Morphine Sulfate

Dosage Forms And Strengths

AVINZA contains white to off-white color pellets, have an outer opaque capsule with colors as identified below and are available in six dose strengths:

Each 30 mg extended-release capsule has a yellow opaque cap with “AVINZA” printed on it and a white opaque body printed with “30” and “505”.

Each 45 mg extended-release capsule has a light blue opaque cap with “AVINZA” printed on it and a white opaque body printed with “45” and “509”.

Each 60 mg extended-release capsule has a bluish-green opaque cap with “AVINZA” printed on it and a white opaque body printed with “60” and “506”.

Each 75 mg extended-release capsule has an orange opaque cap with “AVINZA” printed on it and a white opaque body printed with “75” and “510”.

Each 90 mg extended-release capsule has a red opaque cap with “AVINZA” printed on it and a white opaque body printed with “90” and “507”.

Each 120 mg extended-release capsule has a blue-violet opaque cap with “AVINZA” printed on it and a white opaque body printed with “120” and “508”.

Storage And Handling

30 mg extended-release capsule: size 3 capsule, yellow cap and white, opaque body imprinted AVINZA 30 mg and 505. NDC 60793-605-01: Bottles of 100 capsules.

45 mg extended-release capsule: size 3 capsule, light blue cap and white, opaque body imprinted AVINZA 45 mg and 509. NDC 60793-603-01: Bottles of 100 capsules.

60 mg extended-release capsule: size 3 capsule, bluish-green cap and white, opaque body imprinted AVINZA 60 mg and 506. NDC 60793-606-01: Bottles of 100 capsules.

75 mg extended-release capsule: size 1 capsule, orange cap and white, opaque body imprinted AVINZA 75 mg and 510. NDC 60793-604-01: Bottles of 100 capsules.

90 mg extended-release capsule: size 1 capsule, red cap and white, opaque body imprinted AVINZA 90 mg and 507. NDC 60793-607-01: Bottles of 100 capsules.

120 mg extended-release capsule: size 1 capsule, blue-violet cap and white, opaque body imprinted AVINZA 120 mg and 508. NDC 60793-608-01: Bottles of 100 capsules.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [see USP Controlled Room Temperature]

Protect from light and moisture.

Dispense in a tight, light-resistant container as defined in USP.

CAUTION: DEA Order Form Required.

Manufactured for: Pfizer Inc, New York, NY 10017 by: Alkermes Gainesville LLC, Gainesville, GA. Issued: April 2014

THE MAJOR HAZARDS OF MORPHINE, AS OF OTHER NARCOTIC ANALGESICS, ARE RESPIRA-TORY DEPRESSION AND, TO A LESSER DEGREE, CIRCULATORY DEPRESSION, RESPIRATORY ARREST, SHOCK, AND CARDIAC ARREST HAVE OCCURRED.

The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are suffering severe pain. In such individuals, lower doses are available. Some adverse reactions may be alleviated in the ambulatory patient if he lies down.

Other adverse reactions include the following

Central Nervous System: Euphoria, dysphoria, weakness, headache, insomnia, agitation, disorientation, and visual disturbances.

Gastrointestinal: Dry mouth, anorexia, constipation, and biliary tract spasm.

Cardiovascular: Flushing of the face, bradycardia, palpitation, faintness and syncope.

Allergic: Pruritus, urticaria, other skin rashes, edema, and, rarely hemorrhagic urticaria.

Treatment of the most frequent adverse reactions

Ample intake of water or other liquids should be encouraged. Concomitant administration of a stool softener and a peristaltic stimulant with the narcotic analgesic can be an effective preventive measure for those patients in need of therapeutics. If elimination does not occur for two days, an enema should be administered to prevent impaction.

In the event diarrhea occurs, seepage around fecal impaction is a possible cause to consider before antidiarrheal measures are employed.

Phenothiazines and antihistamines can be effective treatments of nausea of the medullary and vestibular sources respectively. However, these drugs may potentiate the side effects of the narcotic or the antinauseant.

Once pain control is achieved, undesirable sedation can be minimized by titrating the dosage to a level that just maintains a tolerable pain or pain free state.

Drug Abuse And Dependence

Morphine Sulfate, a narcotic, is a Schedule II controlled substance under the Federal Controlled Substance Act. As with other narcotics, some patients may develop a physical and psychological dependence on morphine. They may increase dosage without consulting a physician and subsequently may develop a physical dependence on the drug. In such cases, abrupt discontinuance may precipitate typical withdrawal symptoms, including convulsions. Therefore the drug should be withdrawn gradually from any patient known to be taking excessive dosages over a long period of time.

In treating the terminally ill patient the benefit of pain relief may outweigh the possibility of drug dependence. The chance of drug dependence is substantially reduced when the patient is placed on scheduled narcotic programs instead of a “pain to relief-of-pain” cycle typical of a PRN regimen.

Morphine can cause tolerance, psychological and physical dependence. Withdrawal will occur on abrupt discontinuation or administration of a narcotic antagonist.

Interaction with Other Central Nervous System Depressants

Morphine should be used with caution and in reduced dosage in patients who are concurrently receiving other narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics, tricyclic antidepressants, and other CNS depressants (including alcohol). Respiratory depression, hypotension, and profound sedation or coma may result.

Morphine is an opioid pain medication. An opioid is sometimes called a narcotic.

Morphine is used to treat moderate to severe pain. Short-acting morphine is taken as needed for pain. Extended-release morphine is for use when around-the-clock pain relief is needed.

Morphine is not for treating pain just after surgery unless you were already taking morphine before the surgery.

Morphine may also be used for purposes not listed in this medication guide.

Your pharmacist can provide more information about morphine.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Contraindications

• Hypersensitivity to morphine, morphine salts, or any ingredient in the formulation.170 171 172 192 193 196

• Respiratory depression in the absence of resuscitative equipment.169 170 171 172 192 196

• Acute or severe bronchial asthma or hypercarbia.169 170 171 172 192

• Known or suspected paralytic ileus.169 170 171 172 192

• Epidural or intrathecal injection contraindicated in patients whose concomitant drug therapy or medical condition would contraindicate administration of the drug by these routes, such as when infection is present at the injection site or when the patient has uncontrolled bleeding diathesis or is receiving anticoagulants.192 b

• Extended-release liposomal injection (DepoDur) also contraindicated in patients in circulatory shock.192

Warnings/Precautions

Warnings

The major toxicity associated with morphine.169 170 171 172 192

Occurs most frequently in geriatric and debilitated patients, and those with conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation.169 170 171 172 192

May be severe, requiring maintenance of an adequate airway, use of resuscitative equipment, and administration of oxygen, an opiate antagonist, and/or other resuscitative drugs.b

Use with extreme caution in patients with COPD or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression.169 170 171 172 In such patients, even therapeutic morphine doses may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.170 171 172

Bolus epidural or intrathecal administration may result in early respiratory depression because of direct venous redistribution of the drug to the respiratory centers in the CNS.b Late (up to 24 hours) acute respiratory depression also has occurred following epidural or intrathecal administration of morphine sulfate injection and is thought to result from rostral spread of the drug in the CNS.b Delayed respiratory depression (≥ 48 hours) may occur following administration of morphine sulfate extended-release liposomal injection (DepoDur).192 Risk of respiratory depression may be increased if the surgical procedure is cancelled after administration of the extended-release liposomal injection; monitor carefully.192 Respiratory depression requiring administration of naloxone or ventilatory support reported following intrathecal administration of DepoDur.a (See Precautions Associated with Epidural or Intrathecal Administration under Cautions.)

Intrathecal administration has been associated with a higher incidence of respiratory depression than epidural administration.b A diminished CO2 ventilatory response may be present for up to 22 hours following epidural or intrathecal administration of the drug, despite the absence of clinical evidence of inadequate ventilation.b

In patients receiving chronic epidural or intrathecal therapy, monitor patients in an adequately equipped (e.g., resuscitative equipment, oxygen, an opiate antagonist and other resuscitative drugs) and staffed environment (hospitalization is recommended) for ≥24 hours after administration of an initial test dose and, as appropriate, for several days after catheter implantation for additional monitoring and dosage adjustment.b An opiate antagonist and resuscitative equipment also should be immediately available whenever the reservoir of the microinfusion device is being refilled with morphine sulfate or is being otherwise manipulated.b

In patients receiving morphine sulfate extended-release liposomal injection (DepoDur), monitor patients in an adequately equipped (e.g., resuscitative equipment, oxygen, an opiate antagonist and other resuscitative drugs) and staffed environment for ≥48 hours after administration of the dose.192

Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists.400 Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.400

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function.400 If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued.400 In some patients, switching to a different opiate improved symptoms.400

The respiratory depressant effects of morphine (with CO2 retention and secondary elevation of CSF pressure) may be markedly exaggerated in the presence of head injury, other intracranial lesions, or preexisting increase in intracranial pressure.169 170 171 172

Morphine produces effects (e.g., pupillary changes) that may obscure neurologic signs of further increase in pressure in patients with head injuries.169 170 171 172

May interfere with evaluation of CNS function, and respiratory depression produced by the drug may produce cerebral hypoxia and elevated CSF pressure not caused by the injury itself.200 e

Use with extreme caution, if at all, in patients with severe CNS depression, anoxia, hypercapnia, or respiratory depression or those who are especially prone to respiratory depression such as comatose patients or those with head injury, brain tumor, or elevated CSF pressure.171 e Avoid use of morphine sulfate extended-release liposomal injection (DepoDur) in patients with head injury or increased intracranial pressure.192

Like all opiate analgesics, may cause severe hypotension in individuals whose ability to maintain their BP is compromised by depleted blood volume or concomitant drugs (e.g., phenothiazines, general anesthetics).170 171 172 192 193 Consider avoiding concomitant use of vasodilators.140 (See Specific Drugs under Interactions.)

May produce orthostatic hypotension in ambulatory patients.170 171 172 192

Orthostatic hypotension is a frequent complication of single-dose epidural or intrathecal morphine therapy, and patients with reduced circulatory volume or impaired myocardial function and those receiving sympatholytic therapy may be at particular risk.b 192

Use the minimal effective dose; patient’s legs should be elevated to decrease the possibility of hypotension.b

Use with caution in patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and BP.170 171 172 Morphine sulfate extended-release liposomal injection (DepoDur) is contraindicated in patients in circulatory shock.192

Physical and psychic dependence and tolerance may develop with repeated administration, and abuse potential exists; use with caution.169 170 171 172 Clinicians should consider abuse potential when prescribing or dispensing morphine in situations where they are concerned about an increased risk of misuse, abuse, or diversion.172 However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.172

Abrupt cessation of therapy or sudden reduction in dosage after prolonged use may result in withdrawal symptoms.169 170 172 After prolonged exposure to opioid analgesics, if withdrawal is necessary, it must be undertaken gradually.169 170 172

Health-care professionals should contact the professional licensing board or controlled substance authority in their states for information about prevention and detection of abuse or diversion.172

Administration may complicate assessment of patients with acute abdominal conditions.172

Can diminish propulsive peristaltic waves in the GI tract and may prolong the obstruction.171 192

In patients with GI obstruction, especially paralytic ileus, oral extended-release preparation may remain in the stomach for a prolonged period and subsequently release a bolus of morphine when normal gut motility is restored.172

Contraindicated in patients with known or suspected paralytic ileus.169 170 171 172 192

Myoclonic spasms of skeletal muscle have been reported; treatment of opiate intoxication may be required in some cases.b

In some patients, resumption of therapy after appropriate management of the toxicity may be possible at reduced dosage and/or by replacement of epidural with intrathecal therapy.b

Serious adverse events and deaths have occurred as a result of inadvertent overdosage of concentrated morphine sulfate oral solutions.182 234 235 (See Risk of Medication Errors with Oral Solutions in Boxed Warning.)

In most cases, morphine sulfate oral solutions prescribed in mg were mistakenly interchanged for mL of the concentrated preparation, resulting in 20-fold overdoses.182 234 235

Morphine sulfate 100-mg/5-mL oral solution is indicated for use only in patients who are opiate tolerant (i.e., individuals who have been receiving ≥60 mg of oral morphine sulfate daily, ≥30 mg of oral oxycodone daily, ≥12 mg of hydromorphone hydrochloride daily, or an equianalgesic dosage of another opiate daily for ≥1 week) and have been titrated to a stable analgesic dosage using a preparation containing a lower concentration of morphine sulfate.234 235 236

It is important that prescriptions for morphine sulfate oral solution be written clearly and filled with the proper concentration of morphine sulfate oral solution to prevent potential medication errors.182 234 (See Oral Solutions under Dosage and Administration.)

Sensitivity Reactions

Anaphylaxis reported rarely.170 172

Some commercially available formulations of morphine sulfate injection contain sulfites that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.196 b

Overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.196 b

General Precautions

Avinza extended-release capsules contain fumaric acid.171

Safety of morphine sulfate dosages >1.6 g daily administered as Avinza extended-release capsules has not been established; such dosages contain a quantity of fumaric acid that may be associated with serious renal toxicity.171

Epidural and intrathecal administration of morphine frequently associated with dose-related pruritus; not necessarily confined to the site of administration.b

Urinary retention, which may persist for 10–20 hours after administration, has occurred in about 90% of males who received the drug epidurally or intrathecally and less frequently in females.b Early recognition of urinary difficulty and prompt intervention in cases of retention are important, particularly in patients with prostatic enlargement.192 b

In addition to the usual precautions associated with morphine use, for epidural or intrathecal administration, the drug should only be used by qualified individuals familiar with the techniques of administration and patient management problems associated with these routes of administration.b

Because chronic epidural or intrathecal therapy employing a controlled-microinfusion device is accompanied by considerable patient risk and requires a high level of skill to be accomplished successfully, such therapy should only be undertaken by experienced clinical teams who are well informed about patient selection criteria, evolving technology, and emerging standards of care.b

Safety of intrathecal administration of morphine sulfate extended-release liposomal injection (DepoDur) not evaluated; this preparation is intended for administration by the epidural route.a (See Respiratory Depression under Cautions.)

May impair mental and/or physical abilities needed to perform potentially hazardous activities such as driving or operating machinery.171 172 b Individuals who perform hazardous tasks requiring mental alertness or physical coordination should be warned about possible adverse CNS effects of opiate agonists.171 172 b

High doses may result in seizures.192 Monitor patients with known seizure disorder for seizure activity;172 192 increased risk of seizures in these individuals.172

Use with caution and in reduced dosage in patients with hypothyroidism.170 171 172 e

Use with caution and in reduced dosage in patients with prostatic hypertrophy or urethral stricture.170 172

May cause spasm of the sphincter of Oddi.170 172 Use with caution in patients with biliary tract disease, including acute pancreatitis, and patients undergoing biliary tract surgery.170 172 192 Opiates may increase serum amylase concentrations.170 172

Use with caution and in reduced dosage in patients with Addison’s disease.170 171 172 e

Patients taking Kadian extended-release capsules who are scheduled for cordotomy or other interruption of pain transmission pathways should discontinue the drug 24 hours prior to the procedure and pain should be controlled by parenteral short-acting opiates.172 In addition, the post-procedure titration of analgesics for such patients should be individualized to avoid either oversedation or withdrawal syndromes.172

May increase ventricular response rate through a vagolytic action; use with caution in patients with atrial flutter and other supraventricular tachycardias.b

Ensure accuracy of prescription; similarity in spelling of Kadian and Kapidex (former trade name for dexlansoprazole, a proton-pump inhibitor) may result in errors.217 223

Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy;400 401 402 403 404 causality not established.400 Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility.400 Perform appropriate laboratory testing in patients with manifestations of hypogonadism.400

Specific Populations

Category C.169 171 172 192

Although morphine has been used during labor, use of opiate agonists generally should be avoided during labor when delivery of a premature neonate is anticipated.b (See Pediatric Use under Cautions.)

Because maternally administered opiate agonists are readily distributed into fetal circulation, an opiate antagonist and resuscitative equipment for reversal of opiate-induced respiratory depression should be readily available when the drugs are used during labor and delivery.b

Epidurally and intrathecally administered morphine also is readily distributed into fetal circulation and may result in respiratory depression in the neonate.b

Controlled clinical studies have shown that epidurally administered morphine has little or no effect on labor pain.b

Morphine sulfate extended-release liposomal injection (DepoDur) may be used during cesarean section after the umbilical cord is clamped but should not be used during labor and/or vaginal delivery.192

Distributed into milk; use with caution.169 171 b When morphine sulfate extended-release liposomal injection (DepoDur) is used during cesarean section, decide whether or not to allow nursing during the first 48 hours.192

Safety and efficacy of conventional oral preparations (solution, tablets) not established in children.202

Safety and efficacy of extended-release oral preparations not established in children <18 years of age.169 170 171 172

Opiate agonists generally should not be used in premature neonates since the drugs reportedly cross the immature blood-brain barrier more readily than they do the mature barrier and thereby produce disproportionate respiratory depression.b

Opiate agonists should be administered with caution and in carefully determined dosages to infants and small children since they may be relatively more sensitive to opiates on a body-weight basis.b

Safety and efficacy of epidural or intrathecal administration in children have not been determined and these routes are not recommended.192 b

Clinical studies of extended-release oral preparations did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger adults.170 171 172

Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, use extended-release oral preparations with caution in this age group and select dosage at the lower end of the dosage range.170 171 172

The pharmacodynamics of epidurally or intrathecally administered morphine are more variable in geriatric patients than in younger adults.b Considerable interindividual variation in effective initial dosage, rate of development of tolerance, and frequency and severity of adverse effects exists for epidural or intrathecal therapy with the drug in this population; therefore, initial dosage should be selected carefully based on clinical assessment of response to test doses and consideration of the patient’s age and infirmity on their ability to clear the drug, particularly in those receiving the drug epidurally.b

No overall differences in safety and efficacy of morphine sulfate extended-release liposomal injection (DepoDur) (at same or lower doses) in those ≥65 years of age compared with younger adults, but possibility of increased sensitivity in some geriatric individuals cannot be ruled out.192 Comorbid conditions may predispose geriatric patients to serious adverse events (e.g., respiratory depression, ileus, hypotension, MI).192 Use with caution in this age group and select dosage at the lower end of the dosage range.192

Use with caution and in reduced dosage in patients with severe hepatic impairment.170 171 172 b

Morphine sulfate extended-release liposomal injection (DepoDur) is intended for single-dose administration; accumulation of morphine or its metabolites not expected in patients with hepatic impairment.192

Use with caution and in reduced dosage in patients with severe renal impairment since accumulation (over several days) of high systemic concentrations may occur in some patients.170 171 172 b

Morphine sulfate extended-release liposomal injection (DepoDur) is intended for single-dose administration; accumulation of morphine or its metabolites not expected in patients with renal impairment.192

Common Adverse Effects

CNS effects (dizziness, visual disturbances, mental clouding or depression, sedation, coma, euphoria, dysphoria, weakness, faintness, agitation, restlessness, nervousness, seizures, delirium, insomnia) and GI effects (nausea, vomiting, constipation).e

Opiate agonists may interfere with evaluation of CNS function, especially relative to consciousness levels, pupillary changes, and respiratory depression, thereby masking the patient’s clinical course.e

May increase the risk of water intoxication in postoperative patients because of stimulation of the release of vasopressin.e

Storage

When exposed to air, morphine sulfate gradually loses its water of hydration; the drug darkens on prolonged exposure to light.b

Oral

Tight, light-resistant containers at 15–30°C.b 202

Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).169 170 171 172

Parenteral

15–30°C; protect from light; do not freeze.b

Astramorph/PF, Duramorph, and Infumorph injections and injections for use in a compatible patient-controlled infusion device contain no preservatives and are intended for single use only; discard unused portions.b

Morphine sulfate extended-release liposomal injection (DepoDur): 2–8°C; do not freeze.192 May be stored at 15–30°C for ≤30 days in sealed, intact vials.a Do not heat sterilize or gas sterilize.192 Administer dose within 4 hours after withdrawal from the vial; discard unused portions.192

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Specialized references should be consulted for specific compatibility information.b

Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. There are no available data with Morphine Sulfate Tablets in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see Human Data]. In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse. Administration of Morphine Sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3 to 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% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions: Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal 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 and Precautions (5.3)].

Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid induced respiratory depression in the neonate. Morphine Sulfate Tablets are 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 Tablets, 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.

Data

Human Data: 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.

Animal Data: Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (HDD).

Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of Morphine Sulfate (35 to 322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of Morphine Sulfate to pregnant mice (100 to 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 to 50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated.

In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater.

Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD).

Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered Morphine Sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day Morphine Sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).

Lactation

Risk Summary

Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with Morphine Sulfate Tablets 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 Tablets and any potential adverse effects on the breastfed infant from Morphine Sulfate Tablets or from the underlying maternal condition.

Clinical Considerations

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

Females and Males of Reproductive Potential

Infertility

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

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

Pediatric Use

The safety and effectiveness and the pharmacokinetics of Morphine Sulfate Tablets in pediatric patients below the age of 18 have not been established.

Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to 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.

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 Tablets slowly in geriatric patients and monitor closely for signs of respiratory depression [see Warnings and Precautions (5.5)]. Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hepatic Impairment

Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than usual dosage of Morphine Sulfate Tablets and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Renal Impairment

Morphine Sulfate pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than usual dosage of Morphine Sulfate Tablets and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Clinical Presentation

Acute overdose with Morphine Sulfate Tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].

Treatment of Overdose

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to morphine overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of morphine in Morphine Sulfate Tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

Morphine Sulfate (mor-pheen) Tablets CII

Rx only

10004596/07

Revised December 2016