Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

INFUMORPH (NDA-018565)

(MORPHINE SULFATE)

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

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12/22/2025 (SUPPL-36)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

INFUMORPH contains morphine, a Schedule II controlled substance. As an opioid, INFUMORPH 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 INFUMORPH. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2)].

…

5.3 Life-Threatening Respiratory Depression

Additions and/or revisions underlined:

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents (e.g., naloxone, nalmefene), depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

…

5.4 Risks from Cocomintant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

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

…

5.14 Risks of Gastrointestinal Complications

Subsection title revised

Additions and/or revisions underlined:

INFUMORPH is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The morphine in INFUMORPH 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. As significant morphine is released into the systemic circulation from neuraxial administration, the ensuing smooth muscle hypertonicity may result in biliary colic.

Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2)].

5.16 Withdrawal

Additions and/or revisions underlined:

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 INFUMORPH. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [Drug Interactions (7)].

When discontinuing INFUMORPH, gradually taper the dosage [see Dosage and Administration (2.6)]. Do not rapidly reduce or abruptly discontinue INFUMORPH [see Drug Abuse and Dependence (9.3)].

6 Adverse Reactions

Additions and/or revisions underlined:

…

Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions (5.14)].

Adverse Reactions from Observational Studies

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

Over 12 months:

approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and

approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence (9.2)], respectively, as measured with a validated self-reported instrument.

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

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

7 Drug Interactions

Changes to Table 1: Clinically Significant Drug Interactions with INFUMORPH; please refer to label for complete information

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

Labor or Delivery

INFUMORPH 200 and 500 (10 and 25 mg/mL, respectively) are too highly concentrated for routine use in obstetric neuraxial analgesia. Opioids, including intravenously, epidurally, and intrathecally administered morphine, readily cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, and resuscitative equipment must be available for reversal of opioid-induced respiratory depression in the neonate. INFUMORPH is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including INFUMORPH, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

…

12/15/2023 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

…

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing INFUMORPH. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

…

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

Profound sedation, respiratory depression, coma, and death may result from concomitant use of INFUMORPH 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.

…

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

5.5 Neonatal Opioid Withdrawal Syndrome

Additions and/or revisions underlined:

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

5.8 Opioid-Induced Hyperalgesia and Allodynia

Newly added subsection:

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

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong 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 (safety switching the patient to a different opioid moiety) [see Dosage and Administration (2), Warnings and Precautions (5.16)].

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

Additions and/or revisions underlined:

In patients who may be susceptible to the intracranial effects of CO retention (e.g., those with evidence of increased intracranial pressure or brain tumors), INFUMORPH may reduce respiratory drive, and the resultant CO retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with INFUMORPH. INFUMORPH should be used with extreme caution in patients with head injury or increased intracranial pressure. Pupillary changes (miosis) from morphine may obscure the existence, extent and course of intracranial pathology. High doses of neuraxial morphine may produce myoclonic events [see Warnings and Precautions (5.7)]. Clinicians should maintain a high index of suspicion for adverse drug reactions when evaluating altered mental status or movement abnormalities in patients receiving this modality of treatment.

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

5.16 Withdrawal

Additions and/or revisions underlined:

When discontinuing INFUMORPH, gradually taper the dosage [see Dosage and Administration (2.6)]. Do not abruptly discontinue INFUMORPH [see Drug Abuse and Dependence (9.3)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.8)]

…

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

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.8)]

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

7 Drug Interactions

Changes to Table 1; please refer to label for complete information

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.5)]. Available data with INFUMORPH in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are adverse outcomes reported with fetal exposure to opioid analgesics (see Clinical Considerations). Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see Human Data]. In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse. Administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3-4 times the HDD; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD [see Animal Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

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

Clinical Considerations

Fetal/Neonatal Adverse Reactions

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

…

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Infertility

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

In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see Nonclinical Toxicology (13)].

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Hyperalgesia and Allodynia

Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.8); Adverse Reactions (6.2)].

Serotonin Syndrome

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

…

Pregnancy

Neonatal Opioid Withdrawal Syndrome

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

…

Infertility

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6)].

12/15/2023 (SUPPL-30)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

…

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

Profound sedation, respiratory depression, coma, and death may result from concomitant use of INFUMORPH 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.

…

5.5 Neonatal Opioid Withdrawal Syndrome

Additions and/or revisions underlined:

5.8 Opioid-Induced Hyperalgesia and Allodynia

Newly added subsection:

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

Additions and/or revisions underlined:

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

5.16 Withdrawal

Additions and/or revisions underlined:

When discontinuing INFUMORPH, gradually taper the dosage [see Dosage and Administration (2.6)]. Do not abruptly discontinue INFUMORPH [see Drug Abuse and Dependence (9.3)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.8)]

…

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

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.8)]

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

7 Drug Interactions

Changes to Table 1; please refer to label for complete information

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Clinical Considerations

Fetal/Neonatal Adverse Reactions

…

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Infertility

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Hyperalgesia and Allodynia

Serotonin Syndrome

…

Pregnancy

Neonatal Opioid Withdrawal Syndrome

…

Infertility

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6)].

10/07/2019 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Life-Threatening Respiratory Depression

Newly added information to the end of the subsection.

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

7 Drug Interactions

Table 1: Clinically Significant Drug Interactions with INFUMORPH

Addition of the following to the above table:

Oral P2Y12 Inhibitors

Clinical Impact: The co-administration of oral P2Y12 inhibitors and intravenous morphine sulfate can decrease the absorption and peak concentration of oral P2Y12 inhibitors and delay the onset of the antiplatelet effect.

Intervention: Consider the use of parenteral antiplatelet agent in the setting of acute coronary syndrome requiring co-administration of intravenous morphine sulfate.

Examples: clopidogrel, prasugrel, ticagrelor

Additions and/or revisions underlined:

Serotonergic Drugs

Additions and/or revisions underlined in the following table section:

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).

12/16/2016 (SUPPL-22)

Approved Drug Label (PDF)

Boxed Warning

PLR conversion; newly added section:

WARNING: RISKS WITH NEURAXIAL ADMINISTRATION; LIFE-THREATENING RESPIRATORY DEPRESSION; RISK OF ADDICTION, ABUSE, AND MISUSE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Risks with Neuroaxial Administration

Because of the risk of severe adverse reactions when INFUMORPH is administered by the epidural or intrathecal route of administration, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial (single) test dose and, as appropriate, for the first several days after catheter implantation.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of INFUMORPH. Monitor for respiratory depression, especially during initiation of INFUMORPH or following a dose increase. Patients must be observed in a fully equipped and staffed environment for at least

24 hours after each test dose and, as indicated, for the first several days after surgery.

Addiction, Abuse, and Misuse

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

Neonatal Opioid Withdrawal Syndrome

Prolonged use of INFUMORPH during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

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

Reserve concomitant prescribing of INFUMORPH and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
Limit dosages and durations to the minimum required.
Follow patients for signs and symptoms of respiratory depression and sedation.

4 Contraindications

PLR conversion; section revised:

INFUMORPH is contraindicated in patients with:

Significant respiratory depression
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days
Known or suspected gastrointestinal obstruction, including paralytic ileus
Hypersensitivity to morphine (e.g., anaphylaxis)

Neuraxial administration of INFUMORPH is contraindicated in patients with:

Infection at the injection microinfusion site
Concomitant anticoagulant therapy
Uncontrolled bleeding diathesis
The presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous.

5 Warnings and Precautions

5.1 Risks with Neuraxial Administration

(Precautions, previously untitled, addition of the following)

INFUMORPH should be administered by or under the direction of a physician experienced in the techniques of epidural or intrathecal administration and familiar with the patient management problems associated with epidural or intrathecal drug administration. The physician should be familiar with patient conditions (such as infection at the injection site, bleeding diathesis, anticoagulant therapy, etc.) which call for special evaluation of the benefit versus risk potential.

Because of the risk of severe adverse effects when the epidural or intrathecal route of administration is employed, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial dose.

The facility must be equipped to resuscitate patients with severe opioid overdosage, and the personnel must be familiar with the use and limitations of specific narcotic antagonists (naloxone, naltrexone) in such cases.

5.10 Adrenal Insufficiency

Newly added subsection:

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

5.11 Severe Hypotension

Newly added subsection:

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

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

Precautions; addition of the following:

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

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

5.13 Risks of Use in Patients with Gastrointestinal Conditions

Newly added subsection:

INFUMORPH is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

5.14 Increased Risks of Seizures in Patients with Seizure Disorders

Newly added subsection:

The morphine in INFUMORPH may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical setting associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during INFUMORPH therapy.

5.15 Withdrawal

Newly added subsection:

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients, mixed agonist/antagonist and partial agonist analgesics, including INFUMORPH. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.

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

5.16 Risk of Driving and Operating Machinery

(Newly added subsection)

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

5.17 Risks of Use in Patients with Urinary System Disorders

(Precautions, revised as below)

Urinary retention, which may persist 10 to 20 hours following single epidural or intrathecal administration, is a frequently associated with neuraxial opioid administration and must be anticipated, more frequently in male patients than female patients. Urinary retention may also occur during the first several days of hospitalization for the initiation of continuous intrathecal or epidural morphine therapy. Early recognition of difficulty in urination and

prompt intervention in cases of urinary retention is indicated. Patients who develop urinary retention have responded to cholinomimetic treatment and/or judicious use of catheters.

5.18 Risks of Use in Ambulatory Patients

(Precautions, unchanged)

5.2 Life-Threatening Respiratory Depression

Newly added subsection:

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

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of INFUMORPH, the risk is greatest during the initiation of therapy or following a dosage increase. This respiratory depression and/or respiratory arrest may be severe and could require intervention.

Because of the risk of severe adverse effects, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial (single) test dose and, as appropriate, for the first several days after catheter implantation. The facility must be equipped to resuscitate patients with severe opioid overdosage, and the personnel must be familiar with the use and limitations of specific narcotic antagonists (naloxone, naltrexone) in such cases:
Severe respiratory depression up to 24 hours following epidural or intrathecal administration has been reported.
Intrathecal use has been associated with a higher incidence of respiratory depression than epidural use.
Parenteral administration of narcotics in patients receiving epidural or intrathecal morphine may result in overdosage.

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

5.3 Addiction, Abuse, and Misuse

Newly added subsection:

INFUMORPH contains morphine, a Schedule II controlled substance. As an opioid, INFUMORPH exposes users to the risks of addiction, abuse, and misuse.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing INFUMORPH, and monitor all patients receiving INFUMORPH 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 INFUMORPH, but use in such patients necessitates intensive counseling about the risks and proper use of INFUMORPH along with intensive monitoring for signs of addiction, abuse, and misuse.

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

Each ampule of INFUMORPH contains a large amount of a potent narcotic which has been associated with abuse and dependence among health care providers. Due to the limited indications for this product, the risk of overdosage and the risk of its diversion and abuse, it is recommended that special measures must be taken to control this product within the hospital or clinic. INFUMORPH should be subject to rigid accounting, rigorous control of wastage, and restricted access.

5.4 Neonatal Opioid Withdrawal Syndrome

Newly added subsection:

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

5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Precautions, completed revised as below:

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

Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.

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

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

5.6 Risk of Inflammatory Masses

(Warnings, unchanged)

5.7 Risk of Tolerance and Myoclonic Activity

(Warnings, unchanged)

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

Precautions; completely revised as follows:

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

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

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

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

5.9 Interaction with Monoamine Oxidase Inhibitors

Newly added subsection:

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Morphine Sulfate Injection should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

6 Adverse Reactions

PLR conversion; newly added information:

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

Addiction, Abuse, and Misuse
Life-Threatening Respiratory Depression
Neonatal Opioid Withdrawal Syndrome
Interactions with CNS Benzodiazepines or Other Depressants
Inflammatory Masses
Myoclonic Activity
Adrenal Insufficiency
Severe Hypotension
Gastrointestinal Adverse Reactions
Seizures
Withdrawal
Urinary Retention
Orthostatic Hypotension

The following adverse reactions associated with the use of morphine 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.

Cardiovascular System: While low doses of intravenously administered morphine have little effect on cardiovascular stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in circulating catecholamines. Excitation of the central nervous system, resulting in convulsions, may accompany high doses of morphine given intravenously.

Central Nervous System: myoclonus, seizures, dysphoric reactions, toxic psychosis, dizziness, euphoria, anxiety, confusion, headache. Lumbar puncture-type headache is encountered in a significant minority of cases for several days following intrathecal catheter implantation and generally responds to bed rest and/or other conventional therapy.

Gastrointestinal System: Nausea, vomiting, constipation

Skin: Pruritus, urticaria, wheals, and/or local tissue irritation.

Genito-Urinary System: Urinary retention, oliguria, unexplained genital swelling in male patients, following infusion-device implant surgery.

Other: Other adverse experiences reported following morphine therapy include depression of cough reflex, interference with thermal regulation, peripheral edema.

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.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in INFUMORPH.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids

7 Drug Interactions

PLR conversion; information converted to table format; please refer to label.

Table 1 includes clinically significant drug interactions with INFUMORPH.

Table 1. Clinically Significant Drug Interactions with INFUMORPH

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion with extensive changes; please refer to label.

8.2 Lactation

PLLR Conversion:

Risk Summary

Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with INFUMORPH, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INFUMORPH and any potential adverse effects on the breastfed infant from INFUMORPH or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to INFUMORPH through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped.

8.3 Females and Males of Reproductive Potential

PLLR conversion:

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats.

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

PATIENT COUNSELING INFORMATION

PLR conversion: extensive changes; please refer to label.