The product which contains antioxidant (25 mg/mL and 50 mg/mL concentrations – see DESCRIPTION and HOW SUPPLIED), contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
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 (see DRUG ABUSE AND DEPENDENCE).
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 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 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.
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status (see OVERDOSAGE). 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. Because of a delay in the maximum CNS effect with intravenously administered Morphine Sulfate Injection (30 min), rapid administration may result in overdosing. The respiratory depression may be severe and could require intervention (see OVERDOSAGE). 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 (see DOSAGE AND ADMINISTRATION). Overestimating the Morphine Sulfate Injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper (see DOSAGE AND ADMINISTRATION).
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. 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 (see Pregnancy).
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., 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.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see Drug Interactions).
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 (see Drug Interactions).
While low doses of intravenously administered morphine have little effect on cardiovascular stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in circulatory catecholamines. Have naloxone injection and resuscitative equipment immediately available for use in case of life-threatening or intolerable side effects and whenever morphine therapy is being initiated.
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.
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.
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 in a physically-dependent patient, gradually taper the dosage. Do not abruptly discontinue Morphine Sulfate Injection in these patients (see DRUG ABUSE AND DEPENDENCE).
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.
Give by very slow intravenous injection, in the form of a diluted solution. Rapid intravenous injection of morphine and other narcotic analgesics increases the incidence of adverse reactions; severe respiratory depression, hypotension, apnea, peripheral circulatory collapse, cardiac arrest, and anaphylactic reactions have occurred. These preparations should not be administered intravenously unless a narcotic antagonist and facilities for assisted or controlled respiration are immediately available. When given parenterally, especially intravenously, the patient should be lying down. Use caution when injecting subcutaneously or intramuscularly in 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 reestablished.
The use of bisulfites is contraindicated in asthmatics. Bisulfites and morphine may potentiate each other, preventing use by causing severe adverse reactions.
Use with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, patients with substantially decreased respiratory reserve, and patients with pre-existing respiratory depression, hypoxia or hypercapnia. In such patients, even usual therapeutic doses of narcotics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.
Caution should be used in patients with atrial flutter and other supraventricular tachycardias due to a possible vagolytic action which may produce a significant increase in the ventricular response rate.
Morphine may have a prolonged duration and cumulative effect in patients with renal or hepatic dysfunction.
Morphine may aggravate pre-existing convulsive disorders. Convulsions may occur in individuals without a history of convulsive disorders if dosage is substantially escalated above recommended levels because of tolerance development.
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.
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 (see WARNINGS).
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 (see WARNINGS).
Caution must be exercised in elderly and debilitated patients and in patients who are known to be sensitive to CNS depressants, including those with cardiovascular or pulmonary disease, myxedema, cerebral arteriosclerosis, emphysema, fever, bronchial asthma, kyphoscoliosis, Addison's disease, prostatic hypertrophy or urethral stricture, toxic psychosis.
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 (see WARNINGS). Alternatively, consider the use of non-opioid analgesics in these patients.
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 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 also 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.
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) (see Drug Interactions). 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.
Morphine Sulfate Injection is contraindicated in patients with known or suspected 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.
The administration of morphine or other narcotics may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Use also with caution in patients with gastrointestinal hemorrhage, ulcerative colitis, or recent gastrointestinal or urinary tract surgery.
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.
Opioids can cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications (see Drug Interactions).
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention (see ADVERSE REACTIONS).
Morphine may increase the anticoagulant activity of coumarin and other anticoagulants.
When morphine is to be administered to patients receiving propiomazine (Largon), the dose of morphine should be reduced by one-quarter to one-half.
Atropine antagonizes morphine respiratory depression. Levallorphan and nalorphine antagonize morphine actions, principally the respiratory depression.
| Benzodiazepines and Other 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). |
| 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, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Injection if serotonin syndrome is suspected. |
| Examples: | Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
| 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). |
| Intervention: | Do not use Morphine Sulfate Injection 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, 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 and/or precipitate withdrawal symptoms. |
| Intervention: | Avoid concomitant use. |
| Examples: | butorphanol, nalbuphine, pentazocine, buprenorphine |
| Muscle Relaxants | |
| Clinical Impact: | Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
| Intervention: | Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Injection and/or the muscle relaxant as necessary. |
| Cimetidine | |
| Clinical Impact: | Concomitant administration of Morphine Sulfate Injection and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report. |
| Intervention: | Monitor patients for increased respiratory and CNS depression when receiving cimetidine concomitantly with Morphine Sulfate Injection. |
| 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 is used concomitantly with anticholinergic drugs. |
| 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 a parenteral antiplatelet agent in the setting of acute coronary syndrome requiring co-administration of intravenous morphine sulfate. |
| Examples: | clopidogrel, prasugrel, ticagrelor |
Long-term studies in animals to evaluate the carcinogenic potential of morphine 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 also 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 these 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.
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 human daily dose-HDD of 60 mg based on body surface area) were reported.
Studies from the literature have also reported changes in hormonal levels in male rats (i.e., testosterone, LH) 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).
Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome (see WARNINGS). There are no available data with Morphine Sulfate Injection 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 HDD of 60 mg based on body surface area 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.
Prolonged use of opioid analgesics during pregnancy for medical or non-medical 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 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 signs of neonatal opioid withdrawal syndrome and manage accordingly (see WARNINGS).
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 is not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Morphine Sulfate Injection, can prolong labor through actions that 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 dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
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 the HDD of 60 mg morphine using a body surface area comparison.
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 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 LH 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, 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, and any potential adverse effects on the breastfed infant from Morphine Sulfate Injection, or from the underlying maternal condition.
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).
In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats (see Carcinogenesis, Mutagenesis, Impairment of Fertility).
The safety and effectiveness of Morphine Sulfate Injection in pediatric patients below the age of 18 have not been established.
The pharmacodynamic effects of morphine in the elderly are more variable than in the younger population. Older patients will vary widely in the effective initial dose, rate of development of tolerance and the frequency and magnitude of associated adverse effects as the dose is increased. Initial elderly patients (aged 65 years or older) may have increased sensitivity to morphine. 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 Injection slowly in geriatric patients and monitor closely for signs of CNS and respiratory depression (see PRECAUTIONS).
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.
Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than normal dosage of Morphine Sulfate Injection and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension (see CLINICAL PHARMACOLOGY).
Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than normal dosage of Morphine Sulfate Injection and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension (see CLINICAL PHARMACOLOGY).
The product which contains antioxidant (25 mg/mL and 50 mg/mL concentrations – see DESCRIPTION and HOW SUPPLIED), contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
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 (see DRUG ABUSE AND DEPENDENCE).
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 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 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.
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status (see OVERDOSAGE). 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. Because of a delay in the maximum CNS effect with intravenously administered Morphine Sulfate Injection (30 min), rapid administration may result in overdosing. The respiratory depression may be severe and could require intervention (see OVERDOSAGE). 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 (see DOSAGE AND ADMINISTRATION). Overestimating the Morphine Sulfate Injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper (see DOSAGE AND ADMINISTRATION).
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. 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 (see Pregnancy).
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., 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.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see Drug Interactions).
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 (see Drug Interactions).
While low doses of intravenously administered morphine have little effect on cardiovascular stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in circulatory catecholamines. Have naloxone injection and resuscitative equipment immediately available for use in case of life-threatening or intolerable side effects and whenever morphine therapy is being initiated.
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.
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.
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 in a physically-dependent patient, gradually taper the dosage. Do not abruptly discontinue Morphine Sulfate Injection in these patients (see DRUG ABUSE AND DEPENDENCE).
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.
Give by very slow intravenous injection, in the form of a diluted solution. Rapid intravenous injection of morphine and other narcotic analgesics increases the incidence of adverse reactions; severe respiratory depression, hypotension, apnea, peripheral circulatory collapse, cardiac arrest, and anaphylactic reactions have occurred. These preparations should not be administered intravenously unless a narcotic antagonist and facilities for assisted or controlled respiration are immediately available. When given parenterally, especially intravenously, the patient should be lying down. Use caution when injecting subcutaneously or intramuscularly in 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 reestablished.
The use of bisulfites is contraindicated in asthmatics. Bisulfites and morphine may potentiate each other, preventing use by causing severe adverse reactions.
Use with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, patients with substantially decreased respiratory reserve, and patients with pre-existing respiratory depression, hypoxia or hypercapnia. In such patients, even usual therapeutic doses of narcotics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.
Caution should be used in patients with atrial flutter and other supraventricular tachycardias due to a possible vagolytic action which may produce a significant increase in the ventricular response rate.
Morphine may have a prolonged duration and cumulative effect in patients with renal or hepatic dysfunction.
Morphine may aggravate pre-existing convulsive disorders. Convulsions may occur in individuals without a history of convulsive disorders if dosage is substantially escalated above recommended levels because of tolerance development.
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.
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 (see WARNINGS).
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 (see WARNINGS).
Caution must be exercised in elderly and debilitated patients and in patients who are known to be sensitive to CNS depressants, including those with cardiovascular or pulmonary disease, myxedema, cerebral arteriosclerosis, emphysema, fever, bronchial asthma, kyphoscoliosis, Addison's disease, prostatic hypertrophy or urethral stricture, toxic psychosis.
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 (see WARNINGS). Alternatively, consider the use of non-opioid analgesics in these patients.
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 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 also 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.
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) (see Drug Interactions). 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.
Morphine Sulfate Injection is contraindicated in patients with known or suspected 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.
The administration of morphine or other narcotics may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Use also with caution in patients with gastrointestinal hemorrhage, ulcerative colitis, or recent gastrointestinal or urinary tract surgery.
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.
Opioids can cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications (see Drug Interactions).
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention (see ADVERSE REACTIONS).
Morphine may increase the anticoagulant activity of coumarin and other anticoagulants.
When morphine is to be administered to patients receiving propiomazine (Largon), the dose of morphine should be reduced by one-quarter to one-half.
Atropine antagonizes morphine respiratory depression. Levallorphan and nalorphine antagonize morphine actions, principally the respiratory depression.
| Benzodiazepines and Other 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). |
| 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, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Injection if serotonin syndrome is suspected. |
| Examples: | Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
| 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). |
| Intervention: | Do not use Morphine Sulfate Injection 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, 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 and/or precipitate withdrawal symptoms. |
| Intervention: | Avoid concomitant use. |
| Examples: | butorphanol, nalbuphine, pentazocine, buprenorphine |
| Muscle Relaxants | |
| Clinical Impact: | Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
| Intervention: | Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Injection and/or the muscle relaxant as necessary. |
| Cimetidine | |
| Clinical Impact: | Concomitant administration of Morphine Sulfate Injection and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report. |
| Intervention: | Monitor patients for increased respiratory and CNS depression when receiving cimetidine concomitantly with Morphine Sulfate Injection. |
| 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 is used concomitantly with anticholinergic drugs. |
| 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 a parenteral antiplatelet agent in the setting of acute coronary syndrome requiring co-administration of intravenous morphine sulfate. |
| Examples: | clopidogrel, prasugrel, ticagrelor |
Long-term studies in animals to evaluate the carcinogenic potential of morphine 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 also 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 these 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.
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 human daily dose-HDD of 60 mg based on body surface area) were reported.
Studies from the literature have also reported changes in hormonal levels in male rats (i.e., testosterone, LH) 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).
Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome (see WARNINGS). There are no available data with Morphine Sulfate Injection 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 HDD of 60 mg based on body surface area 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.
Prolonged use of opioid analgesics during pregnancy for medical or non-medical 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 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 signs of neonatal opioid withdrawal syndrome and manage accordingly (see WARNINGS).
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 is not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Morphine Sulfate Injection, can prolong labor through actions that 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 dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
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 the HDD of 60 mg morphine using a body surface area comparison.
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 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 LH 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, 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, and any potential adverse effects on the breastfed infant from Morphine Sulfate Injection, or from the underlying maternal condition.
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).
In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats (see Carcinogenesis, Mutagenesis, Impairment of Fertility).
The safety and effectiveness of Morphine Sulfate Injection in pediatric patients below the age of 18 have not been established.
The pharmacodynamic effects of morphine in the elderly are more variable than in the younger population. Older patients will vary widely in the effective initial dose, rate of development of tolerance and the frequency and magnitude of associated adverse effects as the dose is increased. Initial elderly patients (aged 65 years or older) may have increased sensitivity to morphine. 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 Injection slowly in geriatric patients and monitor closely for signs of CNS and respiratory depression (see PRECAUTIONS).
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.
Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than normal dosage of Morphine Sulfate Injection and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension (see CLINICAL PHARMACOLOGY).
Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than normal dosage of Morphine Sulfate Injection and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension (see CLINICAL PHARMACOLOGY).
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