Kadian (morphine sulfate 150 mg) Dailymed

2 Dosage And Administration

• KADIAN 100 mg, 130 mg, 150 mg, and 200 mg capsules are only for patients in whom tolerance to an opioid of comparable potency has been established. Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg of morphine daily, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid. (2.1)
• For opioid-naïve patients, initiate treatment using an immediate-release morphine formulation and then convert patients to KADIAN. For opioid non-tolerant patients, initiate with a 30 mg capsule orally every 24 hours. (2.1)
• To convert to KADIAN from another opioid, use available conversion factors to obtain estimated dose. (2.1)
• Do not abruptly discontinue KADIAN in a physically dependent patient. (2.3, 5.11)
• Instruct patients to swallow KADIAN capsules intact, or to sprinkle the capsule contents on applesauce and immediately swallow. (2.4)

2.1 Initial Dosing

KADIAN should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

KADIAN 100 mg, 130 mg, 150 mg, and 200 mg capsules are only for patients in whom tolerance to an opioid of comparable potency has been established.  Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg of morphine daily, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid. 

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with KADIAN [see Warnings and Precautions (5.2 )].

KADIAN capsules must be taken whole. Crushing, chewing, or dissolving the pellets in KADIAN capsules will result in uncontrolled delivery of morphine and can lead to overdose or death [see Warnings and Precautions (5.2) ]. Patients who are unable to swallow KADIAN should be instructed to sprinkle the capsule contents on applesauce and immediately swallow without chewing [see Administration of KADIAN (2.4) ].

KADIAN is administered at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours). 

Use of KADIAN as the First Opioid Analgesic

There has been no evaluation of KADIAN 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, begin treatment using an immediate-release morphine formulation and then convert patients to KADIAN as described below.

Use of KADIAN in Patients who are not Opioid Tolerant

The starting dose for patients who are not opioid tolerant is KADIAN 30 mg orally every 24 hours.  Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.

Conversion from Other Opioids to KADIAN

There are no established conversion ratios from other opioids to KADIAN defined by clinical trials.  Discontinue all other around-the-clock opioid drugs when KADIAN therapy is initiated and initiate dosing using KADIAN 30 mg orally every 24 hours. 

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient's 24-hour oral morphine requirements and provide rescue medication (e.g. immediate-release morphine) than to overestimate the 24-hour oral morphine requirements which could result in an adverse reaction. 

Conversion from Other Oral Morphine Formulations to KADIAN

Patients receiving other oral morphine formulations may be converted to KADIAN by administering one-half of the patient's total daily oral morphine dose as KADIAN twice daily or by administering the total daily oral morphine dose as KADIAN once daily. There are no data to support the efficacy or safety of prescribing KADIAN more frequently than every 12 hours.

KADIAN is not bioequivalent to other extended-release morphine preparations.  Conversion from the same total daily dose of another extended-release morphine product to KADIAN may lead to either excessive sedation at peak or inadequate analgesia at trough.  Therefore, monitor patients closely when initiating KADIAN therapy and adjust the dosage of KADIAN as needed.

Conversion from Parenteral Morphine, or Other Opioids to KADIAN

When converting from parenteral morphine or other non-morphine opioids (parenteral or oral) to KADIAN, consider the following general points:

Parenteral to Oral Morphine Ratio: Between 2 mg and 6 mg of oral morphine may be required to provide analgesia equivalent to 1 mg of parenteral morphine. Typically, a dose of oral morphine that is three times the daily parenteral morphine requirement is sufficient.

Other Oral or Parenteral Opioids to Oral Morphine Sulfate: Specific recommendations are not available because of a lack of systematic evidence for these types of analgesic substitutions. Published relative potency data are available, but such ratios are approximations. In general, begin with half of the estimated daily morphine requirement as the initial dose, managing inadequate analgesia by supplementation with immediate-release morphine.

Conversion from Methadone to KADIAN

Close monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

2.2 Titration and Maintenance of Therapy

Individually titrate KADIAN to a dose that provides adequate analgesia and minimizes adverse reactions at a frequency of either once or twice daily.  Continually reevaluate patients receiving KADIAN to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse.  Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.  During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

If the level of pain increases, attempt to identify the source of increased pain, while adjusting the KADIAN dose to decrease the level of pain.  Because steady-state plasma concentrations are approximated within 24 to 36 hours, KADIAN dosage adjustments may be done every 1 to 2 days. 

Patients who experience breakthrough pain may require a dose increase of KADIAN, or may need rescue medication with an appropriate dose of an immediate-release analgesic.  If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the KADIAN dose.  In patients experiencing inadequate analgesia with once daily dosing of KADIAN, consider a twice daily regimen.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced.  Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.3 Discontinuation of KADIAN

When a patient no longer requires therapy with KADIAN, use a gradual downward titration, of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue KADIAN.

2.4 Administration of KADIAN

KADIAN capsules must be taken whole. Crushing, chewing, or dissolving the pellets in KADIAN capsules will result in uncontrolled delivery of morphine and can lead to overdose or death [see Warnings and Precautions (5.2 )].

Alternatively, the contents of the KADIAN capsules (pellets) may be sprinkled over applesauce and then swallowed.  This method is appropriate only for patients able to reliably swallow the applesauce without chewing.  Other foods have not been tested and should not be substituted for applesauce.  Instruct the patient to:

• Sprinkle the pellets onto a small amount of applesauce and consume immediately without chewing.
• Rinse the mouth to ensure all pellets have been swallowed.
• Discard any unused portion of the KADIAN capsules after the contents have been sprinkled on applesauce.

The contents of the KADIAN capsules (pellets) may be administered through a 16 French gastrostomy tube.

• Flush the gastrostomy tube with water to ensure that it is wet.
• Sprinkle the KADIAN Pellets into 10 mL of water.
• Use a swirling motion to pour the pellets and water into the gastrostomy tube through a funnel.
• Rinse the beaker with a further 10 mL of water and pour this into the funnel.
• Repeat rinsing until no pellets remain in the beaker.

Do not administer KADIAN pellets through a nasogastric tube.

• Interaction with CNS depressants: Concomitant use may cause profound sedation, respiratory depression, and death. If coadministration is required, consider dose reduction of one or both drugs because of additive pharmacological effects. (5.4)
• Elderly, cachectic, debilitated patients, and those with chronic pulmonary disease: Monitor closely because of increased risk for life threatening respiratory depression. (5.5, 5.6)
• 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 Addiction, Abuse, and Misuse

KADIAN contains morphine, a Schedule II controlled substance. As an opioid, KADIAN exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. As modified-release products such as KADIAN deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of morphine present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed KADIAN and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing KADIAN and monitor all patients receiving KADIAN for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of KADIAN for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as KADIAN, but use in such patients necessitates intensive counseling about the risks and proper use of KADIAN along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of KADIAN by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the morphine and can result in overdose and death [see Overdosage (10)].

Opioid agonists such as KADIAN are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing KADIAN. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. 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

Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. 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)]. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

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. 

To reduce the risk of respiratory depression, proper dosing and titration of KADIAN are essential [see Dosage and Administration (2 ) ].  Overestimating the KADIAN dose when converting patients from another opioid product can result in fatal overdose with the first dose. 

Accidental injestion of even one dose of KADIAN, especially by children, can result in respiratory depression and death due to an overdose of morphine.

5.3 Neonatal Opioid Withdrawal Syndrome

Prolonged use of KADIAN during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.

5.4 Interactions with Central Nervous System Depressants

Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on KADIAN therapy. The co-ingestion of alcohol with KADIAN may result in increased plasma levels and a potentially fatal overdose of morphine [see Clinical Pharmacology (12.3)].

Hypotension, profound sedation, coma, respiratory depression, and death may result if KADIAN is used concomitantly with alcohol or other central nervous system (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 use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin KADIAN is made, start with a low dose of KADIAN (30 mg or lower) every 24 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7)].

5.5Use inElderly, Cachectic, and Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. 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 )].

5.6 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.

5.7 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  Drug 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 CO₂ 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 CO₂ 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) or partial agonist (buprenorphine) analgesics 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 and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing KADIAN, gradually taper the dose [see Dosage 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.