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Morphine (Morphine Sulfate) - Indications and Dosage

 
 



INDICATIONS AND USAGE

Morphine sulfate extended-release tablets are indicated for the relief of moderate to severe pain. It is intended for use in patients who require repeated dosing with potent opioid analgesics over periods of more than a few days.

The morphine sulfate extended-release tablet, 200 mg strength is a high dose, oral morphine formulation indicated for the relief of pain in opioid tolerant patients only.

DOSAGE AND ADMINISTRATION

(See also: CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS sections)

MORPHINE SULFATE EXTENDED-RELEASE TABLETS ARE TO BE TAKEN WHOLE, AND ARE NOT TO BE BROKEN, CHEWED OR CRUSHED.

TAKING BROKEN, CHEWED OR CRUSHED MORPHINE SULFATE EXTENDED-RELEASE TABLETS COULD LEAD TO THE RAPID RELEASE AND ABSORPTION OF A POTENTIALLY TOXIC DOSE OF MORPHINE.

Morphine sulfate extended-release tablets are intended for use in patients who require more than several days continuous treatment with a potent opioid analgesic. The extended-release nature of the formulation allows it to be administered on a more convenient schedule than conventional immediate-release oral morphine products. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) However, morphine sulfate extended-release tablets do not release morphine continuously over the course of a dosing interval. The administration of single doses of morphine sulfate extended-release tablets on a ql2h dosing schedule will result in higher peak and lower trough plasma levels than those that occur when an identical daily dose of morphine is administered using conventional oral formulations on a q4h regimen. The clinical significance of greater fluctuations in morphine plasma level has not been systematically evaluated.

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. Although it is clearly impossible to enumerate every consideration that is important to the selection of initial dose and dosing interval of morphine sulfate extended-release tablets, attention should be given to 1) the daily dose, potency and precise characteristics of the opioid the patient has been taking previously (e.g., whether it is a pure agonist or mixed agonist/antagonist), 2) the reliability of the relative potency estimate used to calculate the dose of morphine needed [N.B. potency estimates may vary with the route of administration], 3) the degree of opioid tolerance, if any, and 4) the general condition and medical status of the patient.

The following dosing recommendations, therefore, can only be considered suggested approaches to what is actually a series of clinical decisions in the management of the pain of an individual patient.

Conversion from Conventional Oral Morphine to Morphine Sulfate Extended-Release Tablets

A patient’s daily morphine requirement is established using immediate-release oral morphine (dosing every 4 to 6 hours). The patient is then converted to morphine sulfate extended-release tablets in either of two ways: 1) by administering one-half of the patient’s 24-hour requirement as morphine sulfate extended-release tablets on an every 12-hour schedule; or, 2) by administering one-third of the patient's daily requirement as morphine sulfate extended-release tablets on an every eight hour schedule. With either method, dose and dosing interval is then adjusted as needed (see discussion below). The 15 mg extended-release morphine sulfate tablet should be used for initial conversion for patients whose total daily requirement is expected to be less than 60 mg. Morphine sulfate extended-release tablets of 30 mg strength are recommended for patients with a daily morphine requirement of 60 to 120 mg. When the total daily dose is expected to be greater than 120 mg, the appropriate combination of tablet strengths should be employed.

Conversion from Parenteral Morphine or Other Opioids (Parenteral or Oral) to Morphine Sulfate Extended-Release Tablets

Morphine sulfate extended-release tablets can be administered as the initial oral morphine drug product; in this case, however, particular care must be exercised in the conversion process. Because of uncertainty about, and intersubject variation in, relative estimates of opioid potency and cross tolerance, initial dosing regimens should be conservative; that is, an underestimation of the 24-hour oral morphine requirement is preferred to an overestimate. To this end, initial individual doses of morphine sulfate extended-release tablets should be estimated conservatively. In patients whose daily morphine requirements are expected to be less than or equal to 120 mg per day, morphine sulfate extended-release tablets of 30 mg strength are recommended for the initial titration period. Once a stable dose regimen is reached, the patient can be converted to the 60 mg or 100 mg tablet strength, or appropriate combination of tablet strengths, if desired.

Estimates of the relative potency of opioids are only approximate and are influenced by route of administration, individual patient differences, and possibly, by an individual’s medical condition. Consequently, it is difficult to recommend any fixed rule for converting a patient to morphine sulfate extended-release tablets directly. The following general points should be considered, however.

  1. Parenteral to oral morphine ratio: Estimates of the oral to parenteral potency of morphine vary. Some authorities suggest that a dose of oral morphine only three times the daily parenteral morphine requirement may be sufficient in chronic use settings.
  2. Other parenteral or oral opioids to oral morphine: Because there is lack of systemic evidence bearing on these type of analgesic substitutions, specific recommendations are not possible.

Physicians are advised to refer to published relative potency data, keeping in mind that such ratios are only approximate. In general, it is safer to underestimate the daily dose of morphine sulfate extended-release tablets required and rely upon ad hoc supplementation to deal with inadequate analgesia. (See discussion which follows.)

Use of morphine sulfate extended-release tablets as the first opioid analgesic

There has been no systematic evaluation of morphine sulfate extended-release tablets as an initial opioid analgesic in the management of pain. Because it may be more difficult to titrate a patient using an extended-release morphine, it is ordinarily advisable to begin treatment using an immediate-release formulation.

Considerations in the Adjustment of Dosing Regimens

Whatever the approach, if signs of excessive opioid effects are observed early in a dosing interval, the next dose should be reduced. If this adjustment leads to inadequate analgesia, that is, "breakthrough" pain occurs late in the dosing interval, the dosing interval may be shortened. Alternatively, a supplemental dose of a short-acting analgesic may be given. As experience is gained, adjustments can be made to obtain an appropriate balance between pain relief, opioid side effects, and the convenience of the dosing schedule.

In adjusting dosing requirements, it is recommended that the dosing interval never be extended beyond 12 hours because the administration of very large single doses may lead to acute overdose. (N.B. This product is an extended-release formulation; it does not release morphine continuously over the dosing interval.)

For patients with low daily morphine requirements, morphine sulfate extended-release tablets of 15 mg strength should be used.

Special Instructions for Morphine Sulfate Extended-Release Tablets, 200 mg (For use in opioid tolerant patients only.)

Morphine Sulfate Extended-Release tablets, 200 mg are for use only in opioid tolerant patients requiring daily morphine equivalent dosages of 400 mg or more. It is recommended that this strength be reserved for patients that have already been titrated to a stable analgesic regimen using lower strengths of morphine extended-release tablets or other opioids.

Conversion from morphine sulfate extended-release tablets to parenteral opioids:

When converting a patient from morphine sulfate extended-release tablets to parenteral opioids, it is best to assume that the parenteral to oral potency is high. NOTE THAT THIS IS THE CONVERSE OF THE STRATEGY USED WHEN THE DIRECTION OF CONVERSION IS FROM THE PARENTERAL TO ORAL FORMULATIONS. IN BOTH CASES, HOWEVER, THE AIM IS TO ESTIMATE THE NEW DOSE CONSERVATIVELY. For example, to estimate the required 24-hour dose of morphine for IM use, one could employ a conversion of 1 mg of morphine IM for every 6 mg of morphine as morphine sulfate extended-release tablets. Of course, the IM 24-hour dose would have to be divided by six and administered on a q4h regimen. This approach is recommended because it is least likely to cause overdose.

SAFETY AND HANDLING

MORPHINE SULFATE EXTENDED-RELEASE TABLETS ARE TO BE TAKEN WHOLE, AND ARE NOT TO BE BROKEN, CHEWED, OR CRUSHED. TAKING BROKEN, CHEWED, OR CRUSHED MORPHINE SULFATE EXTENDED-RELEASE TABLETS COULD LEAD TO THE RAPID RELEASE AND ABSORPTION OF A POTENTIALLY TOXIC DOSE OF MORPHINE.

The morphine sulfate extended-release tablet, 200 mg strength is for use only in opioid tolerant patients requiring daily morphine equivalent dosages of 400 mg or more. This strength is potentially toxic if accidentally ingested and patients and their families should be instructed to take special care to avoid accidental or intentional ingestion by individuals other than those for whom the medication was originally prescribed.

HOW SUPPLIED

Morphine Sulfate Extended-Release Tablets are supplied as follows:

15 mg

Blue, round tablets, debossed “E652” on one side, and “15” on the other side

Bottles of 100         NDC 60951-652-70

30 mg

Green, round tablets, debossed “E653” on one side, and “30” on the other side.

Bottles of 100         NDC 60951-653-70

60 mg

Orange, capsule-shaped tablets, debossed“E655” on one side, and “60” on the other side.

Bottles of 100         NDC 60951-655-70

100 mg

Blue, capsule-shaped tablets, debossed “E658” on one side, and “100” on the other side.

Bottles of 100         NDC 60951-658-70

200 mg

Green, oval tablets, debossed “E659” on one side and “200” on the other side.

Bottles of 100         NDC 60951-659-70

Store at 25°C (77°F); excursions permitted to 15°– 30°C (59°– 86°F).

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

CAUTION

DEA Order Form Required.

Manufactured for:

Endo Pharmaceuticals Inc.

Chadds Ford, Pennsylvania 19317

Copyright © Endo Pharmaceuticals Inc. 2004

Printed in U.S.A.

415942/Rev. May, 2004

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