MORPHINE SULFATE EXTENDED-RELEASE

MORPHINE SULFATE EXTENDED-RELEASE- morphine sulfate tablet, extended release
STAT Rx USA LLC

*100 mg and 200 mg are for use in opioid-tolerant patients only

WARNING:


Morphine sulfate extended-release tablets contain morphine sulfate, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics.
Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing morphine sulfate extended-release tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
Morphine sulfate extended-release tablets are an extended-release oral formulation of morphine sulfate indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.
Morphine sulfate extended-release tablets are NOT intended for use as a prn analgesic.
Morphine sulfate extended-release 100 mg and 200 mg tablets ARE FOR USE IN OPIOID-TOLERANT PATIENTS ONLY. These tablet strengths may cause fatal respiratory depression when administered to patients not previously exposed to opioids.
MORPHINE SULFATE EXTENDED-RELEASE TABLETS ARE TO BE SWALLOWED WHOLE AND ARE NOT TO BE BROKEN, CHEWED, DISSOLVED, OR CRUSHED. TAKING BROKEN, CHEWED, DISSOLVED, OR CRUSHED MORPHINE SULFATE EXTENDED-RELEASE TABLETS LEADS TO RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF MORPHINE.

DESCRIPTION

Morphine Sulfate Extended-Release Tablets are supplied in tablet form for oral administration.

Chemical Structure
(click image for full-size original)

Morphine sulfate extended-release tablets are opiate analgesics supplied in 15, 30, 60, 100 and 200 mg tablet strengths. The tablet strengths describe the amount of morphine per tablet as the pentahydrated sulfate salt (morphine sulfate USP).

All strengths contain the following inactive ingredients: hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, silicone dioxide, titanium dioxide, and triacetine.

The 15 mg tablets also contain: polyethylene glycol, polydextrose, and FD&C Blue No. 2.

The 30 mg tablets also contain: polyethylene glycol, polydextrose, FD&C Blue No. 2, and D&C Red No. 7.

The 60 mg tablets also contain: polyethylene glycol, polydextrose, FD&C Yellow No. 6, and iron oxide red.

The 100 mg* tablets also contain: iron oxide black.

The 200 mg* tablets also contain: polyethylene glycol, FD&C Blue No. 1, and D&C Yellow No. 10 Lake.

*100 mg and 200 mg ARE FOR USE IN OPIOID-TOLERANT PATIENTS ONLY.

CLINICAL PHARMACOLOGY

Morphine is a pure opioid agonist whose principal therapeutic action is analgesia. Other members of the class known as opioid agonists include substances such as oxycodone, hydromorphone, fentanyl, codeine, and hydrocodone. Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, cough suppression, and analgesia. Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses. With pure opioid agonist analgesics, there is no defined maximum dose; the ceiling to analgesic effectiveness is imposed only by side effects, the more serious which may include somnolence and respiratory depression.

Central Nervous System

The principal actions of therapeutic value of morphine are analgesia and sedation (i.e., sleepiness and anxiolysis).

The precise mechanism of the analgesic action is unknown. However, specific CNS opiate receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are likely to play a role in the expression of analgesic effects.

Morphine produces respiratory depression by direct action on brain stem respiratory centers. The mechanism of respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension, and to electrical stimulation.

Morphine depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of narcotic overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen with worsening hypoxia.

Gastrointestinal Tract and Other Smooth Muscle

Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food is delayed in the small intestine and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.

Cardiovascular System

Morphine produces peripheral vasodilation which may result in orthostatic hypotension. Release of histamine can occur and may contribute to opioid-induced hypotension. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, and sweating.

Endocrine System

Opioids have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagons in humans and other species, rats and dogs. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.

Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown.

Pharmacodynamics

As with all opioids, the minimum effective plasma concentration for analgesia varies widely among patients, especially among patients who have been previously treated with potent agonist opioids. As a result, patients must be treated with individualized titration of dosage to the desired effect. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of new pain syndrome and/or the development of analgesic tolerance.

Plasma Level — Analgesia Relationships

In any particular patient, both analgesic effects and plasma morphine concentrations are related to the morphine dose. In non-tolerant individuals, plasma morphine concentration-efficacy relationships have been demonstrated and suggest that opiate receptors occupy effector compartments, leading to a lag-time, or hysteresis, between rapid changes in plasma morphine concentrations and the effects of such changes. The most direct and predictable concentration-effect relationships can, therefore, be expected at distribution equilibrium and/or steady-state conditions.

While plasma morphine-efficacy relationships can be demonstrated in non-tolerant individuals, they are influenced by a wide variety of factors and are not generally useful as a guide to the clinical use of morphine. The effective dose in opioid-tolerant patients may be significantly greater than the appropriate dose for opioid-naive individuals. Dosages of morphine should be chosen and must be titrated on the basis of clinical evaluation of the patient and the balance between therapeutic and adverse effects.

For any fixed dose and dosing interval, morphine sulfate extended-release tablets will have at steady-state, a lower Cmax and a higher Cmin than conventional morphine.

Concentration — Adverse Experience Relationships

Morphine sulfate extended-release tablets are associated with typical opioid-related adverse experiences. There is a general relationship between increasing morphine plasma concentration and increasing frequency of dose-related opioid adverse experiences such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation is altered by the development of tolerance to opioid-related side effects, and the relationship is not clinically relevant.

As with all opioids, the dose must be individualized (see DOSAGE AND ADMINISTRATION), because the effective analgesic dose for some patients will be too high to be tolerated by other patients.

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