FDA label eb3a3a18-b0cc-4530-bcb0-b431b0c91ecd

BOXED WARNING KADIAN ® contains morphine sulfate, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. KADIAN ® 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 ® capsules are an extended-release oral formulation of morphine sulfate indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. KADIAN® Capsules are NOT for use as a prn analgesic. KADIAN ® 100 mg and 200 mg Capsules ARE FOR USE IN OPIOID-TOLERANT PATIENTS ONLY. Ingestion of these capsules or of the pellets within the capsules may cause fatal respiratory depression when administered to patients not already tolerant to high doses of opioids. KADIAN ® CAPSULES ARE TO BE SWALLOWED WHOLE OR THE CONTENTS OF THE CAPSULES SPRINKLED ON APPLE SAUCE. THE PELLETS IN THE CAPSULES ARE NOT TO BE CHEWED, CRUSHED, OR DISSOLVED DUE TO THE RISK OF RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF MORPHINE.

WARNINGS KADIAN ® Capsules are to be swallowed whole and are not to be chewed, crushed, or dissolved. Taking chewed, crushed, or dissolved KADIAN ® Capsules leads to rapid release and absorption of a potentially fatal dose of morphine. KADIAN ® 100 mg and 200 mg Capsules ARE FOR USE IN OPIOID-TOLERANT PATIENTS ONLY. This capsule strength may cause fatal respiratory depression when ingested or administered to patients who are not previously exposed to opioids. Care should be taken in the prescribing of this capsule strength. Patients should be instructed against use by individuals other than the patient for whom it was prescribed, as such inappropriate use may have severe medical consequences, including death. Misuse, Abuse and Diversion of Opioids 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. Abuse of KADIAN ® 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 (see WARNINGS and DRUG 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 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. 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). 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. 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. 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. Hypotensive Effect KADIAN ® 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 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. Interactions with other CNS Depressants 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. 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. Other Although extremely rare, cases of anaphylaxis have been reported.

ADVERSE REACTIONS Serious adverse reactions that may be associated with KADIAN ® therapy in clinical use are those observed with other opioid analgesics and include: respiratory depression, respiratory arrest, apnea, circulatory depression, cardiac arrest, hypotension, and/or shock (see OVERDOSAGE , WARNINGS ). The less severe adverse events seen on initiation of therapy with KADIAN ® are also typical opioid side effects. These events are dose dependent, and their frequency depends on the clinical setting, the patient's level of opioid tolerance, and host factors specific to the individual. They should be expected and managed as a part of opioid analgesia. The most frequent of these include drowsiness, dizziness, constipation and nausea. In many cases, the frequency of these events during initiation of therapy may be minimized by careful individualization of starting dosage, slow titration, and the avoidance of large rapid swings in plasma concentrations of the opioid. Many of these adverse events, will cease or decrease as KADIAN ® therapy is continued and some degree of tolerance is developed, but others may be expected to remain troublesome throughout therapy. Management of Excessive Drowsiness 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. Management of Nausea and Vomiting Nausea and vomiting are common after single doses of KADIAN ® 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 (see Drug 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 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. Adverse Events Probably Related to KADIAN ® 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 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 Post-marketing Adverse Events Probably Related to KADIAN ® 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. DRUG ABUSE AND DEPENDENCE 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.