Effects on the Central Nervous System

The principal actions of therapeutic value of morphine are analgesia and sedation (i.e., sleepiness and anxiolysis). The precise mechanism of the analgesic action is unknown. However, specific CNS opiate receptors and endogenous compounds with morphine-like activity have been identified throughout the brain and spinal cord and are likely to play a role in the expression of analgesic effects. Morphine produces respiratory depression by direct action on brainstem respiratory centers. The mechanism of respiratory depression involves a reduction in the responsiveness of the brainstem respiratory centers to increases in carbon dioxide tension, and to electrical stimulation. Morphine depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Morphine causes miosis, even in total darkness, and little tolerance develops to this effect. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen with worsening hypoxia in the setting of morphine sulfate extended-release overdose (SeeOVERDOSAGE).

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Gastric, biliary and pancreatic secretions are decreased by morphine. Morphine causes a reduction in motility associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm. The end result is constipation. Morphine can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi.

Effects on the Cardiovascular System

Morphine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Release of histamine may be induced by morphine and can contribute to opioid-induced hypotension. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating.

Pharmacodynamics

Plasma Level-Analgesia Relationships

In any particular patient, both analgesic effects and plasma morphine concentrations are related to the morphine dose.

While plasma morphine-efficacy relationships can be demonstrated in non-tolerant individuals, they are influenced by a wide variety of factors and are not generally useful as a guide to the clinical use of morphine. The effective dose in opioid-tolerant patients may be 10 to 50 times as great (or greater) than the appropriate dose for opioid-naive individuals. Dosages of morphine should be chosen and must be titrated on the basis of clinical evaluation of the patient and the balance between therapeutic and adverse effects.

For any fixed dose and dosing interval, morphine sulfate extended-release will have, at steady-state, a lower Cmax and a higher Cmin than conventional morphine.

Pharmacokinetics

Morphine sulfate extended-release capsules contain polymer coated extended-release pellets of morphine sulfate that release morphine significantly more slowly than from conventional oral preparations. Morphine sulfate extended-release activity is primarily due to morphine. One metabolite, morphine-6- glucuronide, has been shown to have analgesic activity, but does not readily cross the blood-brain barrier.

Following oral administration of morphine, the extent of absorption is essentially the same for immediate or extended-release formulations, although the time to peak blood level (Tmax) will be longer and the Cmax will be lower for formulations that delay the release of morphine in the gastrointestinal tract.

Elimination of morphine is primarily via hepatic metabolism to glucuronide metabolites (55 to 65%) which are then renally excreted. The terminal half-life of morphine is 2 to 4 hours, however, a longer term half-life of about 15 hours has been reported in studies where blood has been sampled up to 48 hours.

The single-dose pharmacokinetics of morphine sulfate extended-release are linear over the dosage range of 30 to 100 mg. The single dose and multiple dose pharmacokinetic parameters of morphine sulfate extended-release in normal volunteers are summarized in Table 1.

# For single dose AUC = AUC0-48h, for multiple dose AUC = AUC0-24h at steady state
+ For single dose parameter normalized to 100 mg, for multiple dose parameter normalized to 100 mg per 24 hours
* Steady-state fluctuation in plasma concentrations = Cmax-Cmin/Cmin
^ Not applicable

Absorption

Following the administration of oral morphine solution, approximately 50% of the morphine absorbed reaches the systemic circulation within 30 minutes. However, following the administration of an equal amount of morphine sulfate extended-release to healthy volunteers, this occurs, on average, after 8 hours. As with most forms of oral morphine, because of pre-systemic elimination, only about 20 to 40% of the administered dose reaches the systemic circulation.

Food Effects: While concurrent administration of food slows the rate of absorption of morphine sulfate extended-release, the extent of absorption is not affected and morphine sulfate extended-release can be administered without regard to meals.

Steady State: When morphine sulfate extended-release is given on a fixed dosing regimen to patients with chronic pain due to malignancy, steady state is achieved in about two days. At steady state, morphine sulfate extended-release will have a significantly lower Cmax and a higher Cmin than equivalent doses of oral morphine solution and some other extended-release preparations (see Graph 1).

Graph 1 (Study # MOB-1/90):
Mean steady state plasma morphine concentrations for
morphine sulfate extended-release capsule (twice a day),
extended-release morphine tablet (twice a day) and oral
morphine solution (every 4 hours); plasma concentrations
are normalized to 100 mg every 24 hours, (n=24).

When given once-daily (every 24 hours) to 24 patients with malignancy, morphine sulfate extended-release had a similar Cmax and higher Cmin at steady state in clinical usage, when compared to twice-daily (every 12 hours) extended-release morphine tablets, given at an equivalent total daily dosage (see Graph 2 and Table 1). Drug-disease interactions are frequently seen in the older and more gravely ill patients, and may result in both altered absorption and reduced clearance as compared to normal volunteers (see Geriatric, Hepatic Failure, and Renal Insufficiency sections).

Graph 2 (Study # MOR-9/92):
Dose normalized mean steady state plasma morphine
concentrations for morphine sulfate extended-release (once
a day), and an equivalent dose of a 12-hour, extended-
release morphine tablet given twice a day. Plasma
concentrations are normalized to 100 mg every 24 hours,
(n=24).

Distribution

Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. The volume of distribution of morphine is approximately 3 to 4 L/kg. Morphine is 30 to 35% reversibly bound to plasma proteins. Although the primary site of action of morphine is in the CNS, only small quantities pass the blood-brain barrier. Morphine also crosses the placental membranes (seePRECAUTIONS - Pregnancy) and has been found in breast milk (seePRECAUTIONS - Nursing Mothers).

Metabolism

The major pathway of the detoxification of morphine is conjugation, either with D-glucuronic acid in the liver to produce glucuronides or with sulfuric acid to give morphine-3-etheral sulfate. Although a small fraction (less than 5%) of morphine is demethylated, for all practical purposes, virtually all morphine is converted to glucuronide metabolites including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5 to 15%). Studies in healthy subjects and cancer patients have shown that the glucuronide metabolite to morphine mean molar ratios (based on AUC) are similar after both single doses and at steady state for morphine sulfate extended-release , 12-hour extended-release morphine sulfate tablets and morphine sulfate solution.

M3G has no significant analgesic activity. M6G has been shown to have opioid agonist and analgesic activity in humans.

Excretion

Approximately 10% of morphine dose is excreted unchanged in the urine. Most of the dose is excreted in the urine as M3G and M6G. A small amount of the glucuronide metabolites is excreted in the bile and there is some minor enterohepatic cycling. Seven to 10% of administered morphine is excreted in the feces.

The mean adult plasma clearance is about 20 to 30 mL/minute/kg. The effective terminal half-life of morphine after IV administration is reported to be approximately 2.0 hours. Longer plasma sampling in some studies suggests a longer terminal half-life of morphine of about 15 hours.

Special Populations

Geriatric: The elderly may have increased sensitivity to morphine and may achieve higher and more variable serum levels than younger patients. In adults, the duration of analgesia increases progressively with age, though the degree of analgesia remains unchanged. Morphine sulfate extended-release pharmacokinetics have not been investigated in elderly patients (>65 years) although such patients were included in the clinical studies.

Nursing Mothers: Morphine is excreted in the maternal milk, and the milk to plasma morphine AUC ratio is about 2.5:1. The amount of morphine received by the infant depends on the maternal plasma concentration, amount of milk ingested by the infant, and the extent of first pass metabolism.

Pediatric: Infants under 1 month of age have a prolonged elimination half-life and decreased clearance relative to older infants and pediatric patients. The clearance of morphine and its elimination half-life begin to approach adult values by the second month of life. Pediatric patients old enough to take capsules should have pharmacokinetic parameters similar to adults, dosed on a per kilogram basis (seePRECAUTIONS - Pediatric Use).

Gender: No meaningful differences between male and female patients were demonstrated in the analysis of the pharmacokinetic data from clinical studies.

Race: Pharmacokinetic differences due to race may exist. Chinese subjects given intravenous morphine in one study had a higher clearance when compared to caucasian subjects (1852 ± 116 mL/min versus 1495 ± 80 mL/min).

Hepatic Failure: The pharmacokinetics of morphine were found to be significantly altered in individuals with alcoholic cirrhosis. The clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine plasma AUC ratios also decreased in these patients indicating a decrease in metabolic activity.

Renal Insufficiency: The pharmacokinetics of morphine are altered in renal failure patients. AUC is increased and clearance is decreased. The metabolites, M3G and M6G accumulate several fold in renal failure patients compared with healthy subjects.

Drug-Drug Interactions: The known drug interactions involving morphine are pharmacodynamic, not pharmacokinetic (seePRECAUTIONS - Drug Interactions).

Morphine sulfate extended-release capsules, USP are NOT intended for use as a prn analgesic.

Morphine sulfate extended-release capsules, USP are not indicated for pain in the immediate postoperative period (the first 12 to 24 hours following surgery), or if the pain is mild or not expected to persist for an extended period of time. Morphine sulfate extended-release capsules, USP are only indicated for postoperative use if the patient is already receiving the drug prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time. Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate. (See American Pain Society guidelines.)

Misuse, Abuse and Diversion of Opioids

Morphine sulfate extended-release contains morphine an opioid agonist and a Schedule II controlled substance. Opioid agonists have the potential for being abused and are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing morphine sulfate extended-release in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Abuse of morphine sulfate extended-release by crushing, chewing, snorting or injecting the dissolved product will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (seeWARNINGS andDRUG ABUSE AND DEPENDENCE)

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.

Interactions with Alcohol and Drugs of Abuse

Morphine sulfate extended-release may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression because respiratory depression, hypotension, and profound sedation or coma may result.

Impaired Respiration

Respiratory depression is the chief hazard of all morphine preparations. Respiratory depression occurs more frequently in elderly and debilitated patients, and those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction (when even moderate therapeutic doses may significantly decrease pulmonary ventilation).

Morphine sulfate extended-release should be used with extreme caution in 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. In such patients, even usual therapeutic doses of morphine may increase airway resistance and decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of morphine with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. Morphine sulfate extended-release produces effects which may obscure neurologic signs of further increases in pressure in patients with head injuries. Morphine should only be administered under such circumstances when considered essential and then with extreme care.

Hypotensive Effect

Morphine sulfate extended-release may cause severe hypotension. There is an added risk to individuals whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or a concurrent administration of drugs such as phenothiazines or general anesthetics. (See alsoPRECAUTIONS - Drug Interactions.) Morphine sulfate extended-release may produce orthostatic hypotension and syncope in ambulatory patients.

Morphine sulfate extended-release, like all opioid analgesics, should be administered with caution to patients in circulatory shock, as vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Interactions with other CNS Depressants

Morphine sulfate extended-release  should be used with great caution and in reduced dosage in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, other tranquilizers, and alcohol because respiratory depression, hypotension, and profound sedation or coma may result.

Gastrointestinal Obstruction

Morphine sulfate extended-release should not be given to patients with gastrointestinal obstruction, particularly paralytic ileus, as there is a risk of the product remaining in the stomach for an extended period and the subsequent release of a bolus of morphine when normal gut motility is restored. As with other solid morphine formulations diarrhea may reduce morphine absorption.

Other

Although extremely rare, cases of anaphylaxis have been reported.

General

Morphine sulfate extended-release is intended for use in patients who require continuous, around-the-clock opioid analgesia for an extended period of time. As with any potent opioid, it is critical to adjust the dosing regimen for morphine sulfate extended-release for each patient, taking into account the patient's prior analgesic treatment experience. Although it is clearly impossible to enumerate every consideration that is important to the selection of the initial dose of morphine sulfate extended-release, attention should be given to the points underDOSAGE AND ADMINISTRATION.

Opioid analgesics have a narrow therapeutic index in certain patient populations, especially when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension.

Selection of patients for treatment with morphine sulfate extended-release should be governed by the same principles that apply to the use of any potent opioid analgesics. Specifically, the increased risks associated with its use in the following populations should be considered: the elderly or debilitated and those with severe impairment of hepatic, pulmonary, or renal function; hypothyroidism; adrenocortical insufficiency (e.g., Addison's Disease); CNS depression or coma; toxic psychosis; prostatic hypertrophy, or urethral stricture; acute alcoholism; delirium tremens; kyphoscoliosis, or inability to swallow.

The administration of morphine sulfate extended-release may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

Morphine sulfate extended-release may aggravate pre-existing convulsions in patients with convulsive disorders.

Cordotomy

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

Use in Pancreatic/Biliary Tract Disease

Morphine sulfate extended-release may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids may cause increases in the serum amylase level.

Tolerance and Physical Dependence

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). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual 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.

In general, opioids should not be abruptly discontinued (seeDOSAGE AND ADMINISTRATION:Cessation of Therapy).

Special Risk Groups

Morphine sulfate extended-release should be administered with caution, and in reduced dosages in elderly or debilitated patients; patients with severe renal or hepatic insufficiency; patients with Addison's disease; myxedema; hypothyroidism; prostatic hypertrophy or urethral stricture.

Caution should also be exercised in the administration of morphine sulfate extended-release to patients with CNS depression, toxic psychosis, acute alcoholism and delirium tremens, and convulsive disorders.

Driving and Operating Machinery

Morphine sulfate extended-release may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Patients must be cautioned accordingly. Patients should also be warned about the potential combined effects of morphine sulfate extended-release with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics and alcohol (seeDrug Interactions).

Information for Patients

If clinically advisable, patients receiving morphine sulfate extended-release, or their caregivers should be given the following information by the physician, nurse, or pharmacist:

1.

Patients should be advised that morphine sulfate extended-release contains morphine and should be taken only as directed.

2.

Patients should be advised that morphine sulfate extended-release capsules should be swallowed whole (not chewed, crushed, or dissolved). Alternately, morphine sulfate extended-release capsules, USP may be opened and the entire contents sprinkled on a small amount of apple sauce immediately prior to ingestion. Morphine sulfate extended-release capsules, USP or the contents of the capsules must not be chewed or crushed due to a risk of fatal overdose.

3.

Patients should be advised that morphine sulfate extended-release  capsules,100 mg are for use only in opioid-tolerant patients. Special care must be taken to avoid accidental ingestion or use by individuals (including children) other than the patient for whom it was originally prescribed, as such unsupervised use may have severe, even fatal, consequences.

4.

Patients should be advised that the dose of morphine sulfate extended-release should not be adjusted without consulting the prescribing health care provider.

5.

Patients should be advised to report episodes of breakthrough pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication.

6.

Patients should be advised that morphine sulfate extended-release may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Patients started on morphine sulfate extended-release or whose dose has been changed should refrain from dangerous activity until it is established that they are not adversely affected.

7.

Patients should be advised that morphine sulfate extended-release should not be taken with alcohol or other CNS depressants (sleeping medication, tranquilizers) except by the orders of the prescribing healthcare provider because dangerous additive effects may occur resulting in serious injury or death.

8.

Women of childbearing potential who become or are planning to become pregnant, should consult their prescribing healthcare provider prior to initiating or continuing therapy with morphine sulfate extended-release.

9.

Patients should be advised that if they have been receiving treatment with morphine sulfate extended-release for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the morphine sulfate extended-release dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their prescribing healthcare provider should provide a dose schedule to accomplish a gradual discontinuation of the medication.

10.

Patients should be advised that morphine sulfate extended-release is a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.

11.

Patients should be advised that severe constipation could occur as a result of taking morphine sulfate extended-release and appropriate laxatives, stool softeners and other appropriate treatments should be initiated from the beginning of opioid therapy.

12.

Patients should be instructed to keep morphine sulfate extended-release in a secure place out of the reach of children. When morphine sulfate extended-release is no longer needed, the unused capsules should be destroyed by flushing down the toilet.

Drug Interactions

CNS Depressants: Morphine should be used with great caution and in reduced dosage in patients who are concurrently receiving other central nervous system (CNS) depressants including sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, other tranquilizers and alcohol because of the risk of respiratory depression, hypotension and profound sedation or coma. When such combined therapy is contemplated, the initial dose of one or both agents should be reduced by at least 50%.

Muscle Relaxants: morphine sulfate extended-release may enhance the neuromuscular blocking action of skeletal relaxants and produce an increased degree of respiratory depression.

Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as morphine sulfate extended-release. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of morphine sulfate extended-release c and/or may precipitate withdrawal symptoms in these patients.

Monoamine Oxidase Inhibitors (MAOIs): MAOIs have been reported to intensify the effects of at least one opioid drug causing anxiety, confusion and significant depression of respiration or coma. Morphine sulfate extended-release should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

Cimetidine: There is an isolated report of confusion and severe respiratory depression when a hemodialysis patient was concurrently administered morphine and cimetidine.

Diuretics: Morphine can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Morphine may also lead to acute retention of urine by causing spasm of the sphincter of the bladder, particularly in men with prostatism.

Carcinogenicity/Mutagenicity/Impairment of Fertility

Long-term studies in animals to evaluate the carcinogenic potential of morphine have not been conducted. There are no reports of carcinogenic effects in humans. In vitro studies have reported that morphine is non-mutagenic in the Ames test with Salmonella, and induces chromosomal aberrations in human leukocytes and lethal mutation induction in Drosophila. Morphine was found to be mutagenic in vitro in human T-cells, increasing the DNA fragmentation. In vivo, morphine was mutagenic in the mouse micronucleus test and induced chromosomal aberrations in spermatids and murine lymphocytes. Chronic opioid abusers (e.g., heroin abusers) and their offspring display higher rates of chromosomal damage. However, the rates of chromosomal abnormalities were similar in nonexposed individuals and in heroin users enrolled in long term opioid maintenance programs.

Pregnancy

Teratogenic Effects (Pregnancy Category C)

Teratogenic effects of morphine have been reported in the animal literature. High parental doses during the second trimester were teratogenic in neurological, soft and skeletal tissue. The abnormalities included encephalopathy and axial skeletal fusions. These doses were often maternally toxic and were 0.3 to 3-fold the maximum recommended human dose (MRHD) on a mg/m2 basis. The relative contribution of morphine-induced maternal hypoxia and malnutrition, each of which can be teratogenic, has not been clearly defined. Treatment of male rats with approximately 3-fold the MRHD for 10 days prior to mating decreased litter size and viability.

Nonteratogenic Effects

Morphine given subcutaneously, at non-maternally toxic doses, to rats during the third trimester with approximately 0.15-fold the MRHD caused reversible reductions in brain and spinal cord volume, and testes size and body weight in the offspring, and decreased fertility in female offspring. The offspring of rats and hamsters treated orally or intraperitoneally throughout pregnancy with 0.04-to 0.3-fold the MRHD of morphine have demonstrated delayed growth, motor and sexual maturation and decreased male fertility. Chronic morphine exposure of fetal animals resulted in mild withdrawal, altered reflex and motor skill development, and altered responsiveness to morphine that persisted into adulthood.

There are no well-controlled studies of chronic in utero exposure to morphine sulfate in human subjects. However, uncontrolled retrospective studies of human neonates chronically exposed to other opioids in utero, demonstrated reduced brain volume which normalized over the first month of life. Infants born to opioid-abusing mothers are more often small for gestational age, have a decreased ventilatory response to CO2 and increased risk of sudden infant death syndrome. Morphine sulfate extended-release should only be used during pregnancy if the need for strong opioid analgesia justifies the potential risk to the fetus.

Labor and Delivery

Morphine sulfate extended-release is not recommended for use in women during and immediately prior to labor, where shorter acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation which tends to shorten labor. Neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression. A specific opioid antagonist, such as naloxone or nalmefene, should be available for reversal of opioid-induced respiratory depression in the neonate.

Neonatal Withdrawal Syndrome

Chronic maternal use of opiates or opioids during pregnancy coexposes the fetus. The newborn may experience subsequent neonatal withdrawal syndrome (NWS). Manifestations of NWS include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The onset, duration, and severity of the disorder differ based on such factors as the addictive drug used, time and amount of mother’s last dose, and rate of elimination of the drug from the newborn. Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital.

Nursing Mothers

Low levels of morphine sulfate have been detected in human milk. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of morphine sulfate is stopped. Because of the potential for adverse reactions in nursing infants from morphine sulfate extended-release, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety of morphine sulfate extended-release, both the entire capsule and the pellets sprinkled on apple sauce, have not been directly investigated in pediatric patients below the age of 18 years. The range of doses available is not suitable for the treatment of very young pediatric patients or those who are not old enough to take capsules safely. The apple sauce sprinkling method is not an appropriate alternative for these patients.

Geriatric Use

Clinical studies of morphine sulfate extended-release did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, 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.

Management of Excessive Drowsiness

Most patients receiving morphine sulfate extended-release will experience initial drowsiness. This usually disappears within 3 to 5 days and is not a cause of concern unless it is excessive, or accompanied by unsteadiness or confusion. Dizziness and unsteadiness may be associated with postural hypotension, particularly in elderly or debilitated patients, and has been associated with syncope and falls in non-tolerant patients started on opioids.

Excessive or persistent sedation should be investigated. Factors to be considered should include: concurrent sedative medications, the presence of hepatic or renal insufficiency, hypoxia or hypercapnia due to exacerbated respiratory failure, intolerance to the dose used (especially in older patients), disease severity and the patient's general condition.

The dosage should be adjusted according to individual needs, but additional care should be used in the selection of initial doses for the elderly patient, the cachectic or gravely ill patient, or in patients not already familiar with opioid analgesic medications to prevent excessive sedation at the onset of treatment.

Management of Nausea and Vomiting

Nausea and vomiting are common after single doses of morphine sulfate extended-release or as an early undesirable effect of chronic opioid therapy. The prescription of a suitable antiemetic should be considered, with the awareness that sedation may result (seeDrug Interactions). The frequency of nausea and vomiting usually decreases within a week or so but may persist due to opioid-induced gastric stasis. Metoclopramide is often useful in such patients.

Management of Constipation

Virtually all patients suffer from constipation while taking opioids, such as morphine sulfate extended-release, on a chronic basis. Some patients, particularly elderly, debilitated or bedridden patients may become impacted. Tolerance does not usually develop for the constipating effects of opioids. Patients must be cautioned accordingly and laxatives, softeners and other appropriate treatments should be used prophylactically from the beginning of opioid therapy.

Adverse Events Probably Related to morphine sulfate extended-release Administration

In clinical studies in patients with chronic cancer pain the most common adverse events reported by patients at least once during therapy were drowsiness (9%), constipation (9%), nausea (7%), dizziness (6%), and anxiety (6%). Other less common side effects expected from morphine sulfate extended-release or seen in less than 3% of patients in the clinical studies were:

Body as a Whole: Asthenia, accidental injury, fever, pain, chest pain, headache, diaphoresis, chills, flu syndrome, back pain, malaise, withdrawal syndrome

Cardiovascular: Tachycardia, atrial fibrillation, hypotension, hypertension, pallor, facial flushing, palpitations, bradycardia, syncope

Central Nervous System: Confusion, dry mouth, anxiety, abnormal thinking, abnormal dreams, lethargy, depression, tremor, loss of concentration, insomnia, amnesia, paresthesia, agitation, vertigo, foot drop, ataxia, hypesthesia, slurred speech, hallucinations, vasodilation, euphoria, apathy, seizures, myoclonus

Endocrine: Hyponatremia due to inappropriate ADH secretion, gynecomastia

Gastrointestinal: Vomiting, anorexia, dysphagia, dyspepsia, diarrhea, abdominal pain, stomach atony disorder, gastro-esophageal reflux, delayed gastric emptying, biliary colic

Hemic & Lymphatic: Anemia, leukopenia, thrombocytopenia

Metabolic & Nutritional: Peripheral edema, hyponatremia, edema

Musculoskeletal: Back pain, bone pain, arthralgia

Respiratory: Hiccup, rhinitis, atelectasis, asthma, hypoxia, dyspnea, respiratory insufficiency, voice alteration, depressed cough reflex, non-cardiogenic pulmonary edema

Skin and Appendages: Rash, decubitus ulcer, pruritus, skin flush

Special Senses: Amblyopia, conjunctivitis, miosis, blurred vision, nystagmus, diplopia

Urogenital: Urinary abnormality, amenorrhea, urinary retention, urinary hesitancy, reduced libido, reduced potency, prolonged labor

Post-marketing Adverse Events Probably Related to Morphine Sulfate Extended-Release

The safety of morphine sulfate extended-release has been evaluated in a randomized, prospective, open-label, 4-week treatment period, post-marketing study consisting of 1418 patients ages 18 to 85 with chronic, non-malignant pain (e.g., back pain, osteoarthritis, neuropathic pain). No control arm was included in this study. The most common adverse events reported at least once during therapy were constipation (12%), nausea (9%) and somnolence (3%). Other less common side effects occurring in less than 3% of patients were vomiting, pruritus, dizziness, sedation, dry mouth, headache, fatigue and rash.

Symptoms

Acute overdosage with morphine is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, sometimes, pulmonary edema, bradycardia, hypotension and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations.

Treatment

Primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Gastric contents may need to be emptied to remove unabsorbed drug when an extended-release formulation such as morphine sulfate extended-release has been taken. Care should be taken to secure the airway before attempting treatment by gastric emptying or activated charcoal.

Supportive measures (including oxygen, vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.

The pure opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression which results from opioid overdose. Since the duration of reversal would be expected to be less than the duration of action of morphine sulfate extended-release, the patient must be carefully monitored until spontaneous respiration is reliably re-established. Morphine sulfate extended-release will continue to release and add to the morphine load for up to 24 hours after administration and the management of an overdose should be monitored accordingly. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be given as directed by the manufacturer of the product.

Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose. Such agents should be administered cautiously to persons who are known, or suspected to be physically dependent on morphine sulfate extended-release. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome.

Opioid Tolerant Individuals: In an individual physically dependent on opioids, administration of the usual dose of the antagonist will precipitate an acute withdrawal. The severity of the withdrawal produced will depend on the degree of physical dependence and the dose of the antagonist administered. Use of an opioid antagonist should be reserved for cases where such treatment is clearly needed. If it is necessary to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

Initiating Therapy with Morphine sulfate extended-release Capsules

Physicians should individualize treatment using a progressive plan of pain management such as outlined by the World Health Organization, the American Pain Society and the Federation of State Medical Boards Model Guidelines. Health care professionals should follow appropriate pain management principles of careful assessment and ongoing monitoring.

It is critical to 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 extended-release capsules, USP, attention should be given to:

1.

the total daily dose, potency and kind of opioid the patient has been taking previously;

2.

the reliability of the relative potency estimate used to calculate the equivalent dose of morphine needed (Note: potency estimates may vary with the route of administration);

3.

the patient's degree of opioid experience and opioid tolerance;

4.

the general condition and medical status of the patient;

5.

concurrent medication;

6.

the type and severity of the patient's pain.

Care should be taken to use low initial doses of morphine sulfate extended-release capsules in patients who are not already opioid-tolerant, especially those who are receiving concurrent treatment with muscle relaxants, sedatives, or other CNS active medications (seePRECAUTIONS).

During periods of changing analgesic requirements including initial titration, frequent communication is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family.

The following dosing recommendations, therefore, can only be considered suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of an individual patient.

Conversion from Other Oral Morphine Formulations to Morphine sulfate extended-release capsules

Patients on other oral morphine formulations may be converted to morphine sulfate extended-release capsules by administering one-half of the patient's total daily oral morphine dose as morphine sulfate extended-release capsules every 12 hours (twice-a-day) or by administering the total daily oral morphine dose as morphine sulfate extended-release capsules every 24 hours (once-a-day). Morphine sulfate extended-release capsules should not be given more frequently than every 12 hours.

Conversion from Parenteral Morphine or Other Parenteral or Oral Opioids to Morphine sulfate extended-release capsules

Morphine sulfate extended-release capsules can be administered to patients previously receiving treatment with parenteral morphine or other opioids. While there are useful tables of oral and parenteral equivalents in cancer analgesia, there is substantial interpatient variation in the relative potency of different opioid drugs and formulations. For these reasons, it is better to underestimate the patient's 24-hour oral morphine requirement and provide rescue medication, than to overestimate and manage an adverse event. The following general points should be considered:

1.

Parenteral to Oral Morphine Ratio: It may take anywhere from 2 to 6 mg of oral morphine to provide analgesia equivalent to 1 mg of parenteral morphine. A dose of oral morphine three times the daily parenteral morphine requirement may be sufficient in chronic use settings.

2.

Other Parenteral or Oral Opioids to Oral Morphine Sulfate: There is lack of systematic evidence bearing on these types of analgesic substitutions. Therefore, specific recommendations are not possible. Physicians are advised to refer to published relative potency data, keeping in mind that such ratios are only approximate. In general, it is safest to give half of the estimated daily morphine demand as the initial dose, and to manage inadequate analgesia by supplementation with immediate-release morphine. (See discussion which follows.)

The first dose of morphine sulfate extended-release capsules may be taken with the last dose of any immediate-release (short-acting) opioid medication due to the long delay until the peak effect after administration of morphine sulfate extended-release capsules.

Use of morphine sulfate extended-release capsules as the First Opioid Analgesic

There has been no evaluation of morphine sulfate extended-release capsules as an initial opioid analgesic in the management of pain. Because it may be more difficult to titrate a patient to adequate analgesia using an extended-release morphine, it is ordinarily advisable to begin treatment using an immediate-release morphine formulation.

Individualization of Dosage

The best use of opioid analgesics in the management of chronic malignant and non-malignant pain is challenging, and is well described in materials published by the World Health Organization and the Agency for Health Care Policy and Research which are available from Alpharma Pharmaceuticals LLC upon request. Morphine sulfate extended-release capsules, USP are a third step drug which is most useful when the patient requires a constant level of opioid analgesia as a "floor" or "platform" from which to manage breakthrough pain. When a patient has reached the point where comfort cannot be provided with a combination of non-opioid medications (NSAIDs and acetaminophen) and intermittent use of moderate or strong opioids, the patient's total opioid therapy should be converted into a 24 hour oral morphine equivalent.

Morphine sulfate extended-release capsules should be started by administering one-half of the estimated total daily oral morphine dose every 12 hours (twice-a-day) or by administering the total daily oral morphine dose every 24 hours (once-a-day). The dose should be titrated no more frequently than every-other-day to allow the patients to stabilize before escalating the dose. If breakthrough pain occurs, the dose may be supplemented with a small dose (less than 20% of the total daily dose) of a short-acting analgesic. Patients who are excessively sedated after a once-a-day dose or who regularly experience inadequate analgesia before the next dose should be switched to twice-a-day dosing.

Patients who do not have a proven tolerance to opioids should be started only on the 10 mg or 20 mg strength, and usually should be increased at a rate not greater than 20 mg every-other-day. Most patients will rapidly develop some degree of tolerance, requiring dosage adjustment until they have achieved their individual best balance between baseline analgesia and opioid side effects such as confusion, sedation and constipation. No guidance can be given as to the recommended maximal dose, especially in patients with chronic pain of malignancy. In such cases the total dose of morphine sulfate extended-release capsules should be advanced until the desired therapeutic endpoint is reached or clinically significant opioid-related adverse reactions intervene.

Alternative Methods of Administration

In a study of healthy volunteers, morphine sulfate extended-release pellets sprinkled over apple sauce were found to be bioequivalent to morphine sulfate extended-release capsules swallowed whole with apple sauce under fasting conditions. Other foods have not been tested. Patients who have difficulty swallowing whole capsules or tablets may benefit from this alternative method of administration.

1.

Sprinkle the pellets onto a small amount of apple sauce. Apple sauce should be room temperature or cooler.

2.

The patient must be cautioned not to chew the pellets which could result in the immediate release of a potentially dangerous, even fatal dose of morphine.

3.

Use immediately.

4.

Rinse mouth to ensure all pellets have been swallowed.

5.

Patients should consume entire portion and should not divide apple sauce into separate doses.

The entire capsule contents may alternatively be administered through a 16 French gastrostomy tube.

1.

Flush the gastrostomy tube with water to ensure that it is wet.

2.

Sprinkle the morphine sulfate extended-release pellets into 10 mL of water.

3.

Use a swirling motion to pour the pellets and water into the gastrostomy tube through a funnel.

4.

Rinse the beaker with a further 10 mL of water and pour this into the funnel.

5.

Repeat rinsing until no pellets remain in the beaker.

THE ADMINISTRATION OF MORPHINE SULFATE EXTENDED-RELEASE PELLETS THROUGH A NASOGASTRIC TUBE SHOULD NOT BE ATTEMPTED.

Considerations in the Adjustment of Dosing Regimens

If signs of excessive opioid effects are observed early in the dosing interval, the next dose should be reduced. If this adjustment leads to inadequate analgesia, that is, if breakthrough pain occurs when morphine sulfate extended-release capsules are administered on an every 24 hours dosing regimen, consideration should be given to dosing every 12 hours. If breakthrough pain occurs on a 12 hour dosing regimen a supplemental dose of a short-acting analgesic may be given. As experience is gained, adjustments in both dose and dosing interval can be made to obtain an appropriate balance between pain relief and opioid side effects. To avoid accumulation the dosing interval of morphine sulfate extended-release capsules should not be reduced below 12 hours.

Cessation of Therapy

When the patient no longer requires therapy with morphine sulfate extended-release capsules, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient.

Conversion from Morphine Sulfate Extended-Release Capsules to Other Extended-Release Oral Morphine Formulations

Morphine sulfate extended-release capsules are not bioequivalent to other extended-release morphine preparations. Although for a given dose the same total amount of morphine is available from morphine sulfate extended-release capsules as from morphine solution or extended-release morphine tablets, the slower release of morphine from morphine sulfate extended-release capsules results in reduced maximum and increased minimum plasma morphine concentrations than with shorter acting morphine products. Conversion from morphine sulfate extended-release capsules to the same total daily dose of other extended-release morphine preparations may lead to either excessive sedation at peak or inadequate analgesia at trough and close observation and appropriate dosage adjustments are recommended.

Conversion from Morphine Sulfate Extended-Release Capsules to Parenteral Opioids

When converting a patient from morphine sulfate extended-release capsules to parenteral opioids, it is best to calculate an equivalent parenteral dose, and then initiate treatment at half of this calculated value. For example, to estimate the required 24 hour dose of parenteral morphine for a patient taking morphine sulfate extended-release capsules, one would take the 24 hour morphine sulfate extended-release capsules dose, divide by an oral to parenteral conversion ratio of 3, divide the estimated 24 hour parenteral dose into six divided doses (for a four hour dosing interval), then halve this dose as an initial trial.

For example, to estimate the required parenteral morphine dose for a patient taking 360 mg of morphine sulfate extended-release capsules a day, divide the 360 mg daily oral morphine dose by a conversion ratio of 1 mg of parenteral morphine for every 3 mg of oral morphine. The estimated 120 mg daily parenteral requirement is then divided into six 20 mg doses, and half of this, or 10 mg, is then given every 4 hours as an initial trial dose.

This approach is likely to require a dosage increase in the first 24 hours for many patients, but is recommended because it is less likely to cause overdose than trying to establish an equivalent dose without titration.

Safety and Handling

Morphine sulfate extended-release capsules contain morphine sulfate which is a controlled substance under Schedule II of the Controlled Substances Act. Morphine, like all opioids, is liable to diversion and misuse and should be handled accordingly. Patients and their families should be instructed to flush any morphine sulfate extended-release capsules that are no longer needed.

Morphine sulfate extended-release capsules may be targeted for theft and diversion by criminals. 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.

Morphine sulfate extended-release capsules consists of closed hard gelatin capsules containing polymer coated morphine sulfate pellets that pose no known handling risk to health care workers. Morphine sulfate extended-release capsules are liable to diversion and misuse both by the general public and health care workers, and should be handled accordingly.