Meperidine Hydrochloride

Check Drug InteractionsCheck known drug interactions.

Meperidine Hydrochloride Prescribing Information

Boxed Warning 12/2023

Indications and Usage (

1 INDICATIONS AND USAGE

Meperidine Hydrochloride Injection is indicated for preoperative medication, support of anesthesia, and obstetrical analgesia.

Meperidine Hydrochloride Injection is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Meperidine Hydrochloride Injection is indicated for preoperative medication, support of anesthesia, for obstetrical analgesia, and for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration , reserve Meperidine Hydrochloride Injection for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

Have not been tolerated, or are not expected to be tolerated
Have not provided adequate analgesia, or are not expected to provide adequate analgesia

Meperidine Hydrochloride Injection should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

Use of Meperidine Hydrochloride Injection for an extended period of time may increase the risk of toxicity (e.g., seizures) from the accumulation of the meperidine metabolite, normeperidine.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [

see

Warnings and Precautions (5.1)

], reserve Meperidine Hydrochloride Injection for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products):

Have not been tolerated or are not expected to be tolerated
Have not provided adequate analgesia or are not expected to provide adequate analgesia

Use of Meperidine Hydrochloride Injection for an extended period of time may increase the risk of toxicity (e.g., seizures) from the accumulation of the meperidine metabolite, normeperidine.

) 12/2023

Dosage and Administration (

2.1 Important Dosage and Administration Instructions

Meperidine Hydrochloride Injection should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
[see
Warnings and Precautions (5)
]
. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Meperidine Hydrochloride Injection for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.

There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
[see
Warnings and Precautions (5.1)
]
.

Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Meperidine Hydrochloride Injection. Consider this risk when selecting an initial dose and when making dose adjustments
[see
Warnings and Precautions (5)
]
.

Inspect Meperidine Hydrochloride Injection for particulate matter and discoloration prior to administration. Do not use if color is darker than pale yellow, if it is discolored in any other way, or if it contains a precipitate.

2.2 For Management of Pain

nitial Dosage

Dosage should be adjusted according to the severity of the pain and the response of the patient. While subcutaneous administration is suitable for occasional use, intramuscular administration is preferred when repeated doses are required. If intravenous administration is required, dosage should be decreased and the injection made very slowly, preferably utilizing a diluted solution.

Adults: Initiate treatment in a dosing range of 50 mg to 150 mg intramuscularly or subcutaneously every 3 to 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Elderly patients should usually be given meperidine at the lower end of the dose range and observed closely.

Children: Initiate treatment in a dosing range of 0.5 mg/lb to 0.8 mg/lb intramuscularly or subcutaneously up to the adult dose, every 3 to 4 hours as necessary, and at the lowest dose necessary to achieve adequate analgesia.

Titration and Maintenance of Therapy

Titrate the dose based upon the individual patient’s response to their initial dose of Meperidine Hydrochloride Injection. Individually titrate Meperidine Hydrochloride Injection to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Meperidine Hydrochloride Injection to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1, 5.15)]. Frequent communication is important among the prescriber, other members of the health and care team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Meperidine Hydrochloride Injection dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage

[see

Warnings and Precautions (5)

]

. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Discontinuation of Meperidine Hydrochloride Injection

When a patient who has been taking Meperidine Hydrochloride Injection regularly and may be physically-dependent no longer requires therapy with Meperidine Hydrochloride Injection, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Meperidine Hydrochloride Injection in a physically-dependent patient

[see Warnings and Precautions (5.15), Drug Abuse and Dependence (9.3)]

) 12/2023

Warnings and Precautions (

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 meperidine 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) [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 Meperidine Hydrochloride Injection if serotonin syndrome is suspected.

) 12/2023

Meperidine Hydrochloride Injection is contraindicated in patients with:

Significant respiratory depression
[see
5.2 Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid 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 Meperidine Hydrochloride 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 Meperidine Hydrochloride Injection are essential [
see
Dosage and Administration (2.3)
]. Overestimating the Meperidine Hydrochloride 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 (2.1)].
]
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
[see
5.2 Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid 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 Meperidine Hydrochloride 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 Meperidine Hydrochloride Injection are essential [
see
Dosage and Administration (2.3)
]. Overestimating the Meperidine Hydrochloride 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 (2.1)].
]

Concomitant use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days

[see

5.6 Fatal Interaction with Monoamine Oxidase Inhibitors

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 pre-existing 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 Meperidine Hydrochloride 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 narcotic antagonists in the treatment of these reactions is unknown.

5.6 Fatal Interaction with Monoamine Oxidase Inhibitors

7 DRUG INTERACTIONS

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

Table 1: Clinically Significant Drug Interactions with Meperidine Hydrochloride Injection
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or those who have recently received such agents. Therapeutic doses of meperidine have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear, but may be related to a pre-existing 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. [see Warnings and Precautions (5.6)].
Intervention:	Do not use Meperidine Hydrochloride 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 narcotic antagonists in the treatment of these reactions is unknown.
Examples:	Phenelzine, tranylcypromine, linezolid
Inhibitors of CYP3A4 and CYP2B6
Clinical Impact:	The concomitant use of Meperidine Hydrochloride Injection and CYP3A4 or CYP2B6 inhibitors can increase the plasma concentration of meperidine, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Meperidine Hydrochloride Injection and CYP2B6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Meperidine Hydrochloride Injection is achieved [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the meperidine plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to meperidine.
Intervention:	If concomitant use is necessary, consider dosage reduction of Meperidine Hydrochloride Injection until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 or CYP2B6 inhibitor is discontinued, consider increasing the Meperidine Hydrochloride Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconizole), protease inhibitors (e.g., ritonavir)
CYP3A4 and CYP2B6 Inducers
Clinical Impact:	The concomitant use of Meperidine Hydrochloride Injection and CYP3A4 inducers, or CYP2B6 inducers can decrease the plasma concentration of meperidine [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to meperidine [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 or CYP2B6 inducer, as the effects of the inducer decline, the meperidine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the Meperidine Hydrochloride Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 or CYP2B6 inducer is discontinued, consider Meperidine Hydrochloride Injection dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension respiratory depression, profound sedation, coma, and death [see Warnings and Precautions (5.3)].
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation.
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.8)].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Meperidine Hydrochloride Injection if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect 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).
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of Meperidine Hydrochloride Injection and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	Butorphanol, nalbuphine, pentazocine, buprenorphine.
Muscle Relaxants
Clinical Impact:	Meperidine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Meperidine Hydrochloride Injection and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Meperidine Hydrochloride Injection is used concomitantly with anticholinergic drugs.
Acyclovir
Clinical Impact:	The concomitant use of acyclovir may increase the plasma concentrations of meperidine and its metabolite, normeperidine.
Intervention:	If concomitant use of acyclovir and Meperidine Hydrochloride Injection is necessary, monitor patients for respiratory depression and sedation at frequent intervals.
Cimetidine
Clinical Impact:	The concomitant use of cimetidine may reduce the clearance and volume of distribution of meperidine also the formation of the metabolite, normeperidine, in healthy subjects.
Intervention:	If concomitant use of cimetidine and Meperidine Hydrochloride Injection is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

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.

]

Known or suspected gastrointestinal obstruction, including paralytic ileus
[see
5.13 Risks
of Use in Patients with Gastrointestinal Conditions
Meperidine Hydrochloride Injection is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The meperidine in Meperidine Hydrochloride 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.
]
Hypersensitivity to meperidine (e.g., anaphylaxis)
[see
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).
Most common adverse reactions were lightheadedness, dizziness, sedation, nausea, vomiting and sweating.

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
.
]

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

Addiction, Abuse, and Misuse
[see
5.1 Addiction, Abuse, and Misuse
Meperidine Hydrochloride Injection contains meperidine, a Schedule II controlled substance. As an opioid, Meperidine Hydrochloride Injection exposes users to the risks of addiction, abuse, and misuse [
see
Drug Abuse and Dependence (9)
]
.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Meperidine Hydrochloride 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 Meperidine Hydrochloride Injection, and monitor all patients receiving Meperidine Hydrochloride Injection for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Meperidine Hydrochloride Injection, but use in such patients necessitates intensive counseling about the risks and proper use of Meperidine Hydrochloride Injection along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
]
Life-Threatening Respiratory Depression
[see
5.2 Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid 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 Meperidine Hydrochloride 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 Meperidine Hydrochloride Injection are essential [
see
Dosage and Administration (2.3)
]. Overestimating the Meperidine Hydrochloride 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 (2.1)].
]
Interactions with Benzodiazepines or Other CNS Depressants
[see
5.3 Risks
from Concomitant Use with Benzodiazepines or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Meperidine Hydrochloride Injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non- benzodiazepine 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.
Advise both patients and caregivers about the risks of respiratory depression and sedation when Meperidine Hydrochloride Injection 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
[see Drug Interactions (7)]
.
]
Neonatal Opioid Withdrawal Syndrome
[see
5.4 Neonatal
Opioid Withdrawal Syndrome
Use of Meperidine Hydrochloride 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)
].
]
Opioid-Induced Hyperalgesia and Allodynia
[see
5.7 Opioid-Induced
Hyperalgesia and Allodynia
Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. 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), Warnings and Precautions (5.15)]
.
]
Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
[see
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 meperidine 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) [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 Meperidine Hydrochloride Injection if serotonin syndrome is suspected.
]
Adrenal Insufficiency
[see
5.10 Adrenal
Insufficiency
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.
]
Severe Hypotension
[see
5.11 Severe
Hypotension
Meperidine Hydrochloride 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)
[see
Drug Interactions (7)
].
Monitor these patients for signs of hypotension after initiating or titrating the dosage of Meperidine Hydrochloride Injection. In patients with circulatory shock, Meperidine Hydrochloride Injection may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Meperidine Hydrochloride Injection in patients with circulatory shock.
]
Gastrointestinal Adverse Reactions
[see
5.13 Risks
of Use in Patients with Gastrointestinal Conditions
Meperidine Hydrochloride Injection is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The meperidine in Meperidine Hydrochloride 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.
]
Seizures
[see
5.14 Increased
Risk of Seizures in Patients with Seizure Disorders
The meperidine in Meperidine Hydrochloride 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 Meperidine Hydrochloride Injection therapy. Prolonged meperidine use may increase the risk of toxicity (e.g., seizures) from the accumulation of the meperidine metabolite, normeperidine.
]
Withdrawal
[see
5.15 Withdrawal
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 Meperidine Hydrochloride Injection. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.
When discontinuing Meperidine Hydrochloride Injection, gradually taper the dosage [
see
Dosage and Administration (2.4)
]. Do not abruptly discontinue Meperidine Hydrochloride Injection [
see
Drug Abuse and Dependence (9.3)
].
]

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

5.18 Risk
of Use in Patients with Atrial Flutter and Other Supraventricular Tachycardias

Meperidine Hydrochloride Injection 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.

5.17 Risks
in Patients with Pheochromocytoma

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

], 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

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)]

12.2 Pharmacodynamics

Effects on the Central Nervous System

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Effects of the Cardiovascular System

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.

[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

[see Dosage and Administration (2.1, 2.2)]

Concentration–Adverse Reaction Relationships

[see Dosage and Administration (2.1, 2.2)]

]

Hyperalgesia and Allodynia:

Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see

5.7 Opioid-Induced
Hyperalgesia and Allodynia

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. 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), Warnings and Precautions (5.15)]

5.7 Opioid-Induced
Hyperalgesia and Allodynia

[see Dependence (9.3)]

[see Dosage and Administration (2), Warnings and Precautions (5.15)]

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).

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

Table 1: Clinically Significant Drug Interactions with Meperidine Hydrochloride Injection
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or those who have recently received such agents. Therapeutic doses of meperidine have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear, but may be related to a pre-existing 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. [see 5.6 Fatal Interaction with Monoamine Oxidase Inhibitors 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 pre-existing 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 Meperidine Hydrochloride 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 narcotic antagonists in the treatment of these reactions is unknown. ].
Intervention:	Do not use Meperidine Hydrochloride 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 narcotic antagonists in the treatment of these reactions is unknown.
Examples:	Phenelzine, tranylcypromine, linezolid
Inhibitors of CYP3A4 and CYP2B6
Clinical Impact:	The concomitant use of Meperidine Hydrochloride Injection and CYP3A4 or CYP2B6 inhibitors can increase the plasma concentration of meperidine, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Meperidine Hydrochloride Injection and CYP2B6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Meperidine Hydrochloride Injection is achieved [see 5.5 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of Meperidine Hydrochloride Injection 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 [ see Warnings and Precautions (5.2) ], particularly when an inhibitor is added after a stable dose of Meperidine Hydrochloride Injection is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Meperidine Hydrochloride Injection-treated patients may increase meperidine plasma concentrations and prolong opioid adverse reactions. When using Meperidine Hydrochloride Injection with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Meperidine Hydrochloride Injection-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Meperidine Hydrochloride Injection until stable drug effects are achieved [see Drug Interactions (7) ] . Concomitant use of Meperidine Hydrochloride Injection 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 Meperidine Hydrochloride Injection 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 [ see Drug Interactions (7) ]. ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the meperidine plasma concentration will decrease [see 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 )]. ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to meperidine.
Intervention:	If concomitant use is necessary, consider dosage reduction of Meperidine Hydrochloride Injection until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 or CYP2B6 inhibitor is discontinued, consider increasing the Meperidine Hydrochloride Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconizole), protease inhibitors (e.g., ritonavir)
CYP3A4 and CYP2B6 Inducers
Clinical Impact:	The concomitant use of Meperidine Hydrochloride Injection and CYP3A4 inducers, or CYP2B6 inducers can decrease the plasma concentration of meperidine [see 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 )]. ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to meperidine [see 5.5 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of Meperidine Hydrochloride Injection 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 [ see Warnings and Precautions (5.2) ], particularly when an inhibitor is added after a stable dose of Meperidine Hydrochloride Injection is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Meperidine Hydrochloride Injection-treated patients may increase meperidine plasma concentrations and prolong opioid adverse reactions. When using Meperidine Hydrochloride Injection with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Meperidine Hydrochloride Injection-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Meperidine Hydrochloride Injection until stable drug effects are achieved [see Drug Interactions (7) ] . Concomitant use of Meperidine Hydrochloride Injection 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 Meperidine Hydrochloride Injection 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 [ see Drug Interactions (7) ]. ]. After stopping a CYP3A4 or CYP2B6 inducer, as the effects of the inducer decline, the meperidine plasma concentration will increase [see 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 )]. ], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the Meperidine Hydrochloride Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 or CYP2B6 inducer is discontinued, consider Meperidine Hydrochloride Injection dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension respiratory depression, profound sedation, coma, and death [see 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Meperidine Hydrochloride Injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non- benzodiazepine 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. Advise both patients and caregivers about the risks of respiratory depression and sedation when Meperidine Hydrochloride Injection 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 [see Drug Interactions (7)] . )].
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation.
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see 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 meperidine 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) [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 Meperidine Hydrochloride Injection if serotonin syndrome is suspected. ].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Meperidine Hydrochloride Injection if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect 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).
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of Meperidine Hydrochloride Injection and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	Butorphanol, nalbuphine, pentazocine, buprenorphine.
Muscle Relaxants
Clinical Impact:	Meperidine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Meperidine Hydrochloride Injection and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Meperidine Hydrochloride Injection is used concomitantly with anticholinergic drugs.
Acyclovir
Clinical Impact:	The concomitant use of acyclovir may increase the plasma concentrations of meperidine and its metabolite, normeperidine.
Intervention:	If concomitant use of acyclovir and Meperidine Hydrochloride Injection is necessary, monitor patients for respiratory depression and sedation at frequent intervals.
Cimetidine
Clinical Impact:	The concomitant use of cimetidine may reduce the clearance and volume of distribution of meperidine also the formation of the metabolite, normeperidine, in healthy subjects.
Intervention:	If concomitant use of cimetidine and Meperidine Hydrochloride Injection is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

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