Drug Safety-related Labeling Changes (SrLC)

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MEPERGAN (NDA-011730)

(MEPERIDINE HYDROCHLORIDE; PROMETHAZINE HYDROCHLORIDE)

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

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12/22/2025 (SUPPL-34)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 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 MEPERGAN 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 (6.2)].

. . .

5.2 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 (e.g., naloxone, nalmefene), 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.

. . .

5.3 Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

The sedative action of promethazine hydrochloride is additive to the sedative effects of central nervous system depressants; therefore, agents such as alcohol, barbiturates, and opioid analgesics should either be eliminated or given in reduced dosage in the presence of promethazine hydrochloride. When given concomitantly with promethazine hydrochloride, the dose of barbiturates should be reduced by at least one-half and the dose of analgesic depressants, such as morphine or meperidine, should be reduced by one-quarter to one-half.

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of MEPERGAN Injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/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.

. . .

5.6 Fatal Interaction with Monoamine Oxidase Inhibitors

Additions and/or revisions underlined:

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.

Do not use MEPERGAN 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 is unknown.

5.13 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 if OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2)].

5.14 Seizures

Additions and/or revisions underlined:

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 accumulation of the meperidine metabolite, normeperidine.

Frequently reevaluate 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.

5.15 Withdrawal

Additions and/or revisions underlined:

. . .

When discontinuing MEPERGAN Injection, gradually taper the dosage [see Dosage and Administration (2.4)]. Do not rapidly reduce or abruptly discontinue MEPERGAN Injection [see Drug Abuse and Dependence (9.3)].

5.21 Intravenous Use

Additions and/or revisions underlined:

If necessary, MEPERGAN Injection may be given intravenously, but the injection should be given very slowly, preferably in the form of a diluted solution. Rapid intravenous injection of MEPERGAN Injection, increases the incidence of adverse reactions; severe respiratory depression, apnea, hypotension, peripheral circulatory collapse, and cardiac arrest have occurred. MEPERGAN Injection should not be administered intravenously unless an opioid overdose reversal agent and the facilities for assisted or controlled respiration are immediately available. When MEPERGAN Injection is given parenterally, especially intravenously, the patient should be lying down.

. . .

6 Adverse Reactions

Additions and/or revisions underlined:

. . .

Other adverse reactions include:

Central Nervous System: Euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, seizures, transient hallucinations and disorientation, visual disturbances and, rarely, extrapyramidal reactions.

. . .

Opioid-Induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking higher 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 (5.13)].

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); please refer to table for complete information:

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)]

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

Do not use MEPERGAN 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.

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

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

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. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. MEPERGAN 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 MEPERGAN 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.

. . .

12/15/2023 (SUPPL-33)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions underlined)

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF MEPERGAN

Addiction, Abuse, and Misuse

Because the use of MEPERGAN Injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of MEPERGAN Injection, especially during the initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of MEPERGAN are essential. [see Warnings and Precautions (5.2)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of MEPERGAN Injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3), Drug Interactions (7)].

Neonatal Opioid Withdrawal Syndrome (NOWS)

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risks of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.4)].

Cytochrome P450 3A4 Interaction

The concomitant use of MEPERGAN Injection with all cytochrome P450 3A4 inhibitors may result in an increase in meperidine plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in meperidine plasma concentration. Regularly evaluate patients receiving MEPERGAN Injection and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.5), Drug Interactions (7)].

Concomitant Use of MEPERGAN Injection with Monoamine Oxidase (MAO) Inhibitors

Concomitant use of MEPERGAN Injection with monoamine oxidase (MAO) inhibitors can result in coma, severe respiratory depression, cyanosis, and hypotension. Use of MEPERGAN Injection with MAO inhibitors within last 14 days is contraindicated [see Contraindications (4), Warnings and Precautions (5.6), Drug Interactions (7)].

5 Warnings and Precautions

5.2 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 antagonists, 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.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of MEPERGAN Injection, the risk is greatest during the initiation of therapy or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of MEPERGAN Injection are essential [see Dosage and Administration (2)]. Overestimating the MEPERGAN Injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

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 (2.4)].

5.3 Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants

(Newly added subsection)

The sedative action of promethazine hydrochloride is additive to the sedative effects of central nervous system depressants; therefore, agents such as alcohol, barbiturates, and narcotic analgesics should either be eliminated or given in reduced dosage in the presence of promethazine hydrochloride. When given concomitantly with promethazine hydrochloride, the dose of barbiturates should be reduced by at least one-half and the dose of analgesic depressants, such as morphine or meperidine, should be reduced by one-quarter to one-half.

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of MEPERGAN Injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non- benzodiazepines sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). 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 [see Drug Interactions (7)].

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. Monitor patients closely for signs and symptoms of respiratory depression and sedation.

5.4 Neonatal Opioid Withdrawal Syndrome

(Additions and/or revisions underlined)

Use of MEPERGAN Injection 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 management by neonatology experts will be available at delivery [see Use in Specific Populations (8.1)].

5.7 Opioid-Induced Hyperalgesia and Allodynia

(Newly added subsection)

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 biological 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), Warnings and Precautions (5.2)].

5.8 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

(Newly added subsection)

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of MEPERGAN Injection 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, trazadone, 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) [see Drug Interactions (7)]. 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) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of concomitant use but may occur later than that. Discontinue MEPERGAN Injection if serotonin syndrome is suspected.

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

(Additions and/or revisions underlined)

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

…

Monitor such patients closely, particularly when initiating and titrating MEPERGAN Injection and when MEPERGAN Injection is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2, 5.3), Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients

6 Adverse Reactions

(Additions and/or revisions underlined)

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 [see Warnings and Precautions (5.9)]

• 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)]

…

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).

8 Use in Specific Populations

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

(Additions and/or revisions underlined)

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 MEPERGAN Injection in pregnant women 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, promethazine, or the combination. 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 2.6 and 4.4 times the total human daily dose of 400 mg meperidine hydrochloride. Increased resorptions of fetuses in pregnant mice and rats and skeletal fragility, decreased pup weight, and developmental delays were reported in rat pups born to dams treated with promethazine during gestation at doses within the human dosing range during gestation have been reported [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.

8.5 Geriatric Use

(Additions and/or revisions underlined)

Elderly patients (aged 65 years or older) may have increased sensitivity to meperidine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of MEPERGAN Injection slowly in geriatric patients and monitor for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.9)].

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Addiction, Abuse, and Misuse

Inform patients that the use of MEPERGAN Injection, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)].

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting MEPERGAN Injection or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)].

Hyperalgesia and Allodynia

Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.7), Adverse Reactions (6)].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop after discharge from the hospital. Instruct patients to inform their healthcare provider if they are taking or plan to take serotonergic medications [see Warnings and Precautions (5.8), Drug Interactions (7)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].

10/07/2019 (SUPPL-32)

5 Warnings and Precautions

5.2 Life-Threatening Respiratory Depression

Newly added information to the end of the 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.

5.8 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Additions and/or revisions underlined:

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of MEPERGAN Injection 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).

7 Drug Interactions

Clinically Significant Drug Interactions with MEPERGAN Injection

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).

12/16/2016 (SUPPL-31)

Approved Drug Label (PDF)

Boxed Warning

(section added)

WARNING: RISK OF ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; and NEONATAL OPIOID WITHDRAWAL SYNDROME

Addiction, Abuse, and Misuse

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

Life-Threatening Respiratory Depression

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

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Mepergan injection 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.

4 Contraindications

(additions underlined)

Mepergan injection is contraindicated in patients with:

• Significant respiratory depression

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

• Known or suspected gastrointestinal obstruction, including paralytic ileus

• Hypersensitivity to meperidine or promethazine

• Under no circumstances should Mepergan be given by intra-arterial injection, due to the likelihood of severe arteriospasm and the possibility of resultant gangrene

• Mepergan should not be given by the subcutaneous route; evidence of chemical irritation has been noted, and necrotic lesions have resulted on rare occasions following subcutaneous injection. The preferred parenteral route of administration is by deep intramuscular injection.

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

(subsection added)

Mepergan injection contains meperidine HCl, a Schedule II controlled substance. As an opioid, Mepergan injection 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 Mepergan injection. 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 Mepergan injection, and monitor all patients receiving Mepergan injection for the development of these behaviors or 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 Mepergan injection, but use in such patients necessitates intensive counseling about the risks and proper use of Mepergan injection along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug users and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Mepergan injection. 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.

5.10 Risks of Use in Patients with Gastrointestinal Conditions

(subsection added)

Mepergan injection is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.

The meperidine HCl in Mepergan injection 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.

5.11 Increased Risks of Seizures in Patients with Seizure Disorders

(subsection added)

The meperidine HCl in Mepergan injection 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. Monitor patients with a history of seizure disorders for worsened seizure control during Mepergan injection therapy.

5.12 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 opiod agonist analgesic, including Mepergan injection. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.

When discontinuing Mepergan injection, gradually taper the dosage. Do not abruptly discontinue Mepergan injection.

5.13 Risk of Driving and Operating Machinery

(subsection added)

Mepergan injection 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 Mepergan injection and know how they will react to the medication.

5.14 Supraventricular Tachycardias

(subsection revised, additions underlined)

Meperidine should be used with caution in patients with atrial flutter and other supraventricular tachycardias because of a possible vagolytic action which may produce a significant increase in the ventricular response rate.

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 Mepergan injection, 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 Mepergan injection.

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

5.3 Neonatal Opioid Withdrawal Syndrome

(subsection added)

Prolonged use of Mepergan injection 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. 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.

5.4 Risk due to Interactions with Central Nervous System Depressants

(subsection added)

Hypotension, profound sedation, respiratory depression, coma, and death may result if Mepergan injection is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids).

When considering the use of Mepergan injection in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that can cause CNS depression. If the decision to begin Mepergan injection is made, start with a lower dosage of Mepergan injection, monitor patients for signs of respiratory depression, sedation, and hypotension, and consider using a lower dose of the concomitant CNS depressant.

The sedative action of promethazine hydrochloride is additive to the sedative effects of central nervous system depressants; therefore, agents such as alcohol, barbiturates, and narcotic analgesics should either be eliminated or given in reduced dosage in the presence of promethazine hydrochloride. When given concomitantly with promethazine hydrochloride, the dose of barbiturates should be reduced by at least one-half and the dose of analgesic depressants, such as morphine or meperidine, should be reduced by one-quarter to one-half.

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

(subsection added)

The use of Mepergan injection 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: Mepergan injection -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 decreased respiratory drive including apnea, even at recommended doses of Mepergan injection.

Elderly, Cachetic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachetic, 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 Mepergan injection and when Mepergan injection is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

5.6 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

(subsection added)

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of Mepergan injection 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, trazadone, tramadol), 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). 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 Mepergan injection if serotonin syndrome is suspected.

5.7 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.

5.8 Severe Hypotension

(subsection added)

Mepergan injection 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 Mepergan injection. In patients with circulatory shock, Mepergan injection may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Mepergan injection in patients with circulatory shock.

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

(subsection added)

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), Mepergan injection 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 Mepergan injection.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Mepergan injection in patients with impaired consciousness or coma.

6 Adverse Reactions

6.1 Clinical Trials Experience

(subsection added)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

(subsection added)

The following adverse reactions have been identified during post approval use of meperidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliable estimate their frequency or establish a causal relationship to drug exposure.

·       Serotonin syndrome

·       Adrenal insufficiency

·       Anaphylaxis

Androgen deficiency: Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

(subsection revised, 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 CNS Depressants

·       Serotonin Syndrome

·       Adrenal Insufficiency

·       Severe Hypotension

·       Gastrointestinal Adverse Reactions

·       Seizures

·       Withdrawal

The major hazards of meperidine, as with other narcotic 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 light-headedness, 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:

Central Nervous System: Euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, transient hallucinations and disorientation, visual disturbances and, rarely, extrapyramidal reactions.

Gastrointestinal: Dry mouth, constipation, biliary-tract spasm.

Cardiovascular: Flushing of the face, tachycardia, bradycardia, palpitation, faintness, syncope.

Cardiovascular effects from promethazine have been rare. Minor increases in blood pressure and occasional mild hypotension have been reported. Venous thrombosis at the injection site has been reported. Intra-arterial injection of Mepergan may result in gangrene of the affected extremity.

Genitourinary: Urinary retention.

Allergic: Pruritus, urticaria, other skin rashes, wheal and flare over the vein with IV injection.

Photosensitivity, although extremely rare, has been reported. Occurrence of photosensitivity may be a contraindication to further treatment with promethazine or related drugs.

Other: Pain at injection site; local tissue irritation, induration, and possible tissue necrosis, particularly when injection is repeated at same site; antidiuretic effect.

Patients may occasionally complain of autonomic reactions, such as dryness of the mouth, blurring of vision and, rarely, dizziness following the use of promethazine.

Very rare cases have been reported where patients receiving promethazine have developed leukopenia. In one instance agranulocytosis has been reported. In nearly every instance reported, other toxic agents known to have caused these conditions have been associated with the administration of promethazine.

7 Drug Interactions

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

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with Mepergan injection are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Meperidine should not be used in pregnant women prior to the labor period, unless in the udgement of the physician the potential benefits outweigh the possible hazards, because safe use in pregnancy prior to labor has not been established relative to possible adverse effects on fetal development.

When used as an obstetrical analgesic, meperidine crosses the placental barrier and can produce respiratory depression in the newborn; resuscitation may be required

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Mepergan 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 Mepergan 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.

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 Mepergan injection and any potential adverse effects on the breastfed infant from Mepergan injection or from the underlying maternal condition.

Clinical Considerations

Infants exposed to Mepergan injection through breast milk should be monitored 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)

Elderly patients (aged 65 years or older) may have increased sensitivity to meperidine In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Mepergan injection slowly in geriatric patients.

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

17 PATIENT COUNSELING INFORMATION

(new section added)

Addiction, Abuse, and Misuse

Inform patients that the use of Mepergan injection, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death. Instruct patients not to share Mepergan injection with others and to take steps to protect Mepergan injection from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Mepergan injection or when the dosage is increased, and that it can occur even at recommended dosages Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Interactions with CNS Depressants

Inform patients that potentially serious additive effects may occur if Mepergan injection is used with CNS depressants and to seek medical attention if they experience increased sedation of difficulty breathing.

Serotonin Syndrome

Inform patients that Mepergan injection could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications.

Hypotension

Inform patients that Mepergan injection may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).

Anaphylaxis

Inform patients that anaphylaxis have been reported with ingredients contained in Mepergan injection. Advise patients how to recognize such a reaction and when to seek medical attention.

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform patients that prolonged use of Mepergan injection during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that Mepergan injection can (or may) cause fetal harm and to inform the prescriber of a known or suspected pregnancy.

Lactation

Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs .

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

Other

(PLR conversion and additional revisions to the Package Insert to incorporate the opioid

analgesic template language)