DOSAGE AND ADMINISTRATION
KADIAN® CAPSULES SHOULD BE SWALLOWED WHOLE (NOT CHEWED, CRUSHED, OR DISSOLVED).
ALTERNATIVELY, KADIAN® CAPSULES MAY BE OPENED AND THE ENTIRE CONTENTS SPRINKLED ON A SMALL AMOUNT OF APPLESAUCE IMMEDIATELY PRIOR TO INGESTION. THE PELLETS IN KADIAN® CAPSULES SHOULD NOT BE CHEWED, CRUSHED, OR DISSOLVED DUE TO RISK OF OVERDOSE.
TAKING CHEWED OR CRUSHED KADIAN® CAPSULES OR PELLETS WILL LEAD TO THE RAPID RELEASE AND ABSORPTION OF A POTENTIALLY TOXIC DOSE OF MORPHINE.
KADIAN® CAPSULES MAY BE OPENED AND THE ENTIRE CONTENTS SPRINKLED OVER ABOUT 10 ML OF WATER AND FLUSHED WITH SWIRLING THROUGH A PRE-WETTED 16 FRENCH GASTROSTOMY TUBE FITTED WITH FUNNEL AT THE PORT END. ADDITIONAL ALIQUOTS OF WATER ARE USED TO TRANSFER ALL PELLETS AND TO FLUSH THE TUBE. THE ADMINISTRATION OF KADIAN® PELLETS THROUGH A NASOGASTRIC TUBE SHOULD NOT BE ATTEMPTED.
The sustained release nature of KADIAN® allows it to be administered on either a once-a-day or twice-a-day schedule. KADIAN® produces analgesia similar to that produced by conventional immediate-release and controlled-release formulations for the same total daily dose of morphine. However, peak and trough blood levels depend on the release characteristics of each specific formulation, and other oral morphines may not be therapeutically equivalent to KADIAN® for an individual patient.
KADIAN® capsules have the same extent of absorption (AUC) as immediate-release oral formulations and controlled-release oral formulations of morphine sulfate. However, key pharmacokinetic parameters (e.g. Cmax, Tmax) for KADIAN® are significantly different from other controlled-release oral formulations.
As with any potent opioid drug product, 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:
the total daily dose, potency and kind of opioid the patient has been taking previously;
the reliability of the relative potency estimate used to calculate the equivalent dose of morphine needed;
the patient's degree of opioid tolerance;
the general condition and medical status of the patient;
the type and severity of the patient's pain.
The following dosing recommendations, therefore, can only be considered suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of an individual patient.
CONVERSION FROM OTHER ORAL MORPHINE FORMULATIONS TO KADIAN®
Patients on other oral morphine formulations may be converted to KADIAN® by administering one-half of the patient's total daily oral morphine dose as KADIAN® capsules every 12 hours (twice-a-day) or by administering the total daily oral morphine dose as KADIAN® capsules every 24 hours (once-a-day). KADIAN® should not be given more frequently than every 12 hours.
CONVERSION FROM PARENTERAL MORPHINE OR OTHER PARENTERAL OR ORAL OPIOIDS TO KADIAN®
KADIAN® can be administered to patients previously receiving treatment with parenteral morphine or other opioids. While there are useful tables of oral and parenteral equivalents in cancer analgesia, there is substantial interpatient variation in the relative potency of different opioid drugs and formulations. For these reasons, it is better to underestimate the patient's 24 hour oral morphine requirement and provide rescue medication, than to overestimate and manage an adverse event. The following general points should be considered:
Parenteral to oral morphine ratio: It may take anywhere from 2-6 mg of oral morphine to provide analgesia equivalent to 1 mg of parenteral morphine. A dose of oral morphine three times the daily parenteral morphine requirement may be sufficient in chronic use settings.
Other parenteral or oral opioids to oral morphine sulfate: Physicians are advised to refer to published relative potency data, keeping in mind that such ratios are only approximate. In general, it is safest to give half of the estimated daily morphine demand as the initial dose, and to manage inadequate analgesia by supplementation with immediate-release morphine. (See discussion which follows.)
The first dose of KADIAN® may be taken with the last dose of any immediate-release (short-acting) opioid medication due to the long delay until the peak effect after administration of KADIAN®.
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 a sustained release morphine, it is ordinarily advisable to begin treatment using an immediate-release morphine formulation.
INDIVIDUALIZATION OF DOSAGE
The best use of opioid analgesics in the management of chronic malignant and non-malignant pain is challenging, and is well described in materials published by the World Health Organization and the Agency for Health Care Policy and Research which are available from Alpharma upon request. KADIAN® is a third step drug which is most useful when the patient requires a constant level of opioid analgesia as a "floor" or "platform" from which to manage breakthrough pain. When a patient has reached the point where comfort cannot be provided with a combination of non-opioid medications (NSAIDs and acetaminophen) and intermittent use of moderate or strong opioids, the patient's total opioid therapy should be converted into a 24 hour oral morphine equivalent.
KADIAN® should be started by administering one-half of the estimated total daily oral morphine dose every 12 hours (twice-a-day) or by administering the total daily oral morphine dose every 24 hours (once-a-day). The dose should be titrated no more frequently than every-other-day to allow the patients to stabilize before escalating the dose. If breakthrough pain occurs, the dose may be supplemented with a small dose (less than 20% of the total daily dose) of a short-acting analgesic. Patients who are excessively sedated after a once-a-day dose or who regularly experience inadequate analgesia before the next dose should be switched to twice-a-day dosing.
Patients who do not have a proven tolerance to opioids should be started only on the 20 mg strength, and usually should be increased at a rate not greater than 20 mg every-other-day. Most patients will rapidly develop some degree of tolerance, requiring dosage adjustment until they have achieved their individual best balance between baseline analgesia and opioid side effects such as confusion, sedation and constipation. No guidance can be given as to the recommended maximal dose, especially in patients with chronic pain of malignancy. In such cases the total dose of KADIAN® should be advanced until the desired therapeutic endpoint is reached or clinically significant opioid-related adverse reactions intervene.
ALTERNATIVE METHODS OF ADMINISTRATION
In a study of healthy volunteers, KADIAN® pellets sprinkled over applesauce were found to be bioequivalent to KADIAN® capsules swallowed whole with applesauce under fasting conditions. Other foods have not been tested. Patients who have difficulty swallowing whole capsules or tablets may benefit from this alternative method of administration.
Sprinkle the pellets onto a small amount of applesauce. Applesauce should be room temperature or cooler.
Rinse mouth to ensure all pellets have been swallowed.
Patients should consume entire portion and should not divide applesauce into separate doses.
The entire capsule contents 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.
THE ADMINISTRATION OF KADIAN® PELLETS THROUGH A NASOGASTRIC TUBE SHOULD NOT BE ATTEMPTED.
CONSIDERATIONS IN THE ADJUSTMENT OF DOSING REGIMENS
If signs of excessive opioid effects are observed early in the dosing interval, the next dose should be reduced. If this adjustment leads to inadequate analgesia, that is, if breakthrough pain occurs when KADIAN® is administered on an every 24 hours dosing regimen, consideration should be given to dosing every 12 hours. If breakthough pain occurs on a 12 hour dosing regimen a supplemental dose of short-acting analgesic may be given. As experience is gained, adjustments in both dose and dosing interval can be made to obtain an appropriate balance between pain relief and opioid side effects. To avoid accumulation the dosing interval of KADIAN® should not be reduced below 12 hours.
CONVERSION FROM KADIAN® TO OTHER CONTROLLED-RELEASE ORAL MORPHINE FORMULATIONS
KADIAN® is not bioequivalent to other controlled-release morphine preparations. Although for a given dose the same total amount of morphine is available from KADIAN® as from morphine solution or controlled-release morphine tablets, the slower release of morphine from KADIAN® results in reduced maximum and increased minimum plasma morphine concentrations than with shorter acting morphine products. Conversion from KADIAN® to the same total daily dose of controlled-release morphine preparations may lead to either excessive sedation at peak or inadequate analgesia at trough and close observation and appropriate dosage adjustments are recommended.
CONVERSION FROM KADIAN® TO PARENTERAL OPIOIDS
When converting a patient from KADIAN® to parenteral opioids, it is best to calculate an equivalent parenteral dose, and then initiate treatment at half of this calculated value. For example, to estimate the required 24 hour dose of parenteral morphine for a patient taking KADIAN®, one would take the 24 hour KADIAN® dose, divide by an oral to parenteral conversion ratio of 3, divide the estimated 24 hour parenteral dose into six divided doses (for a four hour dosing interval),
then halve this dose as an initial trial.
For example, to estimate the required parenteral morphine dose for a patient taking 360 mg of KADIAN® a day, divide the 360 mg daily oral morphine dose by a conversion ratio of 1 mg of parenteral morphine for every 3 mg of oral morphine. The estimated 120 mg daily parenteral requirement is then divided into six 20 mg doses, and half of this, or 10 mg, is then given every 4 hours as an initial trial dose.
This approach is likely to require a dosage increase in the first 24 hours for many patients, but is recommended because it is less likely to cause overdose than trying to establish an equivalent dose without titration.
Opioid analgesic agents may not effectively relieve dysesthetic pain, post-herpetic neuralgia, stabbing pains, activity-related pain, and some forms of headache. This does not mean that patients suffering from these types of pain should not be given an adequate trial of opioid analgesics. However, such patients may need to be promptly evaluated for other types of pain therapy.
SAFETY AND HANDLING
KADIAN® consists of closed hard gelatin capsules containing polymer coated morphine sulfate pellets that pose no known handling risk to health care workers. Oral morphine products are not known to be associated with a high risk of diversion, but all strong opioids are liable to diversion and misuse both by the general public and health care workers, and should be handled accordingly.