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Guide
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.
MORPHINE SULFATE (NDA-020631)
(MORPHINE SULFATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/15/2023 (SUPPL-3)
Boxed Warning
Extensive changes; please refer to label
5 Warnings and Precautions
Addiction, Abuse, and MisuseAdditions and revisions underlined:
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use.
Newly added subsection:
Use of Morphine Sulfate 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 appropriate treatment will be available (see PRECAUTIONS, Information for Patients/Caregivers, Pregnancy).
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). 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 WARNINGS, DOSAGE AND ADMINISTRATION).
Additions and revisions underlined:
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Morphine Sulfate 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, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Monitor patients closely for signs of respiratory depression and sedation.
6 Adverse Reactions
Additions and revisions underlined:
The following serious adverse reactions are described, or described in greater detail, in other sections:
Addiction, Abuse, and Misuse (see WARNINGS)
Life-Threatening Respiratory Depression (see WARNINGS)
Interactions with Benzodiazepines or Other CNS Depressants (see WARNINGS)
Neonatal Opioid Withdrawal Syndrome (see WARNINGS)
Opioid-Induced Hyperalgesia and Allodynia
Cardiovascular Instability (see WARNINGS)
Adrenal Insufficiency (see WARNINGS)
Severe Hypotension (see WARNINGS)
Gastrointestinal Adverse Reactions (see WARNINGS)
Seizures (see WARNINGS)
Withdrawal (see WARNINGS)
Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time (see CLINICAL PHARMACOLOGY).Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration (see WARNINGS).
Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).
8 Use in Specific Populations
PregnancyAdditions and revisions underlined:
Risk Summary
Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome.
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.
Females and Males of Reproductive Potential
Infertility
Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Information for Patients/CaregiversAdditions and revisions underlined:
Addiction, Abuse, and Misuse
Inform patients that the use of Morphine Sulfate Injection, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death (see WARNINGS).
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Morphine Sulfate Injection or when the dosage is increased, and that it can occur even at recommended dosages (see WARNINGS).
Hyperalgesia and Allodynia
Advise patients to inform their
healthcare professional if they experience symptoms of hyperalgesia, including
worsening pain, increased sensitivity to pain, or new pain (see WARNINGS, ADVERSE REACTIONS).
Serotonin Syndrome
Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking or plan to take serotonergic medications (see PRECAUTIONS, Drug Interactions).
10/07/2019 (SUPPL-2)
5 Warnings and Precautions
PRECAUTIONSInteractions
Serotonergic Drugs
Additions and/or revisions underlined:
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as 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), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome
Newly added information:
Oral P2Y12 Inhibitors
The co-administration of oral P2Y12 inhibitors (e.g., clopidogrel, prasugrel, ticagrelor) and intravenous morphine sulfate can decrease the absorption and peak concentration of oral P2Y12 inhibitors and delay the onset of the antiplatelet effect.
Consider the use of a parenteral antiplatelet agent in the setting of acute coronary syndrome requiring co-administration of intravenous morphine sulfate.
Life-Threatening Respiratory Depression
Newly added information to the end of this titled 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.
12/16/2016 (SUPPL-1)
Boxed Warning
(section added)
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING
RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Addiction, Abuse, and Misuse
Morphine Sulfate Injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Morphine Sulfate Injection, and monitor all patients regularly for the development of these behaviors or conditions.
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of Morphine Sulfate Injection. Monitor for respiratory depression, especially during initiation of Morphine Sulfate Injection or following a dose increase.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of Morphine Sulfate Injection during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
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 (see WARNINGS and Drug Interactions).
Reserve concomitant prescribing of Morphine Sulfate Injection 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
(additions underlined)
Morphine Sulfate Injection is contraindicated in patients with:
Significant respiratory depression
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
Known or suspected gastrointestinal obstruction, including paralytic ileus
Hypersensitivity to morphine (e.g., anaphylaxis)
5 Warnings and Precautions
Addiction, Abuse, and Misuse(subsection added)
Morphine Sulfate Injection contains morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Injection exposes users to the risks of addiction, abuse, and misuse.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Morphine Sulfate 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 Morphine Sulfate Injection, and monitor all patients receiving Morphine Sulfate Injection for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Morphine Sulfate Injection, but use in such patients necessitates intensive counseling about the risks and proper use of Morphine Sulfate Injection along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Morphine Sulfate Injection. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
(subsection added)
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 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.
(subsection added)
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 Morphine Sulfate Injection and when Morphine Sulfate Injection is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.
(subsection revised, additions underlined)
The morphine in Morphine Sulfate 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 Morphine Sulfate Injection therapy.
(subsection revised, additions underlined)
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. 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 Morphine Sulfate Injection, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of Morphine Sulfate Injection.
To reduce the risk of respiratory depression, proper dosing and titration of Morphine Sulfate Injection are essential.Overestimating the Morphine Sulfate Injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
(subsection added)
The use of Morphine Sulfate Injection in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
(subsection revised, additions underlined)
Prolonged use of Morphine Sulfate Injection during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
(subsection added)
Morphine Sulfate Injection-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Morphine Sulfate Injection .
(additions underlined)
Morphine Sulfate Injection may impair the mental or physical abilities needed to perform potentially hazardous activities, such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Morphine Sulfate Injection and know how they will react to the medication.
(subsection added)
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Morphine Sulfate Injection with benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when Morphine Sulfate 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.
(subsection added)
Morphine Sulfate Injection is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.
The morphine in Morphine Sulfate 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.
(subsection added)
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Morphine Sulfate Injection may reduce the 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 Morphine Sulfate Injection.
Opioids may obscure the clinical course in a patient with a head injury. Avoid the use of Morphine Sulfate Injection in patients with impaired consciousness or coma.
(subsection revised, additions underlined)
Morphine Sulfate Injection may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Morphine Sulfate Injection. In patients with circulatory shock, Morphine Sulfate Injection may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Morphine Sulfate Injection in patients with circulatory shock.
(subsection added)
Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Morphine Sulfate Injection. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.
When discontinuing Morphine Sulfate Injection, gradually taper the dosage. Do not abruptly discontinue Morphine Sulfate Injection.
6 Adverse Reactions
The following serious adverse reactions are described, or described in greater detail, in other sections:
Addiction, Abuse, and Misuse
Life-Threatening Respiratory Depression
Neonatal Opioid Withdrawal Syndrome
Interactions with CNS Depressants
Adrenal Insufficiency
Severe Hypotension
Gastrointestinal Adverse Reactions
Seizures
Withdrawal
Other adverse reactions include:
Blood and lymphatic system disorders: thrombocytopenia
Cardiac disorders: tachycardia, bradycardia, palpitation
Eye disorders: miosis, visual impairment
Gastrointestinal disorders: dry mouth, constipation. Patients with chronic ulcerative colitis may experience increased colonic motility, toxic dilatation of the intestine or megacolon has been reported in patients with acute ulcerative colitis.
General disorders and administration site conditions: asthenia, edema, injection site erythema
Hepatobiliary disorders: biliary colic
Immune system disorders: anaphylactic reaction
Metabolism and nutritional disorders: decreased appetite
Nervous system disorders: headache, somnolence, coma, tremor, muscular incoordination, mental impairment, lethargy, syncope
Psychiatric disorders: dysphoria, euphoric mood, delirium, insomnia, agitation, mental status changes, anxiety, fear, drug dependence, mood altered, transient hallucination, disorientation, confusional state, decreased libido
Renal and urinary disorders: ureteral spasm, spasm of vesicular sphincter, urinary retention, urinary hesitation, oliguria, antidiuretic effect
Reproductive system and breast disorders: erectile dysfunction
Skin and subcutaneous tissue disorders: pruritus, hemorrhagic urticaria, rash
Social circumstances: physical disability
Vascular disorders: flushing of face, peripheral circulatory failure, hypotension, phlebitis
(subsection added)
The following adverse reactions have been identified during post-approval use of morphine. Because these reactions are 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.
Endocrine disorders: adrenal insufficiency, androgen deficiency
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because of the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.
Nervous system disorders: serotonin syndrome
7 Drug Interactions
(Extensive additions and revisions, please refer to label)
8 Use in Specific Populations
Females and Males of Reproductive Potential(additions underlined)
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.
(additions underlined)
Elderly patients (aged 65 years or older) may have increased sensitivity to morphine sulfate. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of morphine sulfate slowly in geriatric patients.
(additions underlined)
Risk Summary: The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for morphine sulfate and any potential adverse effects on the breastfed infant from morphine sulfate or from the underlying maternal condition.
Clinical Considerations: Infants exposed to morphine sulfate through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.
(extensive additions, please refer to label)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 Patient Counceling Information(extensive revisions and additions, please refer to label)