, with metric units of measurements (i.e., mL), to correctly measure the prescribed amount of medication.

Inform patients and caregivers that oral dosing devices may be obtained from their pharmacy and to never use household teaspoons or tablespoons to measure DEMEROL Oral Solution [see Warnings and Precautions (5.1)].

If the prescribed dosage is changed, instruct patients and caregivers on how to correctly measure the new dose to avoid errors which could result in accidental overdose and death.

…

Hyperalgesia and Allodynia

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.9); Adverse Reactions (6.2)].

…

Important Administration Instructions

Instruct patients how to properly take DEMEROL Tablets or Oral Solution [see Dosage and Administration (2.1), Warnings and Precautions (5.1)].

• Strongly advise patients and caregivers to always use a graduated oral syringe/dosing cup when administering DEMEROL Oral Solution to correctly measure the prescribed amount of medication [see Warnings and Precautions (5.1)].

• Instruct patients and caregivers to never use household teaspoons or tablespoons to measure DEMEROL Oral Solution.

• Instruct patients and caregivers not to adjust the dose of DEMEROL Tablets or Oral Solution without consulting with a physician or other healthcare professional.

• Instruct patients and caregivers 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.

…

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that use of DEMEROL Tablets or Oral Solution for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)].

…

MEDICATION GUIDE

Additions and/or revisions underlined:

Tell your healthcare provider if you are:

• noticing your pain getting worse. If your pain gets worse after you take DEMEROL Tablets and Oral Solution, do not take more of DEMEROL Tablets and Oral Solution without first talking to your healthcare provider. Talk to your healthcare provider if the pain you have increases, if you feel more sensitive to pain, or if you have new pain after taking DEMEROL Tablets and Oral Solution.

• pregnant or planning to become pregnant. Use of DEMEROL Tablets and Oral Solution for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.

• breastfeeding. DEMEROL Tablets and Oral Solution passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs.

…

When taking DEMEROL Tablets and Oral Solution:

…

• For acute (short-term) pain, you may only need to take DEMEROL Tablets or Oral Solution for a few days. You may have some DEMEROL Tablets or Oral Solution left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused DEMEROL Tablets and Oral Solution.

03/04/2021 (SUPPL-59)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

… Patients at increased risk may be prescribed opioids such as DEMEROL Tablets or Oral Solution, but use in such patients necessitates intensive counseling about the risks and proper use of DEMEROL Tablets or Oral Solution along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].

5.4 Life-Threatening Respiratory Depression

Additions and/or revisions underlined:

… Accidental ingestion of even one dose of DEMEROL Tablets or Oral Solution, especially by children, can result in respiratory depression and death due to an overdose of meperidine.

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 Patient Counseling Information (17)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.6)].

Newly added information:

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. 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). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

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. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Warnings and Precautions (5.2, 5.7), Patient Counseling Information (17)].

5.7 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

… If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].

7 Drug Interactions

Table 1: Clinically Significant Drug Interactions with DEMEROL Tablets and Oral Solution

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Under Intervention, the following language is added:

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)].

Muscle Relaxants

Under Intervention, the following language is added:

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)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Important information about DEMEROL Tablets and Oral Solution:

Additions and/or revisions underlined:

• Get emergency help or call 911 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 emergency treatment of an opioid overdose.

Before taking DEMEROL Tablets or Oral Solution, tell your healthcare provider if you have a history of:

• abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.

Tell your healthcare provider if you are:

• living in a household where there are small children or someone who has abused street or prescription drugs

Get emergency medical help or call 911 right away if you have: …

PATIENT COUNSELING INFORMATION

Life-Threatening Respiratory Depression

Newly added information:

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)].

Newly added information:

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 Administrations (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.

10/07/2019 (SUPPL-58)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.4 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression

Newly added information to the end of this subsection:

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep- related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.

Additions and/or revisions underlined:

5.10 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of Demerol Tablets and Demerol Oral Solution with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

5.16 Withdrawal

Do not abruptly discontinue DEMEROL Tablets or Oral Solution in a patient physically dependent on opioids. When discontinuing DEMEROL Tablets or Oral Solution in a physically dependent patient, gradually taper the dosage. Rapid tapering of meperidine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain.

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including DEMEROL Tablets and Oral Solution.

7 Drug Interactions

Table 1: Clinically Significant Drug Interactions with DEMEROL Tablets and Oral Solution

Serotonergic Drugs

Additions and/or revisions underlined:

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 (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

09/18/2018 (SUPPL-57)

Approved Drug Label (PDF)

Boxed Warning

In the boxed warning title, the following underlined language was added after “ADDICTION, ABUSE, AND MISUSE”: RISK EVALUATION AND MITIGATION STRATEGY (REMS)

Addition of the following information:

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 Risk Evaluation and Mitigation Strategy (REMS) for these products. 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 strongly 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 pharmacist, and
• consider other tools to improve patient, household, and community safety.

5 Warnings and Precautions

Addition of the following subsection after the warning regarding addiction, abuse and misuse:

5.3 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 Risk Evaluation and Mitigation Strategy (REMS) for these products. 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 strongly encouraged to do all of the following:

• Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.

• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.

• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.

• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503- 0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

08/16/2017 (SUPPL-55)

Approved Drug Label (PDF)

Boxed Warning

Addition of or Oral Solution to DEMEROL Tablets throughout this section

Addition of the following:

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.

5 Warnings and Precautions

5.1 Risks of Accidental Overdose and Death Due to Medication Errors

Addition of the following:

Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with meperidine solutions of different concentrations, when prescribing, dispensing, and administering DEMEROL Oral Solution. Ensure that the dose is communicated clearly and dispensed accurately.

Do not use a teaspoon or a tablespoon to measure a dose. A household teaspoon is not an adequate measuring device. Given the inexactitude of the household spoon measure and the risk of mistakenly using a tablespoon instead of a teaspoon, which could lead to overdosage, it is strongly recommended that caregivers obtain and use a calibrated measuring device. Healthcare providers should recommend a calibrated device that can measure and deliver the prescribed dose accurately, and instruct caregivers to use extreme caution in measuring the dosage.

6 Adverse Reactions

Addition of the following:

To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1- 866-982-5438 (1-866-9VALIDUS) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Addition of or Oral Solution to DEMEROL Tablets throughout this section.

PATIENT COUNSELING INFORMATION

Addition of the following:

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.

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.

Additions and/or revisions underlined:

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.

• If patients have been receiving treatment with DEMEROL Tablets or Oral Solution for more …

12/16/2016 (SUPPL-54)

Approved Drug Label (PDF)

Boxed Warning

(section added)

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; and MONOAMINE OXIDASE INHIBITORS (MAOIs) INTERACTIONS

 

Addiction, Abuse, and Misuse

DEMEROL Tablets exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing DEMEROL Tablets, and monitor all patients regularly for the development of these behaviors and conditions.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of DEMEROL Tablets. Monitor for respiratory depression, especially during initiation of DEMEROL Tablets or following a dose increase.

Accidental Ingestion

Accidental ingestion of DEMEROL Tablets, especially by children, can result in a fatal overdose of meperidine .

Neonatal Opioid Withdrawal Syndrome

Prolonged use of DEMEROL Tablets 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.

Cytochrome P450 3A4 (CYP3A4) Interaction

The concomitant use of DEMEROL Tablets 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 and any CYP3A4 inhibitor or inducer.

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

•         Reserve concomitant prescribing of DEMEROL Tablets 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 with Monoamine Oxidase Inhibitors (MAOIs)

Concomitant use of DEMEROL Tablets with monoamine oxidase inhibitors (MAOIs) can result   in   coma,   severe   respiratory   depression,   cyanosis,   and   hypotension.   Use   of DEMEROL Tablets with MAOIs within last 14 days is contraindicated.

4 Contraindications

(additions underlined)

DEMEROL Tablets are contraindicated in patients with:

·       Significant respiratory depression

·       Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

·       Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days of having taken an MAOI

·       Known or suspected gastrointestinal obstruction, including paralytic ileu

·       Hypersensitivity to meperidine or to any of other ingredients of the product (e.g., anaphylaxis)

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

(additions underlined)

DEMEROL Tablets contain meperidine, a Schedule II controlled substance. As an opioid, DEMEROL Tablets exposes users to the risks of addiction, abuse and misuse.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed DEMEROL Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing DEMEROL Tablets, and monitor all patients receiving DEMEROL Tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as DEMEROL Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of DEMEROL Tablets along with intensive monitoring for signs of addiction, abuse, and misuse.

 

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing DEMEROL Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. 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.

DEMEROL Tablets have been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose or death.

5.10 Severe Hypotension

(additions underlined)

DEMEROL Tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of DEMEROL Tablets. In patients with circulatory shock, DEMEROL Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of DEMEROL Tablets in patients with circulatory shock.

5.11 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

(additions underlined)

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), DEMEROL may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with DEMEROL Tablets.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of

DEMEROL Tablets in patients with impaired consciousness or coma.

5.12 Risks of Use in Patients with Gastrointestinal Conditions

(subsection added)

DEMEROL Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The meperidine in DEMEROL Tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

(subsection revised)

The meperidine in DEMEROL Tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. If dosage is escalated substantially above recommended levels because of tolerance development, seizures may occur in individuals without a history of seizures disorders. Monitor patients with a history of seizure disorders for worsened seizure control during DEMEROL Tablets therapy. Prolonged meperidine use may increase the risk of toxicity (e.g., seizures) from the accumulation of the meperidine metabolite, normeperidine.

5.14 Withdrawal

(subsection added)

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including DEMEROL Tablets. In these patients, mixed agonist/antagonist and partia agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms due to competitive blocking of receptors.

When discontinuing DEMEROL Tablets in a physically-dependent patient, gradually taper the dosage. Do not abruptly discontinue DEMEROL Tablets in these patients.

5.15 Risks of Driving and Operating Machinery

(additions underlined)

DEMEROL Tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of DEMEROL Tablets and know how they will react to the medication.

5.16 Risks in Patients with Pheochromocytoma

(subsection added)

In patients with pheochromocytoma, DEMEROL Tablets has been reported to provoke hypertension.

5.2 Life-Threatening Respiratory Depression

(subsection added)

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended.     Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status.Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of DEMEROL Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of DEMEROL Tablets.

To reduce the risk of respiratory depression, proper dosing and titration of DEMEROL Tablets are essential .Overestimating the DEMEROL Tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of DEMEROL Tablets, especially by children, can result in respiratory depression and death due to an overdose of meperidine.

5.3 Neonatal Opioid Withdrawal Syndrome

(subsection added)

Prolonged use of DEMEROL Tablets during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.   Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

5.4 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 (CYP3A4) Inhibitors and Inducers

(subsection added)

Concomitant use of DEMEROL Tablets with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of meperidine and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression, particularly when an inhibitor is   added   after a stable dose of   DEMEROL Tablets   is   achieved.   Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in DEMEROL Tablets-treated patients may increase meperidine plasma concentrations and prolong opioid adverse reactions. When using DEMEROL with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in DEMEROL Tablets- treated patients, monitor patients closely at frequent intervals and consider dosage reduction of DEMEROL Tablets until stable drug effects are achieved.

Concomitant use of DEMEROL Tablets with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease meperidine plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to meperidine. When using DEMEROL Tablets with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur.

5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

(subsection added)

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of DEMEROL Tablets with benzodiazepines or other CNS depressants (e.g., non- benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when DEMEROL Tablets is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.

5.6 Fatal Interaction with Monoamine Oxidase Inhibitors (MAOIs)

(additions underlined)

Meperidine is contraindicated in patients who are receiving monoamine oxidase inhibitors (MAOIs) or those who have recently received such agents.   Therapeutic doses of meperidine have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear, but may be related to a preexisting hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of acute narcotic overdose. Serotonin syndrome with agitation, hyperthermia, diarrhea, tachycardia, sweating, tremors and impaired consciousness may also occur. In other reactions the predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension.

Do not use DEMEROL Tablets 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.

5.7 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

(additions underlined)

The use of DEMEROL Tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: DEMEROL Tablets-treated patients with significant chronic  obstructive pulmonary disease or cor pulmonale, and those with a  substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of respiratory drive including apnea, even at recommended dosages of DEMEROL.

Debilitated Patients:  Life- threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

Monitor such patients closely, particularly when initiating and titrating DEMEROL Tablets and when DEMEROL Tablets are given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

5.8 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

 

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of DEMEROL Tablets with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), St John’s wort, tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue DEMEROL Tablets if serotonin syndrome is suspected.

5.9 Adrenal Insufficiency

(subsection added)

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

6 Adverse Reactions

(additions underlined)

The following serious adverse reactions are described, or described in greater detail, in other sections:

 

•         Addiction, Abuse, and Misuse

•         Life-Threatening Respiratory Depression

•         Neonatal Opioid Withdrawal Syndrome

•         Interactions with Benzodiazepines or Other CNS Depressants

•         Serotonin Syndrome

•         Adrenal Insufficiency

•         Severe Hypotension

•         Gastrointestinal Adverse Reactions

•         Seizures

•         Withdrawal

 

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

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

7 Drug Interactions

(Extensive additions and revisions, please refer to Table 1 in label)

8 Use in Specific Populations

8.1 PREGNANCY

(PLLR conversion, please refer to label)

8.2 Lactation

(PLLR conversion)

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 and any potential adverse effects on the breastfed infant from DEMEROL Tablets or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to DEMEROL Tablets 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

(PLLR conversion)

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.

8.5 Geriatric Use

(additions underlined)

Clinical studies of DEMEROL Tablets 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 slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression.

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

(additions underlined)

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 slowly in patients with hepatic impairment and monitor closely for signs of central nervous system and respiratory depression.

8.7 Renal Impairment

(additions underlined)

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 slowly in patients with renal impairment and monitor closely for signs of central nervous system and respiratory depression.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Extensive additions, please refer to label)

Medication Guide

(Newly added, please refer to label)

Other

(PLR conversion and revisions to the Package Insert to incorporate the opioid analgesic template language)