FDA Label for Kadian

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 KADIAN^® 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 KADIAN^®, the extent of absorption is not affected and KADIAN^® can be administered without regard to meals.

Steady State: When KADIAN^® 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, KADIAN^® will have a significantly lower C_max and a higher C_min 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 KADIAN^® (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).

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 KADIAN^®, 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.

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 20-30 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.

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.  KADIAN^® pharmacokinetics have not been investigated in elderly patients (>65 years) although such patients were included in the clinical studies.

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.

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

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).

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.

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.

KADIAN^® 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 KADIAN^® in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

KADIAN^® 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.

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).

KADIAN^® 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.

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. KADIAN^® 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.

KADIAN^® 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.

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.

Although extremely rare, cases of anaphylaxis have been reported.

Precautions

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.

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.

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.

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.

If clinically advisable, patients receiving KADIAN^®, or their caregivers should be given the following information by the physician, nurse, or pharmacist:

Adverse Reactions

Most patients receiving KADIAN^® will experience initial drowsiness.  This usually disappears within 3-5 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.

Virtually all patients suffer from constipation while taking opioids, such as KADIAN^®, 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.

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 KADIAN^® 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 and Lymphatic:  Anemia, leukopenia, thrombocytopenia

Metabolic and 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

The safety of KADIAN^® has been evaluated in a randomized, prospective, open-label, 4-week treatment period, post-marketing study consisting of 1418 patients ages 18-85 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.

KADIAN^® is a mu-agonist opioid with an abuse liability similar to other opioid agonists and is a Schedule II controlled substance.  KADIAN^® and other opioids used in analgesia can be abused and are subject to criminal diversion.

KADIAN^® is an opioid with no approved use in the management of addiction disorders.  Its proper usage in individuals with drug or alcohol dependence, either active or in remission, is for the management of pain requiring opioid analgesia.

Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm.  Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common.

“Drug-seeking” behavior is very common in addicts and drug abusers.  Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s).  “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts.  In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. KADIAN^®, like other opioids, has been diverted for non-medical use.  Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

KADIAN^® is intended for oral use only.  Abuse of chewed, crushed, or dissolved capsules or pellets poses a hazard of overdose and death.  This risk is increased with concurrent abuse of alcohol and other substances. Due to the presence of talc as one of the excipients in capsules, parenteral abuse can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury.  Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Overdosage

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.

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 KADIAN^® 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 KADIAN^®, the patient must be carefully monitored until spontaneous respiration is reliably re-established.  KADIAN^® 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 KADIAN^®.  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.

Dosage And Administration

KADIAN^® may be administered once or twice daily.

KADIAN^® capsules should be swallowed whole.  The pellets in KADIAN^® capsules should not be chewed, crushed, or dissolved due to the risk of rapid release and absorption of a potentially fatal dose of morphine.

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 KADIAN^®, attention should be given to: