CONTRAINDICATIONS
KADIAN® is contraindicated in patients with a known hypersensitivity to morphine, morphine salts or any of the capsule components.
KADIAN® is contraindicated in patients with respiratory depression in the absence of resuscitative equipment, and in patients with acute or severe bronchial asthma.
KADIAN® is contraindicated in any patient who has or is suspected of having paralytic ileus.
WARNINGS
(See also CLINICAL PHARMACOLOGY)
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 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.
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 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
KADIAN®, like all opioid analgesics, may cause severe hypotension in an individual 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 also PRECAUTIONS - Drug Interactions). KADIAN® may produce orthostatic hypotension and syncope in ambulatory patients.
KADIAN®, 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.
GASTROINTESTINAL OBSTRUCTION
KADIAN® 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.
PRECAUTIONS (See also CLINICAL PHARMACOLOGY)
GENERAL
KADIAN® is intended for use in patients who require continuous treatment with a potent opioid analgesic. As with any potent opioid, it is critical to adjust the dosing regimen for KADIAN® 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 KADIAN®, attention should be given to the points under DOSAGE AND ADMINISTRATION.
CORDOTOMY
Patients taking KADIAN® who are scheduled for cordotomy or other interruption of pain transmission pathways should have KADIAN® 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
KADIAN® 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.
SPECIAL RISK GROUPS
KADIAN® 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 KADIAN® to patients with CNS depression, toxic psychosis, acute alcoholism and delirium tremens, and convulsive disorders.
DRIVING AND OPERATING MACHINERY
Morphine 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 with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics and alcohol (see Drug Interactions).
INFORMATION FOR PATIENTS
If clinically advisable, patients receiving KADIAN® should be given the following instructions by the physician:
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KADIAN® capsules should be swallowed whole (not chewed, crushed, or dissolved). Alternatively, KADIAN® capsules may be opened and the entire contents sprinkled on a small amount of applesauce immediately prior to ingestion. The pellets should NOT be chewed, crushed, or dissolved due to risk of overdose. When prescribing KADIAN® by the sprinkle method, details of proper technique should be explained to the patient. KADIAN® capsules may also be opened and the entire contents sprinkled over about 10 mL of water in a beaker then flushed with swirling through a pre-wetted 16-French gastrostomy tube fitted with a plastic funnel at the port end. The beaker is rinsed with additional aliquots of water as necessary to transfer all of the pellets to flush the tube. NASOGASTRIC TUBES SHOULD NOT BE USED. (also see DOSAGE AND ADMINISTRATION)
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The dose of KADIAN® should not be adjusted without consulting the physician.
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Morphine may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g. driving, operating machinery). Patients started on KADIAN® or whose dose has been changed should refrain from dangerous activity until it is established that they are not adversely affected.
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Morphine should not be taken with alcohol or other CNS depressants (sleeping medication, tranquilizers) because additive effects including CNS depression may occur. A physician should be consulted if other medications are currently being used or are prescribed for future use.
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Women of childbearing potential who become or are planning to become pregnant, should consult a physician.
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Upon completion of therapy, it may be appropriate to taper the morphine dose, rather than abruptly discontinuing it.
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While psychological dependence ("addiction") to morphine used in the treatment of pain is very rare, morphine is one of a class of drugs known to be abused and should be handled accordingly.
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As with other opioids, patients taking KADIAN® should be advised that severe constipation could occur and appropriate laxatives, stool softeners and other appropriate treatments should be initiated from the beginning of opioid therapy.
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 may enhance the neuromuscular blocking action of skeletal relaxants and produce an increased degree of respiratory depression.
Mixed Agonist/Antagonist Opioid Analgesics: From a theoretical perspective, mixed agonist/antagonist analgesics (i.e. pentazocine, nalbuphine and butorphanol) should NOT be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. 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. We do not recommend the use of KADIAN® 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.
Food: KADIAN® capsules should be swallowed whole (not chewed, crushed, or dissolved). Alternatively, KADIAN® capsules may be opened and the entire contents sprinkled on a small amount of applesauce immediately prior to ingestion. The pellets in KADIAN® should NOT be chewed, crushed, or dissolved due to risk of overdose. (see DOSAGE AND ADMINISTRATION, and INFORMATION FOR PATIENTS)
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 should only be used during pregnancy if the need for strong opioid analgesia justifies the potential risk to the fetus.
LABOR AND DELIVERY
KADIAN® 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 paragoric 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 KADIAN®, 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
There are studies from the literature reporting the safe and effective use of both immediate and sustained release oral morphine preparations for analgesia in pediatric patients who were dosed on a per kilogram basis. However, the safety of KADIAN®, both the entire capsule and the pellets sprinkled on applesauce, 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 applesauce sprinkling method is not an appropriate alternative for these patients.
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