Morphine Sulfate Injection - Product Information
|Manufacture:||Fresenius Kabi USA, LLC|
|Condition:||Chronic Pain, Pain|
|Form:||Liquid solution, Intramuscular (IM), Intravenous (IV)|
Indications and Usage
Morphine sulfate is an opioid agonist indicated for the management of pain not responsive to non-narcotic analgesics.
Dosage and Administration
Morphine Sulfate Injection is intended for intravenous and intramuscular administration.
General Dosing Considerations
Avoid Medication Errors
Morphine Sulfate Injection is available in five concentrations for direct injection. Take care when prescribing and administering Morphine Sulfate Injection to avoid dosing errors due to confusion between different concentrations and between mg and mL, which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and total dose in volume.
Administration of Morphine Sulfate Injection should be limited to use by those familiar with the management of respiratory depression. Morphine must be injected slowly; rapid intravenous administration may result in chest wall rigidity.
Selection of patients for treatment with morphine sulfate should be governed by the same principles that apply to the use of similar opioid analgesics. Individualize treatment in every case, using non-opioid analgesics, opioids on an as needed basis and/or combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality, and the American Pain Society.
Individualization of Dosage
Adjust the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience. In the selection of the initial dose of Morphine Sulfate Injection, USP, give attention to the following:
- the total daily dose, potency and specific characteristics of the opioid the patient has been taking previously;
- the reliability of the relative potency estimate used to calculate the equivalent Morphine Sulfate Injection, USP dose needed;
- the patient's degree of opioid tolerance;
- the general condition and medical status of the patient;
- concurrent medications;
- the type and severity of the patient's pain;
- risk factors for abuse, addiction or diversion, including a prior history of abuse, addiction.
The following dosing recommendation, therefore, can only be considered suggested approaches to what is actually a series of clinical decisions over time in management of the pain of each individual patient.
Continual re-evaluation of the patient receiving Morphine Sulfate Injection, USP is important, with special attention to the management of pain and the occurrence of side effects associated with therapy.
Direct Intravenous Injection
The usual starting dose in adults is 0.1 mg to 0.2 mg per kg every 4 hours as needed to manage pain.
- Inspect Morphine Sulfate Injection for particulate matter and discoloration prior to administration.
- Administer the injection slowly.
- Monitor the patient closely for signs of respiratory and central nervous system depression.
The initial IM dose is 10 mg, every 4 hours as needed to manage pain (based on a 70 kg adult).
- Inspect Morphine Sulfate Injection for particulate matter and discoloration prior to administration.
- Monitor the patient closely for signs of respiratory and central nervous system depression.
Dosing with Hepatic and Renal Impairment
Morphine Sulfate pharmacokinetics have been reported to be significantly altered in patients with cirrhosis and renal failure. Start these patients with lower doses of Morphine Sulfate Injection, USP and titrate slowly while carefully monitoring for respiratory and central nervous system depression [see Use in Specific Populations].
Dosage Forms and Strengths
Morphine Sulfate Injection, USP is available in the following strengths for intravenous and intramuscular administration.
2 mg/mL in 1 mL prefilled disposable syringe for IV or IM use.
4 mg/mL in 1 mL prefilled disposable syringe for IV or IM use.
5 mg/mL in 1 mL prefilled disposable syringe for IV or IM use.
8 mg/mL in 1 mL prefilled disposable syringe for IV or IM use.
10 mg/mL in 1 mL prefilled disposable syringe for IV or IM use.
Morphine sulfate is contraindicated in:
- patients with known hypersensitivity to morphine.
- patients with respiratory depression in the absence of resuscitative equipment.
- patients with acute or severe bronchial asthma or hypercarbia.
- any patient who has or is suspected of having paralytic ileus.
Warnings and Precautions
Risk of Medication Errors
Morphine Sulfate Injection is available in five concentrations for direct injection. Take care when prescribing and administering Morphine Sulfate Injection to avoid dosing errors due to confusion between different concentrations and between mg and mL, which could result in accidental overdose and death. Take care to ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume.
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.
Respiratory depression is the primary risk of Morphine Sulfate Injection, USP. Respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied by hypoxia, hypercapnia or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation. Morphine administration should be limited to use by those familiar with the management of respiratory depression. Rapid intravenous administration may result in chest wall rigidity.
Patients with chronic obstructive pulmonary disease or cor pulmonale and in patients having a substantially decreased respiratory reserve (e.g., severe kyphoscoliosis), hypoxia, hypercapnia or pre-existing respiratory depression have an increased risk of increased airway resistance and decrease respiratory drive to the point of apnea with use of Morphine Sulfate Injection, USP. Therefore, consider alternative non-opioid analgesics, and use Morphine Sulfate Injection, USP only under careful medical supervision at the lowest effective dose in such patients.
Central Nervous System (CNS) Toxicity
Excitation of the central nervous system, resulting in convulsion, may accompany high doses of morphine given intravenously. Dysphoric reactions may occur after any size dose and toxic psychoses have been reported.
Misuse, Abuse and Diversion of Opioids
Morphine sulfate is an opioid agonist and a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty [see Drug Abuse and Dependence].
Morphine sulfate can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Morphine Sulfate Injection, USP in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.
Concerns about abuse, addiction and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.
Central Nervous System (CNS) Depressants
The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistamines or psychotropic drugs. Use of morphine in conjunction with other CNS active drugs may increase the risk of respiratory depression, hypotension, profound sedation, coma, or death.
Increased Intracranial Pressure or Head Injury
Use Morphine Sulfate Injection with extreme caution in patients with head injury or increased intracranial pressure. In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the possible respiratory depressant effects of Morphine Sulfate Injection, USP and its potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Pupillary changes (miosis) from morphine may obscure the existence, extent and course of intracranial pathology. Clinicians should maintain a high index of suspicion for adverse drug reactions when evaluating altered mental status or movement abnormalities in patients receiving this modality of treatment.
Morphine sulfate may cause severe hypotension in an individual whose ability to maintain their blood pressure has been compromised by a depleted blood volume, shock, impaired myocardial function or concurrent administration of sympatholytic drugs, and drugs such as phenothiazines or general anesthetics. Orthostatic hypotension is a frequent complication in single-dose parenteral morphine analgesia in ambulatory patients.
The vasodilation produced by Morphine Sulfate Injection, USP may further reduce cardiac output and blood pressure in patients in circulatory shock.
Driving and Operating Machinery
Morphine may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Caution patients accordingly.
Do not administer Morphine Sulfate Injection, USP to patients with gastrointestinal obstruction, especially paralytic ileus because Morphine Sulfate Injection, USP diminishes propulsive peristaltic waves in the gastrointestinal tract and may prolong the obstruction.
The administration of Morphine Sulfate Injection, USP may obscure the diagnosis or clinical course in patients with acute abdominal condition.
Use in Biliary Surgery or Disorders of the Biliary Tract
Morphine sulfate should be used with caution in patients with biliary tract disease, including acute pancreatitis, as morphine sulfate may cause spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions.
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.
Special Risk Groups
Use Morphine Sulfate injection in reduced dosages in patients with severe renal or hepatic impairment, Addison's disease, hypothyroidism, prostatic hypertrophy, or urethral stricture, and in elderly or debilitated patients. Monitor these patients closely for signs of respiratory and central nervous system depression [see Use in Specific Populations].
Serious adverse reactions associated with Morphine Sulfate Injection, USP include respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest. Rarely, anaphylactoid reactions have been reported when morphine or other phenanthrene alkaloids of opium are administered intravenously.
The most frequently observed adverse reactions include sedation, lightheadedness, dizziness, nausea, vomiting, constipation and diaphoresis. 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.
Other possible adverse reactions include:
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 – Pruritus, urticaria and skin rashes. Anaphylactoid reactions have been reported following intravenous administration.
Other – Opiate-induced histamine release may be responsible for the flushing of the face, diaphoresis 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 may alter temperature regulation in susceptible individuals and will depress the cough reflex.
Central Nervous System (CNS) Depressants
Central nervous system depressants including other narcotic analgesics, general anesthetics, phenothiazines, tricyclic antidepressants, tranquilizers, sedatives, hypnotics, antiemetics or alcohol increase the risks of respiratory depression, hypotension, profound sedation and coma if given concomitantly with morphine sulfate injection.
Morphine sulfate may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Mixed Agonist/Antagonist Opioid Analgesics
Do not administer mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine and butorphanol) to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic such as Morphine Sulfate Injection, USP. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic and/or may precipitate withdrawal symptoms.
Concomitant administration of morphine sulfate and cimetidine has been reported to precipitate apnea, confusion and muscle twitching in an isolated report. Monitor patients for increased respiratory and CNS depression when receiving cimetidine concomitantly with Morphine Sulfate Injection, USP.
Monoamine Oxidase Inhibitors (MAOIs)
MAOIs markedly potentiate the action of Morphine Sulfate Injection, USP. Allow at least 14 days after stopping treatment with MAOIs before initiating treatment with Morphine Sulfate Injection, USP.
Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention, severe constipation or paralytic ileus.
Use in Specific Populations
Teratogenic Effects (Pregnancy Category C)
No formal studies to assess the teratogenic effects of morphine in animals have been conducted. It is also not known whether morphine can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Morphine should be given to a pregnant woman only if clearly needed.
In humans, the frequency of congenital anomalies have been reported to be no greater than expected among the children of 70 women who were treated with morphine during the first four months of pregnancy or in 448 women treated with morphine anytime during pregnancy. Furthermore, no malformations were observed in the infant of a woman who attempted suicide by taking an overdose of morphine and other medication during the first trimester of pregnancy.
Several literature reports indicate that morphine administered subcutaneously during the early gestational period in mice and hamsters produced neurological, soft tissue and skeletal abnormalities. With one exception, the effects that have been reported were following doses that were maternally toxic and the abnormalities noted were characteristic of those observed when maternal toxicity is present. In one study, following subcutaneous infusion of doses greater than or equal to 0.15 mg/kg to mice, exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae and malformed xiphoid were noted in the absence of maternal toxicity. In the hamster, morphine sulfate given subcutaneously on gestation day 8 produced exencephaly and cranioschisis. In rats treated with subcutaneous infusions of morphine during the period of organogenesis, no teratogenicity was observed.
No maternal toxicity was observed in this study however, increased mortality and growth retardation were seen in the offspring. In two studies performed in the rabbit, no evidence of teratogenicity was reported at subcutaneous doses up to 100 mg/kg.
Controlled studies of chronic in utero morphine exposure in pregnant women have not been conducted. Infants born to mothers who have taken opioids chronically may exhibit withdrawal symptoms, reversible reduction in brain volume, small size, decreased ventilatory response to CO2 and increased risk of sudden infant death syndrome. Morphine sulfate should be used by a pregnant woman only if the need for opioid analgesia clearly outweighs the potential risks to the fetus.
Published literature has reported that exposure to morphine during pregnancy is associated with reduction in growth and a host of behavioral abnormalities in the offspring of animals. Morphine treatment during gestational periods of organogenesis in rats, hamsters, guinea pigs and rabbits resulted in the following treatment-related embryotoxicity and neonatal toxicity in one or more studies: decreased litter size, embryo-fetal viability, fetal and neonatal body weights, absolute brain and cerebellar weights, delayed motor and sexual maturation, and increased neonatal mortality, cyanosis and hypothermia. Decreased fertility in female offspring 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. Decreased litter size and viability were observed in the offspring of male rats administered morphine (25 mg/kg, ip) for 1 day prior to mating. Behavioral abnormalities resulting from chronic morphine exposure of fetal animals included altered reflex and motor skill development, mild withdrawal and altered responsiveness to morphine persisting into adulthood.
Labor and Delivery
Morphine readily passes into the fetal circulation and may result in respiratory depression and psycho-physiologic effects in neonates. Naloxone and resuscitative equipment should be available for reversal of narcotic-induced respiratory depression in the neonate. In addition, parenteral morphine may reduce the strength, duration and frequency of uterine contractions resulting in prolonged labor. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression.
Low levels of Morphine Sulfate Injection, USP have been detected in maternal milk. The milk:plasma morphine AUC ratio is about 2:5:1. The amount of Morphine Sulfate Injection, USP delivered to the infant depends on the plasma concentration of the mother, the amount of milk ingested by the infant and the extent of first-pass metabolism. Because of the potential for serious adverse reactions in nursing infants from Morphine Sulfate Injection, USP including respiratory depression, sedation and possibly withdrawal symptoms upon cessation of Morphine Sulfate Injection, USP administration to the mother, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
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 doses should be based on careful clinical observation following “test doses” after making due allowances for the effects of the patient's age and infirmity on his/her ability to clear the drug.
Elderly patients may be more susceptible to respiratory depression and/or respiratory arrest following administration of morphine.
In general, use caution when selecting a dose 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.
While evidence of greater post-operative Morphine Sulfate Injection, USP consumption in men compared to women is present in the literature, clinically significant differences in analgesic outcomes and pharmacokinetic parameters have not been consistently demonstrated. Some studies have shown an increased sensitivity to the adverse effects of Morphine Sulfate Injection, USP, including respiratory depression, in women compared to men.
Morphine sulfate pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine AUC ratio is also decreased in these subjects, indicating diminished metabolic activity. Start these patients cautiously with lower doses of Morphine Sulfate Injection, USP and titrate slowly while carefully monitoring for side effects.
Morphine sulfate pharmacokinetics are altered in patients with renal failure. 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. Start these patients cautiously with lower doses of Morphine Sulfate Injection, USP and titrate slowly while carefully monitoring for side effects.
Drug Abuse and Dependence
Morphine sulfate is an opioid agonist and a Schedule II controlled substance. Morphine sulfate, like other opioids, can be abused and is subject to criminal diversion.
Morphine Sulfate Injection, USP contains a potent narcotic which has been associated with abuse and dependence. Abuse is defined as the intentional non-therapeutic use of a drug, even once, for its rewarding psychological or physiological effects. Due to the risk of overdosage and the risk of its diversion and abuse, it is recommended that special measures be taken to control this product within the hospital or clinic.
Morphine Sulfate Injection, USP should be subject to rigid accounting, rigorous control of wastage and restricted access.
“Drug-seeking” behavior is very common in addicts and drug abusers. 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 physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Drug addiction is characterized by compulsive use, use for non-medical purposes and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-discipline approach, but relapse is common.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence. The converse is also true. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Careful record-keeping of prescribing information, including quantity, frequency and renewal requests 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. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations].
Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. 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) and euphoria. Physical dependence and tolerance are frequent during chronic opioid therapy.
The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia and mydriasis. Other 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.
Withdrawal symptoms may occur when morphine is discontinued abruptly or upon administration of a narcotic antagonist. In general, taper morphine rather than abruptly discontinue, especially when used for more than a few days.
Acute overdosage with morphine is characterized by respiratory depression, with or without concomitant CNS depression. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur.
Morphine sulfate may cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdosage but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.
Give primary attention to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompany overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
The opioid antagonist naloxone is a specific antidote to respiratory depression resulting from opioid overdose. Since the duration of reversal is expected to be less than the duration of action of Morphine Sulfate Injection, USP, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to opioid antagonists is sub -optimal or only brief in nature, administer additional antagonist as directed by the manufacturer of the product. Do not administer opioid antagonists in the absence of clinically significant respiratory or circulatory depression secondary to Morphine Sulfate Injection, USP overdose. Administer such agents cautiously to persons who are known or suspected to be physically dependent on Morphine Sulfate Injection, USP. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome.
In an individual physically dependent on opioids, administration of the usual dose 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. Reserve use of an opioid antagonist for cases where such treatment is clearly needed. If it is necessary to treat serious respiratory depression in the physically dependent patient, initiate administration of the antagonist with care and titrate with smaller than usual doses.
How Supplied/Storage and Handling
Morphine Sulfate Injection, USP is available for intravenous (IV) or intramuscular (IM) use as: 2 mg/mL in 1 mL pre-filled disposable syringe, NDC 76045-004-10
4 mg/mL in 1 mL pre-filled disposable syringe, NDC 76045-005-10
5 mg/mL in 1 mL pre-filled disposable syringe, NDC 76045-006-10
8 mg/mL in 1 mL pre-filled disposable syringe, NDC 76045-007-10
10 mg/mL in 1 mL pre-filled disposable syringe, NDC 76045-008-10
Available in a carton of twenty-four (24) syringes for each strength.
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
PROTECT FROM LIGHT. DO NOT FREEZE.
This product is for single dose only.
Contains no preservative or antioxidant.
DISCARD ANY UNUSED PORTION.
DO NOT HEAT-STERILIZE.
DO NOT place syringe on a sterile field.
DO NOT autoclave syringe.
DO NOT introduce any other fluid into the syringe at any time.
Retain in carton until time of use.
All steps must be done sequentially.
Patient Counseling Information
Physicians should provide the following information to patients receiving parenteral morphine:
- Morphine analgesics may produce orthostatic hypotension in ambulatory patients.
- There is potential for severe constipation; appropriate laxatives and/or stool softeners as well as other appropriate treatments should be initiated from the onset of opioid therapy.
- Analgesic doses of morphine cloud judgment and impair the mental and/or physical abilities required for the performance of tasks such as driving a vehicle or operating machinery.
- Morphine will add to the effect of alcohol and other CNS depressants, including sedatives, hypnotics, tranquilizers, phenothiazines and antihistamines.
- The most common adverse events that may occur while taking morphine include nausea, somnolence, lightheadedness, dizziness, sedation, vomiting, diaphoresis and constipation.
Fresenius Kabi USA, LLC
Lake Zurich, IL 60047