FDA label 64e55f9c-fa9e-42cb-aca7-50accaefbb99

WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, AND ACCIDENTAL EXPOSURE Abuse Potential KADIAN contains morphine, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit [see WARNINGS AND PRECAUTIONS ( 5.1 )] . Assess each patient’s risk for opioid abuse or addiction prior to prescribing KADIAN. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depressive disorder). Routinely monitor all patients receiving KADIAN for signs of misuse, abuse, and addiction during treatment [see DRUG ABUSE AND DEPENDENCE ( 9 )] . Life-threatening Respiratory Depression Respiratory depression, including fatal cases, may occur with use of KADIAN, even when the drug has been used as recommended and not misused or abused [see WARNINGS AND PRECAUTIONS ( 5.2 )] . Proper dosing and titration are essential and KADIAN should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Monitor for respiratory depression, especially during initiation of KADIAN or following a dose increase. Instruct patients to swallow KADIAN capsules whole or to sprinkle the contents of the capsule on applesauce and swallow without chewing. Crushing, dissolving, or chewing the pellets within the capsule can cause rapid release and absorption of a potentially fatal dose of morphine. Accidental Exposure Accidental consumption of KADIAN, especially in children, can result in a fatal overdose of morphine [see WARNINGS AND PRECAUTIONS ( 5.3 )] . WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, AND ACCIDENTAL EXPOSURE See full prescribing information for complete boxed warning. KADIAN contains pellets of morphine sulfate, a Schedule II controlled substance. Monitor for signs of misuse, abuse, and addiction during KADIAN therapy. ( 5.1 , 9 ) Fatal respiratory depression may occur, with highest risk at initiation and with dose increases. Instruct patients on proper administration of KADIAN capsules to reduce the risk. ( 5.2 ) Accidental ingestion of KADIAN can result in fatal overdose of morphine, especially in children. ( 5.3 )

5 WARNINGS AND PRECAUTIONS Elderly, cachectic, and debilitated patients and patients with chronic pulmonary disease: Monitor closely because of increased risk of respiratory depression. ( 5.4 , 5.5 ) Interaction with CNS depressants: Consider dose reduction of one or both drugs because of additive effects. ( 5.6 , 7.2 ) Hypotensive effect: Monitor during dose initiation and titration ( 5.7 ) Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression and avoid use of KADIAN in patients with impaired consciousness or coma susceptible to intracranial effects of CO2 retention. ( 5.8 ) 5.1 Abuse Potential KADIAN contains morphine, an opioid agonist and a Schedule II controlled substance. Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing KADIAN in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain. Assess each patient’s risk for opioid abuse or addiction prior to prescribing KADIAN. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use. Misuse or 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 that could result in overdose and death. [see O VERDOSAGE ( 10 )] . Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Respiratory depression is the primary risk of KADIAN. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see OVERDOSAGE ( 10 )] . While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of KADIAN, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with KADIAN and following dose increases. Instruct patients against use by individuals other than the patient for whom KADIAN was prescribed and to keep KADIAN out of the reach of children, as such inappropriate use may result in fatal respiratory depression. To reduce the risk of respiratory depression, proper dosing and titration of KADIAN are essential [see DOSAGE AND ADMINISTRATION ( 2.1 , 2.2 )] . Overestimating the KADIAN dose when converting patients from another opioid product can result in fatal overdose with the first dose. Respiratory depression has also been reported with use of modified-release opioids when used as recommended and not misused or abused. To further reduce the risk of respiratory depression, consider the following: • Proper dosing and titration are essential and KADIAN should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. KADIAN 100 mg and 200 mg capsules are for use in opioid-tolerant patients only. Ingestion of this strength of KADIAN capsules or of the pellets within the capsule may cause fatal respiratory depression when administered to patients not already tolerant to high doses of opioids. • Instruct patients to swallow KADIAN capsules intact or to sprinkle the capsule contents on applesauce and swallow without chewing. The pellets in the capsules are not to be crushed, dissolved, or chewed. The resulting morphine dose may be fatal, particularly in opioid-naïve individuals. • KADIAN is contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression [see CONTRAINDICATIONS ( 4 )] . 5.3 Accidental Exposure Accidental consumption of KADIAN, especially in children, can result in a fatal overdose of morphine. 5.4 Elderly, Cachectic, and Debilitated Patients Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance compared to younger, healthier patients. Therefore, monitor such patients closely, particularly when initiating and titrating KADIAN and when KADIAN is given concomitantly with other drugs that depress respiration [see WARNINGS AND PRECAUTIONS ( 5.2 )] . 5.5 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with KADIAN, as in these patients, even usual therapeutic doses of KADIAN may decrease respiratory drive to the point of apnea [see WARNINGS AND PRECAUTIONS ( 5.2 ) ] . Consider the use of alternative non-opioid analgesics in these patients if possible. 5.6 Interactions with CNS Depressants and Illicit Drugs Hypotension, profound sedation, coma, or respiratory depression may result if KADIAN is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of KADIAN in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient’s use, if any, of alcohol or illicit drugs that cause CNS depression. If KADIAN therapy is to be initiated in a patient taking a CNS depressant, start with a lower KADIAN dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see DRUG INTERACTIONS ( 7.2 ) ] . 5.7 Hypotensive Effect KADIAN may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [ see D RUG INTERACTIONS ( 7.2 ) ] . Monitor these patients for signs of hypotension after initiating or titrating the dose of KADIAN. In patients with circulatory shock, KADIAN may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of KADIAN in patients with circulatory shock. 5.8 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking KADIAN who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with KADIAN. KADIAN may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure . Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of KADIAN in patients with impaired consciousness or coma. 5.9 Use in Patients with Gastrointestinal Conditions KADIAN is contraindicated in patients with paralytic ileus. Avoid the use of KADIAN in patients with other GI obstruction. The morphine in KADIAN may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase. 5.10 Use in Patients with Convulsive or Seizure Disorders The morphine in KADIAN may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during KADIAN therapy. 5.11 Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including KADIAN. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing KADIAN, gradually taper the dose [ see D OSAGE AND ADMINISTRATION ( 2.3 ) ] . Do not abruptly discontinue KADIAN. 5.12 Driving and Operating Machinery KADIAN may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of KADIAN and know how they will react to the medication.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Respiratory Depression [see WARNINGS AND PRECAUTIONS ( 5.2 ) ] Chronic Pulmonary Disease [see WARNINGS AND PRECAUTIONS ( 5.5 ) ] Head Injuries and Increased Intracranial Pressure [see WARNINGS AND PRECAUTIONS ( 5.8 ) ] Interactions with Other CNS Depressants [see WARNINGS AND PRECAUTIONS ( 5.6 ) ] Hypotensive Effect [see WARNINGS AND PRECAUTIONS ( 5.7 ) ] Gastrointestinal Effects [see WARNINGS AND PRECAUTIONS ( 5.9 ) ] Seizures [see WARNINGS AND PRECAUTIONS ( 5.10 ) ] In the randomized study, the most common adverse reactions with KADIAN therapy were drowsiness, constipation, nausea, dizziness, and anxiety. The most common adverse reactions leading to study discontinuation were nausea, constipation (may be severe), vomiting, fatigue, dizziness, pruritus, and somnolence. Most common adverse reactions (>10%): constipation, nausea, and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical trial patients with chronic cancer pain (n = 227) (AE by Body System as seen in 2% or more of patients) Percentage % CENTRAL NERVOUS SYSTEM 28 Drowsiness 9 Dizziness 6 Anxiety 5 Confusion 4 Dry Mouth 3 Tremor 2 GASTROINTESTINAL 26 Constipation 9 Nausea 7 Diarrhea 3 Anorexia 3 Abdominal Pain 3 Vomiting 2 BODY AS A WHOLE 16 Pain 3 Disease Progression 3 Chest Pain 2 Diaphoresis 2 Fever 2 Asthenia 2 Accidental Injury 2 RESPIRATORY 3 Dyspnea 3 SKIN & APPENDAGES 3 Rash 3 METABOLIC & NUTRITIONAL 3 Peripheral Edema 3 HEMIC & LYMPHATIC 4 Anemia 2 Leukopenia 2 In clinical trials 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 2% of patients in the clinical trials were: Body as a Whole: Headache, chills, flu syndrome, back pain, malaise, withdrawal syndrome Cardiovascular: Tachycardia, atrial fibrillation, hypotension, hypertension, pallor, facial flushing, palpitations, bradycardia, syncope Central Nervous System: Confusion, anxiety, abnormal thinking, abnormal dreams, lethargy, depression, 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: Dysphagia, dyspepsia, stomach atony disorder, gastroesophageal reflux, delayed gastric emptying, biliary colic Hemic and Lymphatic: Thrombocytopenia Metabolic and Nutritional: Hyponatremia, edema Musculoskeletal: Back pain, bone pain, arthralgia Respiratory: Hiccup, rhinitis, atelectasis, asthma, hypoxia, respiratory insufficiency, voice alteration, depressed cough reflex, non-cardiogenic pulmonary edema Skin and Appendages: 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 Four-Week Open-Label Safety Study In the open-label, 4-week safety study, 1418 patients ages 18 to 85 with chronic, non-malignant pain (e.g., back pain, osteoarthritis, neuropathic pain) were enrolled. 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. 6.2 Post-Marketing Experience Anaphylaxis has been reported with ingredients contained in KADIAN. Advise patients how to recognize such a reaction and when to seek medical attention.

<table> <colgroup> <col width="432"/> <col width="114"/> </colgroup> <tbody> <tr> <td styleCode="Lrule Rrule Toprule"> <content styleCode="bold">Clinical trial patients with chronic cancer pain (n = 227)</content> <content styleCode="bold">(AE by Body System as seen in 2% or more of patients)</content> </td> <td styleCode="Lrule Rrule Toprule"> <content styleCode="bold">Percentage %</content> </td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> <content styleCode="bold">CENTRAL NERVOUS SYSTEM</content> </td> <td align="center" styleCode="Lrule Rrule Toprule"> <content styleCode="bold">28</content> </td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Drowsiness</td> <td align="center" styleCode="Lrule Rrule Toprule"> 9</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Dizziness</td> <td align="center" styleCode="Lrule Rrule Toprule"> 6</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Anxiety</td> <td align="center" styleCode="Lrule Rrule Toprule"> 5</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Confusion</td> <td align="center" styleCode="Lrule Rrule Toprule"> 4</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Dry Mouth</td> <td align="center" styleCode="Lrule Rrule Toprule"> 3</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Tremor</td> <td align="center" styleCode="Lrule Rrule Toprule"> 2</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> <content styleCode="bold">GASTROINTESTINAL</content> </td> <td align="center" styleCode="Lrule Rrule Toprule"> <content styleCode="bold">26</content> </td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Constipation</td> <td align="center" styleCode="Lrule Rrule Toprule"> 9</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Nausea</td> <td align="center" styleCode="Lrule Rrule Toprule"> 7</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Diarrhea</td> <td align="center" styleCode="Lrule Rrule Toprule"> 3</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Anorexia</td> <td align="center" styleCode="Lrule Rrule Toprule"> 3</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Abdominal Pain</td> <td align="center" styleCode="Lrule Rrule Toprule"> 3</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Vomiting</td> <td align="center" styleCode="Lrule Rrule Toprule"> 2</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> <content styleCode="bold">BODY AS A WHOLE</content> </td> <td align="center" styleCode="Lrule Rrule Toprule"> <content styleCode="bold">16</content> </td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Pain</td> <td align="center" styleCode="Lrule Rrule Toprule"> 3</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Disease Progression</td> <td align="center" styleCode="Lrule Rrule Toprule"> 3</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Chest Pain</td> <td align="center" styleCode="Lrule Rrule Toprule"> 2</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Diaphoresis</td> <td align="center" styleCode="Lrule Rrule Toprule"> 2</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Fever</td> <td align="center" styleCode="Lrule Rrule Toprule"> 2</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Asthenia</td> <td align="center" styleCode="Lrule Rrule Toprule"> 2</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Accidental Injury</td> <td align="center" styleCode="Lrule Rrule Toprule"> 2</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> <content styleCode="bold">RESPIRATORY</content> </td> <td align="center" styleCode="Lrule Rrule Toprule"> <content styleCode="bold">3</content> </td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Dyspnea</td> <td align="center" styleCode="Lrule Rrule Toprule"> 3</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> <content styleCode="bold">SKIN &amp; APPENDAGES</content> </td> <td align="center" styleCode="Lrule Rrule Toprule"> <content styleCode="bold">3</content> </td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Rash</td> <td align="center" styleCode="Lrule Rrule Toprule"> 3</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> <content styleCode="bold">METABOLIC &amp; NUTRITIONAL</content> </td> <td align="center" styleCode="Lrule Rrule Toprule"> <content styleCode="bold">3</content> </td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Peripheral Edema</td> <td align="center" styleCode="Lrule Rrule Toprule"> 3</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> <content styleCode="bold">HEMIC &amp; LYMPHATIC</content> </td> <td align="center" styleCode="Lrule Rrule Toprule"> <content styleCode="bold">4</content> </td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Anemia</td> <td align="center" styleCode="Lrule Rrule Toprule"> 2</td> </tr> <tr> <td styleCode="Lrule Rrule Toprule"> Leukopenia</td> <td align="center" styleCode="Lrule Rrule Toprule">2</td> </tr> </tbody> </table>