PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL

NDC 0641-6054-01 Rx only****
Meperidine
HCl Injection, USP
100 mg/mL CII
For IM, SC or
slow IV use
Do not use
if precipitated
****1 mL Vial


NDC 0641-6054-25 Rx only****
Meperidine
HCl Injection, USP
100 mg/mL CII
For Intramuscular, Subcutaneous
or slow Intravenous use
****25 x 1 mL Single Dose Vials


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RECENT MAJOR CHANGES SECTION

Highlight: Boxed Warning 12/2023

Indications and Usage (1) 12/2023

Dosage and Administration (2.1,2.2) 12/2023

Warnings and Precautions (5.8) 12/2023

RECENT MAJOR CHANGES

Boxed Warning 12/2023

Indications and Usage (1) 12/2023

Dosage and Administration (2.1,2.2) 12/2023

Warnings and Precautions (5.8) 12/2023

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DESCRIPTION SECTION

11 DESCRIPTION

Meperidine Hydrochloride Injection, USP is an opioid agonist, available as a sterile aqueous solution, for intramuscular, subcutaneous or slow intravenous administration.

Each mL contains meperidine hydrochloride, either 25 mg, 50 mg or 100 mg in Water for Injection. Buffered with acetic acid-sodium acetate. pH 3.5-6.0.

The meperidine hydrochloride chemical name is 4-Piperidinecarboxylic acid, 1- methyl-4-phenyl-,ethyl ester, hydrochloride. The molecular weight is 283.79. Its molecular formula is C15H21NO2·HCl, and it has the following chemical structure.


Meperidine hydrochloride is a white crystalline substance with a melting point of 186° C to 189° C. It is readily soluble in water and has a neutral reaction and a slightly bitter taste. The solution is not decomposed by a short period of boiling.

CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Meperidine hydrochloride is an opioid agonist with multiple actions qualitatively similar to those of morphine; the most prominent of these involve the central nervous system and organs composed of smooth muscle. The principal actions of therapeutic value are analgesia and sedation.

12.2 Pharmacodynamics

Effects on the Central Nervous System

Meperidine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Meperidine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Meperidine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid- induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects of the Cardiovascular System

Meperidine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, and sweating and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormones (LH) in humans [see Adverse Reactions (6)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Use of opioids for an extended period of time may influence the hypothalamic- pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of meperidine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.2)].

Meperidine, in 60 mg to 80 mg parenteral doses, is approximately equivalent in analgesic effect to 10 mg of morphine. The onset of action is slightly more rapid than with morphine, and the duration of action is slightly shorter. Meperidine is significantly less effective by the oral than by the parenteral route, but the exact ratio of oral to parenteral effectiveness is unknown.

Concentration–Adverse Reaction Relationships

There is a relationship between increasing meperidine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.2)].

12.3 Pharmacokinetics

Elimination

The half-life of meperidine is 2 to 5 hours, and the half-life of normeperidine is 15 to 30 hours.

Metabolism

Meperidine is metabolized through biotransformation. In vitro data show meperidine is metabolized to normeperidine in liver mainly by CYP3A4 and CYP2B6.

Excretion

Meperidine and normeperidine are excreted by kidneys.

Hepatic Impairment

The elimination half-life is 3 to 8 hours in healthy volunteers and is 1.3 to 2 times greater in post-operative or cirrhotic patients.

Age

In clinical studies reported in the literature, changes in several pharmacokinetic parameters with increasing age have been observed. The initial volume of distribution and steady-state volume of distribution may be higher in elderly patients than in younger patients. The free fraction of meperidine in plasma may be higher in patients over 45 years of age than in younger patients.

Drug Interactions Studies

Phenytoin: The hepatic metabolism of meperidine may be enhanced by phenytoin. Concomitant administration resulted in reduced half-life and bioavailability with increased clearance of meperidine in healthy subjects; however, blood concentrations of normeperidine were increased [see Drug Interactions, (7)].

Ritonavir: Plasma concentrations of the active metabolite normeperidine may be increased by ritonavir [see Drug Interactions, (7)].

Acyclovir: Plasma concentrations of meperidine and its metabolite, normeperidine, may be increased by acyclovir [see Drug Interactions, (7)].

Cimetidine: Cimetidine reduced the clearance and volume of distribution of meperidine and also the formation of the metabolite, normeperidine, in healthy subjects [see Drug Interactions, (7)].

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DOSAGE FORMS & STRENGTHS SECTION

Highlight: * Single Dose vials: 25 mg/mL, 50 mg/mL and 100 mg/mL. (3)

3 DOSAGE FORMS AND STRENGTHS

Single Dose vials: 25 mg/mL, 50 mg/mL and 100 mg/mL.

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CONTRAINDICATIONS SECTION

Highlight: * Significant respiratory depression. (4)

• Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. (4)
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAIOs within the last 14 days. (7)
• Known or suspected gastrointestinal obstruction, including paralytic ileus. (4)
• Hypersensitivity to meperidine or to any other ingredients of the product. (4)

4 CONTRAINDICATIONS

Meperidine Hydrochloride Injection is contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.2)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.2)]
• Concomitant use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.6), Drug Interactions (7)]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.13)]
• Hypersensitivity to meperidine (e.g., anaphylaxis) [see Adverse Reactions (6)]

BOXED WARNING SECTION

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

HYDROCHLORIDE INJECTION

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DRUG INTERACTIONS SECTION

Highlight: * Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Meperidine Hydrochloride Injection because they may reduce analgesic effect of Meperidine Hydrochloride Injection or precipitate withdrawal symptoms. (7)

7 DRUG INTERACTIONS

Table 1 includes clinically significant drug interactions with Meperidine Hydrochloride Injection.

Table 1: Clinically Significant Drug Interactions with Meperidine Hydrochloride Injection

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: Pregnancy: May cause fetal harm. (8.1)

Geriatric Patients: Use caution during dose selection, starting at the low end of the dosing range while carefully monitoring for side effects. (8.5)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Prolonged use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)]. Available data with Meperidine Hydrochloride Injection are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics (see Clinical Considerations). Formal animal reproduction studies have not been conducted with meperidine. Neural tube defects (exencephaly and cranioschisis) have been reported in hamsters administered a single bolus dose of meperidine during a critical period of organogenesis at 0.85 and 1.5 times the total human daily dose of 1200 mg. [see Data]

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4)].

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho- physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Meperidine Hydrochloride Injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Meperidine Hydrochloride Injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Animal Data

Formal reproductive and developmental toxicology studies for meperidine have not been completed.

In a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of meperidine hydrochloride (127 and 218 mg/kg, respectively) on Gestation Day 8 to pregnant hamsters (0.85 and 1.5 times the total daily dose of 1200 mg/day based on body surface area). The findings cannot be clearly attributed to maternal toxicity.

8.2 Lactation

Risk Summary

Meperidine appears in the milk of nursing mothers receiving the drug. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Meperidine Hydrochloride Injection and any potential adverse effects on the breastfed infant from Meperidine Hydrochloride Injection or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to Meperidine Hydrochloride Injection through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

8.3 Females and Males of Reproductive Potential

Infertility

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

8.4 Pediatric Use

The safety and efficacy of Meperidine Hydrochloride Injection in patients less than 18 years of age have not been established.

The safety and effectiveness of meperidine in pediatric patients has not been established. Literature reports indicate that meperidine has a slower elimination rate in neonates and young infants compared to older children and adults. Neonates and young infants may also be more susceptible to the effects, especially the respiratory depressant effects. If meperidine use is contemplated in neonates or young infants, any potential benefits of the drug need to be weighed against the relative risk of the patient.

8.5 Geriatric Use

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

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Meperidine Hydrochloride Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.2)].

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

8.6 Hepatic Impairment

Accumulation of meperidine and/or its active metabolite, normeperidine, can also occur in patients with hepatic impairment. Elevated serum levels have been reported to cause central nervous system excitatory effects. Meperidine should therefore be used with caution in patients with hepatic impairment. Titrate the dosage of Meperidine Hydrochloride Injection slowly in patients with hepatic impairment and monitor closely for signs of central nervous system and respiratory depression.

8.7 Renal Impairment

Accumulation of meperidine and/or its active metabolite, normeperidine, can occur in patients with renal impairment. Meperidine should therefore be used with caution in patients with renal impairment. Titrate the dosage of Meperidine Hydrochloride Injection slowly in patients with renal impairment and monitor closely for signs of central nervous system and respiratory depression.

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DRUG ABUSE AND DEPENDENCE SECTION

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

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

9.2 Abuse

Meperidine Hydrochloride Injection contains meperidine, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling its use(e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of Meperidine Hydrochloride Injection increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of Meperidine Hydrochloride Injection with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Meperidine Hydrochloride Injection abuse include those with a history of prolonged use of any opioid, including products containing meperidine, those with a history of drug or alcohol abuse, or those who use Meperidine Hydrochloride Injection in combination with other abused drugs.

"Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating health care provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Meperidine Hydrochloride Injection, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re- evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Meperidine Hydrochloride Injection

Abuse of Meperidine Hydrochloride Injection poses a risk of overdose and death. The risk is increased with concurrent abuse of Meperidine Hydrochloride Injection with alcohol and other CNS depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

9.3 Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Meperidine Hydrochloride Injection should not be abruptly discontinued [see Dosage and Administration (2.4)]. If Meperidine Hydrochloride Injection is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur, typically characterized by restlessness, lacrimation, rhinorrhea, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically-dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

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ADVERSE REACTIONS SECTION

Highlight: Most common adverse reactions were lightheadedness, dizziness, sedation, nausea, vomiting and sweating. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6 ADVERSE REACTIONS

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

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
• Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.7)]
• Serotonin Syndrome with Concomitant Use of Serotonergic Drugs [see Warnings and Precautions (5.8)]
• Adrenal Insufficiency [see Warnings and Precautions (5.10)]
• Severe Hypotension [see Warnings and Precautions (5.11)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.13)]
• Seizures [see Warnings and Precautions (5.14)]
• Withdrawal [see Warnings and Precautions (5.15)]

The following adverse reactions associated with the use of meperidine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The major hazards of meperidine, as with other opioid analgesics, are respiratory depression and, to a lesser degree, circulatory depression; respiratory arrest, shock, and cardiac arrest have occurred.

The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not experiencing severe pain. In such individuals, lower doses are advisable. Some adverse reactions in ambulatory patients may be alleviated if the patient lies down.

Other adverse reactions include:

Nervous System: Mood changes (e.g. euphoria, dysphoria), weakness, headache, agitation, tremor, involuntary muscle movements (e.g. muscle twitches, myoclonus), severe convulsions, transient hallucinations and disorientation, confusion, delirium, visual disturbances. Inadvertent injection about a nerve trunk may result in sensory-motor paralysis which is usually, though not always, transitory.

Gastrointestinal: Dry mouth, constipation, biliary tract spasm.

Cardiovascular: Flushing of the face, tachycardia, bradycardia, palpitation, hypotension [see Warnings and Precautions (5.18)], syncope, phlebitis following intravenous injection.

Genitourinary: Urinary retention.

Allergic:. Pruritus, urticaria, other skin rashes, wheal and flare over the vein with intravenous injection.
Hypersensitivity reactions, anaphylaxis.
Histamine release leading to hypotension and/or tachycardia, flushing, sweating, and pruritus.

Other: Pain at injection site; local tissue irritation and induration following subcutaneous injection, particularly when repeated; antidiuretic effect.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life- threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids for an extended period of time [see Clinical Pharmacology (12.2)].

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.7)].

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

For Parenteral Use

Meperidine Hydrochloride Injection, USP is clear and colorless and is available in the following packages:

25 mg/mL

1 mL Single Dose vials packaged in 25s (NDC 0641-6052-25)

50 mg/mL

1 mL Single Dose vials packaged in 25s (NDC 0641-6053-25)

100 mg/mL

1 mL Single Dose vials packaged in 25s (NDC 0641-6054-25)

Store at 20**° to 25****°C (68****° to 77****°F), excursions permitted to 15****° to 30****°C (59****° to 86****°F) [See USP Controlled Room Temperature].**

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