Label: MORPHINE SULFATE- morphine sulfate injection
- NDC Code(s): 11704-235-01
- Packager: Meridian Medical Technologies, Inc.
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: CII
- Marketing Status: New Drug Application
Updated March 22, 2017
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- BOXED WARNING(What is this?)
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; and NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
- HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use MORPHINE SULFATE INJECTION, USP (AUTO-INJECTOR) safely and effectively. See full prescribing information for MORPHINE SULFATE INJECTION (AUTO-INJECTOR).
Morphine Sulfate Injection, (Auto-Injector) for intramuscular use, CII
Initial U.S. Approval: 1941
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
See full prescribing information for complete boxed warning.
- Morphine Sulfate Injection, (Auto-Injector) exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and monitor closely for these behaviors and conditions. (5.1)
- Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation and following any subsequent increase in the frequency of injections. (5.2)
- Prolonged use of Morphine Sulfate Injection, (Auto-Injector) during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.3)
- 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 for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.4, 7)
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
Morphine Sulfate Injection, (Auto-Injector) is an opioid agonist indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. (1)
Limitations of Use (1)
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Morphine Sulfate Injection, (Auto-Injector) 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
DOSAGE AND ADMINISTRATION
- Initiate treatment with a single injection of Morphine Sulfate Injection, (Auto-Injector). (2.2)
- The morphine sulfate auto-injector delivers a fixed dose of 10 mg of morphine sulfate, which will generally provide adequate analgesia for a 70 kg adult. (2.2)
- The auto-injector is not intended for repeated administration. However, if repeated doses are needed to control the pain, the usual adult dosage for repeated administration is one injector (10 mg morphine sulfate) every 4 hours as needed. (2.2)
DOSAGE FORMS AND STRENGTHS
Injection, 10 mg morphine sulfate in 0.7 mL sterile solution. (3)
- Significant respiratory depression. (4)
- Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. (4)
- Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (4)
- Known or suspected gastrointestinal obstruction, including paralytic ileus. (4)
- Hypersensitivity to morphine. (4)
WARNINGS AND PRECAUTIONS
- Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation. (5.5)
- Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.7)
- Severe Hypotension: Monitor during dosage initiation and subsequent injections. Avoid use of Morphine Sulfate Injection, (Auto-Injector) in patients with circulatory shock. (5.8)
- Risk of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of Morphine Sulfate Injection, (Auto-Injector) in patients with impaired consciousness or coma. (5.9)
Most common adverse reactions (incidence >5%) were sedation, lightheadedness, dizziness, nausea, vomiting, and sweating. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or http://www.meridianmeds.com or FDA at 1-800-FDA-1088 or www.fda.gov.medwatch.
- Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue Morphine Sulfate Injection, (Auto-Injector) if serotonin syndrome is suspected. (7)
- Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Morphine Sulfate Injection, (Auto-Injector) because they may reduce analgesic effect of Morphine Sulfate Injection, (Auto-Injector) or precipitate withdrawal symptoms. (7)
USE IN SPECIFIC POPULATIONS
Pregnancy: May cause fetal harm. (8)
See 17 for PATIENT COUNSELING INFORMATION.
- FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; and NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
5.5 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS AND USAGE
- 2 DOSAGE AND ADMINISTRATION
2.2 Initial Dosage
The auto-injector is not intended for repeated administration, but if repeated doses must be given, the usual adult dosage for repeated administration is one injector (10 mg) every 4 hours as needed to control the pain.
2.3 Instructions for Use of the Morphine Sulfate Auto-Injector
- Remove red safety cap.
- Place purple end on patient's outer thigh and push the unit firmly against the patient until injector functions.
- 3 DOSAGE FORMS AND STRENGTHS
Morphine Sulfate Injection, USP (Auto-Injector) contains 10 mg morphine sulfate in 0.7 mL of sterile solution.Close
- 4 CONTRAINDICATIONS
Morphine Sulfate Injection, (Auto-Injector) is contraindicated in patients with:
- 5 WARNINGS AND PRECAUTIONS
5.5 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
5.14 Exposure, Hypothermia, Immersion, and Shock
Caution must be used when injecting any opioid intramuscularly into chilled areas or in patients with hypotension or shock, since impaired perfusion may prevent complete absorption. If repeated injections are administered, an excessive amount may be suddenly absorbed if normal circulation is re-established.
5.15 Accidental Activation
Morphine Sulfate Injection, (Auto-Injector) contains a spring-driven injection mechanism and is capable of inflicting injury if accidentally misused. The product should remain in its original container with the safety in place until actually in use, and in no case should the product be carried with the red safety cap removed. Intramuscular or subcutaneous naloxone in the dosage of 0.4 mg is antidotal in case of accidental injection, but may have to be repeated at 30-60 minute intervals for several doses.
- 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)]
- Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)]
- Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.4)]
- Adrenal Insufficiency [see Warnings and Precautions (5.7)]
- Severe Hypotension [see Warnings and Precautions (5.8)]
- Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.10)]
- Seizures [see Warnings and Precautions (5.11)]
- Withdrawal [see Warnings and Precautions (5.12)]
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.
The major hazards of morphine, as with other narcotic analgesics, are respiratory depression, and to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest have occurred, particularly with overdosage, rapid intravenous administration, and pre-existing hypovolemic shock. Rarely, anaphylactoid reactions have been reported when morphine or other phenanthrene alkaloids of opium are administered intravenously.
The most frequently observed adverse reactions included sedation, lightheadedness, dizziness, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not experiencing severe pain. Some adverse reactions in ambulatory patients may be alleviated if the patient lies down [see Warnings and Precautions (5.8)].
Other possible adverse reactions included:
Central Nervous System: Euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, visual disturbances, transient hallucinations and disorientation.
Gastrointestinal: Constipation, biliary tract spasm.
Cardiovascular: Tachycardia, bradycardia, palpitation, faintness, syncope, and orthostatic hypotension.
Genitourinary: Oliguria and urinary retention; an antidiuretic effect has been reported.
Allergic: Allergic reactions to opioids occur infrequently; pruritus, urticaria and other skin rashes are most common. Rarely, anaphylactoid reactions have been reported following intravenous administration.
Other: Opioid-induced histamine release may be responsible for the flushing of the face, sweating, and pruritus often seen with these drugs. Wheals and urticaria at the site of injection are probably related to histamine release. Local tissue irritation, pain and induration have been reported following repeated subcutaneous injection. Morphine, like other opioids, may alter temperature regulation in susceptible individuals and will depress the cough reflex.
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 Morphine Sulfate Injection, (Auto-Injector).
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].Close
- 7 DRUG INTERACTIONS
Table 1 includes clinically significant drug interactions with Morphine Sulfate Injection, (Auto-Injector).
Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Injection, (Auto-Injector) 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. 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 [see Warnings and Precautions (5.4)]. 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. Intervention: If concomitant use is warranted, carefully observe the patient during treatment initiation. Discontinue Morphine Sulfate Injection, (Auto-Injector) 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 effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.6)]. Intervention: Do not use Morphine Sulfate Injection, (Auto-Injector) in patients taking MAOIs or within 14 days of stopping such treatment.
If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Morphine Sulfate Injection, (Auto-Injector) and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Morphine sulfate 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 frequency of injections of Morphine Sulfate Injection, (Auto-Injector) and/or decrease the dose of 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 Morphine Sulfate Injection, (Auto-Injector) is used concomitantly with anticholinergic drugs.
- 8 USE IN SPECIFIC POPULATIONS
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. There are no available data with Morphine Sulfate Injection, (Auto-Injector) in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. 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 estimated 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 2-4% and 15-20%, respectively.
Fetal/Neonatal Adverse Reactions
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)].
Labor or Delivery
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Morphine Sulfate Injection, (Auto-Injector) is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Morphine Sulfate Injection, (Auto-Injector), 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.
This product is intended for fixed-dose administration by non-medical personnel and is not recommended for routine obstetrical analgesia.
The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design.
Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (HDD).
Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35-322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100-500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear.
Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity.
An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10-50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated.
In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater.
Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD).
Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).
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 Morphine Sulfate Injection, (Auto-Injector), 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 Morphine Sulfate Injection, (Auto-Injector) and any potential adverse effects on the breastfed infant from Morphine Sulfate Injection, (Auto-Injector) or from the underlying maternal condition.
Monitor infants exposed to Morphine Sulfate Injection, (Auto-Injector) 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
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 [see 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)].
8.4 Pediatric Use
The morphine sulfate auto-injector delivers a fixed dose of 10 mg at a fixed injection depth and volume. It was not designed for use in pediatric patients under the age of 14 or weighing less than 40 kg (90 lb).
8.5 Geriatric Use
Elderly patients (aged 65 years or older) may have increased sensitivity to morphine sulfate 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 [see Warnings and Precautions (5.5)].
Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
8.6 Hepatic Impairment
Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Monitor for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].
8.7 Renal Impairment
Morphine pharmacokinetics are altered in patients with renal failure. Monitor for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].
- 9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
Morphine Sulfate Injection, (Auto-Injector) contains morphine sulfate, a Schedule II controlled substance.
Morphine Sulfate Injection, (Auto-Injector) contains morphine sulfate, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and tapentadol. Morphine Sulfate Injection, (Auto-Injector) can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].
All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
Morphine Sulfate Injection, (Auto-Injector), like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
Morphine Sulfate Injection, (Auto-Injector) should not be abruptly discontinued. If Morphine Sulfate Injection, (Auto-Injector) is abruptly discontinued in a physically dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].
- 10 OVERDOSAGE
Acute overdosage with Morphine Sulfate Injection, (Auto-Injector) can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].
Treatment of Overdose
In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.
The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to morphine sulfate overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine sulfate overdose.
Because the duration of opioid reversal is expected to be less than the duration of action of morphine sulfate in Morphine Sulfate Injection, (Auto-Injector), carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product's prescribing information.
In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.
- 11 DESCRIPTION
Morphine Sulfate Injection, USP (Auto-Injector) (morphine sulfate) is an opioid agonist, available as 10 mg morphine sulfate in a 0.7 mL sterile solution contained in a unit-dose auto-injector system for intramuscular administration. The chemical name is 7,8-didehydro-4,5α-epoxy-17-methylmorphinan-3, 6α -diol sulfate (2:1) (salt), pentahydrate. The molecular weight is 758.83. Its molecular formula is (C17H19NO3)2·H2SO4·5H2O, and it has the following chemical structure.
Morphine sulfate USP is an odorless, white crystalline powder with a bitter taste. It has a solubility of 1 in 21 parts of water and 1 in 1000 parts of alcohol, but is practically insoluble in chloroform or ether. The octanol:water partition coefficient of morphine is 1.42 at physiologic pH and the pKa is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4).
When activated, each auto-injector dispenses 10 mg morphine sulfate in 0.7 mL Water for Injection, USP with 10.5 mg benzyl alcohol and 0.7 mg edetate disodium. Sulfuric acid may be added to adjust pH. The pH range is 2.5 - 6.0. The product is pyrogen free.
The inactive ingredients in Morphine Sulfate Injection, USP (Auto-Injector) include: Water for Injection, benzyl alcohol, edetate disodium and sulfuric acid.Close
- 12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of morphine is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.
The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.
Effects on the Central Nervous System
Morphine sulfate 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 CO2 tension and electrical stimulation.
Morphine sulfate 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
Morphine sulfate causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and 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 on the Cardiovascular System
Morphine sulfate 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, sweating and/or orthostatic hypotension.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [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.
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 morphine sulfate 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.
Onset of analgesia occurs within 5-20 minutes following intramuscular administration of morphine, rising to peak analgesia sixty minutes after a single intramuscular injection. The duration of analgesia after a single injection is usually three to four hours.
Concentration–Adverse Reaction Relationships
There is a relationship between increasing morphine sulfate 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.
Morphine sulfate is completely absorbed following intramuscular administration and has an apparent volume of distribution ranging from 1.0 to 4.7 L/kg.
Peak plasma levels for a 70 kg adult following intramuscular administration of 10 mg of morphine sulfate are between 30-140 ng/mL (the minimum effective analgesic concentration of morphine sulfate is 20-40 ng/mL in studies of patient-controlled analgesia). The blood-brain barrier exists for the drug with plasma concentrations of morphine sulfate remaining higher than the corresponding CSF morphine sulfate levels following intramuscular administration.
Morphine sulfate circulates unbound in plasma, with a mean total plasma clearance which ranges from 0.9 to 1.2 L/kg/hour in post-operative patients.
The major pathway of clearance is hepatic glucuronidation to morphine-3-glucuronide, which is pharmacologically inactive.
The major excretion path of the conjugate is through the kidneys, with about 10% in the feces. Morphine sulfate is also eliminated by the kidneys, 2 to 12% being excreted unchanged in the urine. The terminal half-life in normal patients is 1.5 to 2.0 hours.
Morphine pharmacokinetics are altered in individuals with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine plasma AUC ratios also decreased in these subjects, indicating diminished metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.
Morphine pharmacokinetics are altered in patients with renal failure. The AUC is increased and clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted.
- 13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to evaluate the carcinogenic potential of morphine sulfate have not been conducted.
No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, morphine was found to be mutagenic in vitro increasing DNA fragmentation in human T-cells. Morphine was reported to be mutagenic in the in vivo mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the in vivo clastogenic effects reported with morphine in mice may be related to increases in glucocorticoid levels produced by morphine in this species. In contrast to the above positive findings, in vitro studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in Drosophila.
Impairment of Fertility
No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted.
Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. One study in which male rats were administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects including reduction in total pregnancies and higher incidence of pseudopregnancies at 20 mg/kg/day (3.2 times the HDD) were reported.
Studies from the literature have also reported changes in hormonal levels in male rats (i.e. testosterone, luteinizing hormone) following treatment with morphine at 10 mg/kg/day or greater (1.6 times the HDD).
Female rats that were administered morphine sulfate intraperitoneally prior to mating exhibited prolonged estrous cycles at 10 mg/kg/day (1.6 times the HDD).
Exposure of adolescent male rats to morphine has been associated with delayed sexual maturation and following mating to untreated females, smaller litters, increased pup mortality, and/or changes in reproductive endocrine status in adult male offspring have been reported (estimated 5 times the plasma levels at the HDD).
- 16 HOW SUPPLIED/Storage and Handling
Morphine Sulfate Injection, USP (Auto-Injector) (morphine sulfate) 10 mg/0.7 mL is supplied in packages of 10 or 100. The National Stock Code number for Morphine Sulfate Injection, USP (Auto-Injector) is NSN 6505-01-302-5530 and the National Drug Code number is NDC 11704-235-01. For military use, the auto-injectors are supplied through the Directorate of Medical Materiel, Defense Supply Center Philadelphia or other analogous agency.
Federal law prohibits the transfer of this drug to any person other than the patient for whom it was prescribed.
Store at 25°C (77°F); Excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature] Avoid freezing.
Morphine sulfate auto-injectors have a significant risk of illicit diversion and should be handled strictly in accordance with current directives in order to assure their availability under emergency conditions.Close
- 17 PATIENT COUNSELING INFORMATION
Addiction, Abuse, and Misuse
Inform patients that the use of Morphine Sulfate Injection, (Auto-Injector), even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share Morphine Sulfate Injection, (Auto-Injector) with others and to take steps to protect Morphine Sulfate Injection, (Auto-Injector) from theft or misuse.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Morphine Sulfate Injection, (Auto-Injector) or when the frequency of injections is increased, and that it can occur even at recommended frequency [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Interactions with Benzodiazepines and Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if Morphine Sulfate Injection, (Auto-Injector) is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.4), Drug Interactions (7)].
Inform patients that Morphine Sulfate Injection, (Auto-Injector) could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see Drug Interactions (7)].
Inform patients not to take Morphine Sulfate Injection, (Auto-Injector) while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Morphine Sulfate Injection [see Warnings and Precautions (5.6), Drug Interactions (7)].
Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.7)].
Inform patients that Morphine Sulfate Injection, (Auto-Injector) may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.8)].
Inform patients that anaphylaxis have been reported with ingredients contained in Morphine Sulfate Injection, (Auto-Injector). Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of Morphine Sulfate Injection, (Auto-Injector) during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)].
Inform female patients of reproductive potential that Morphine Sulfate Injection, (Auto-Injector) can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].
Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2)].
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6)].
Manufactured for and Distributed by:
Meridian Medical Technologies, Inc.
Columbia, MD 21046
A Pfizer Company
- PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – MORPHINE SULFATE INJECTION, 10 MG AUTO-INJECTOR LABEL
MERIDIAN MEDICAL TECHNOLOGIES™
A subsidiary of King Pharmaceuticals®, Inc.
Columbia, MD 21046, U.S.A.
Site at 25°C (77° F); Excursions permitted to 15 - 30°C (59 - 86°F).
[See USP Controlled Room Temperature]. Avoid freezing.
MORPHINE SULFATE INJECTION, 10 mg
- REMOVE RED SAFETY CAP
- PLACE PURPLE END ON OUTER THIGH AND PUSH FIRMLY
- INGREDIENTS AND APPEARANCE
morphine sulfate injection
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:11704-235 Route of Administration INTRAMUSCULAR DEA Schedule CII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Morphine Sulfate (UNII: X3P646A2J0) (Morphine - UNII:76I7G6D29C) Morphine Sulfate 10 mg in 0.7 mL Inactive Ingredients Ingredient Name Strength Benzyl Alcohol (UNII: LKG8494WBH) 10.5 mg in 0.7 mL Edetate Disodium (UNII: 7FLD91C86K) 0.7 mg in 0.7 mL Sulfuric Acid (UNII: O40UQP6WCF) Water (UNII: 059QF0KO0R) 0.7 mg in 0.7 mL Nitrogen (UNII: N762921K75) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:11704-235-01 1 in 1 POUCH 07/12/1990 1 0.7 mL in 1 SYRINGE, PLASTIC; Type 2: Prefilled Drug Delivery Device/System (syringe, patch, etc.) Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA019999 07/12/1990 Labeler - Meridian Medical Technologies, Inc. (167671341) Establishment Name Address ID/FEI Business Operations Meridian Medical Technologies, Inc. 038889234 MANUFACTURE(11704-235) , ANALYSIS(11704-235) Establishment Name Address ID/FEI Business Operations Meridian Medical Technologies, Inc. 078808315 MANUFACTURE(11704-235) , LABEL(11704-235) , PACK(11704-235) Establishment Name Address ID/FEI Business Operations Meridian Medical Technologies, Inc. 167671341 MANUFACTURE(11704-235) , LABEL(11704-235) , PACK(11704-235) , ANALYSIS(11704-235)