2.1 Important Dosage and Administration Instructions

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 and 200 mg capsules, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, are only for use in 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 oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone daily, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].
  
• Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, 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 and following dosage increases with KADIAN and adjust the dosage accordingly [see Warnings and Precautions (5.2)].

Instruct patients to swallow KADIAN capsules whole [see Patient Counseling Information (17)].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 (5.1)].

Instruct patients who are unable to swallow KADIAN capsules to sprinkle the capsule contents on applesauce and immediately swallow without chewing [see Dosage and Administration (2.5)].

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

2.2 Initial Dosage

Use of KADIAN as the First Opioid Analgesic (opioid-naïve patients)

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 (opioid non-tolerant patients)

The starting dose for patients who are not opioid tolerant is KADIAN 30 mg orally every 24 hours.

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

Conversion from Other Opioids to KADIAN

Discontinue all other around-the-clock opioid drugs when KADIAN therapy is initiated.

There are no established conversion ratios from other opioids to KADIAN defined by clinical trials. Initiate dosing using KADIAN 30 mg orally every 24 hours.

It is safer to underestimate a patient's 24-hour oral morphine dosage and provide rescue medication (e.g. immediate-release morphine) than to overestimate the 24-hour oral morphine dosage and manage an adverse reaction due to an overdose. While useful tables of opioid equivalents are readily available, there is inter-patient variability in the potency of opioid drugs and formulations.

Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to KADIAN.

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 Ratios

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.

2.3 Titration and Maintenance of Therapy

Individually titrate KADIAN to a dose that provides adequate analgesia and minimizes adverse reactions. 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 [see Warnings and Precautions (5.1)]. 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.

Patients who experience breakthrough pain may require a dosage adjustment 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 dosage. In patients experiencing inadequate analgesia with once daily dosing of KADIAN, consider a twice daily regimen. Because steady-state plasma concentrations are approximated within 24 to 36 hours, KADIAN dosage adjustments may be done every 1 to 2 days.

If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.4 Discontinuation of KADIAN

When a patient no longer requires therapy with KADIAN, taper the dose gradually, by 25% to 50 %, every 2 to 4 days, while monitoring for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue KADIAN [see Warnings and Precautions (5.12), Drug Abuse and Dependence (9.3).

2.5 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 (5.1)].

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.

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

Do not administer KADIAN pellets through a nasogastric tube.