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Morphine Sulfate Extended-Release (Tablet)

Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/399

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Morphine Sulfate Extended-Release (Tablet)
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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 controlled-release nature of the formulation allows it to be administered on a more convenient schedule than conventional immediate-release oral morphine products. 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 q12h 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.<br/>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 every12-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 tablet should be used for initial conversion for patients whose total daily requirement is expected to be less than 60 mg. The 30 mg tablet strength is 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.<br/>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, the 30 mg tablet strength is 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 an 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 systematic evidence bearing on these types 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.)<br/>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 a controlled-release morphine, it is ordinarily advisable to begin treatment using an immediate-release formulation.<br/>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. Morphine sulfate extended-release tablets are a controlled-release formulation; it does not release morphine continuously over the dosing interval.) For patients with low daily morphine requirements, the 15 mg tablet should be used.<br/>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.
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Pharmacokinetics and Metabolism: Morphine sulfate extended-release tablet is a controlled-release tablet containing morphine sulfate. Following oral administration of a given dose of morphine, the amount ultimately absorbed is essentially the same whether the source is morphine sulfate extended-release tablets or a conventional formulation. Morphine is released from morphine sulfate extended-release tablets somewhat more slowly than from conventional oral preparations. Because of pre-systemic elimination (i.e., metabolism in the gut wall and liver) only about 40% of the administered dose reaches the central compartment. Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen, and brain. Morphine also crosses the placental membranes and has been found in breast milk. Although a small fraction (less than 5%) of morphine is demethylated, for all practical purposes, virtually all morphine is converted to glucuronide metabolites; among these, morphine-3-glucuronide is present in the highest plasma concentration following oral administration. The glucuronide system has a very high capacity and is not easily saturated even in disease. Therefore, rate of delivery of morphine to the gut and liver should not influence the total and, probably, the relative quantities of the various metabolites formed. Moreover, even if rate affected the relative amounts of each metabolite formed, it should be unimportant clinically because morphine's metabolites are ordinarily inactive. The following pharmacokinetic parameters show considerable inter-subject variation but are representative of average values reported in the literature. The volume of distribution (Vd) for morphine is 4 liters per kilogram, and its terminal elimination half-life is normally 2 to 4 hours. Following the administration of conventional oral morphine products, approximately fifty percent of the morphine that will reach the central compartment intact reaches it within 30 minutes. Following the administration of an equal amount of morphine sulfate extended-release tablets to normal volunteers, however, this extent of absorptionoccurs, on average, after 1.5 hours. The possible effect of food upon the systemic bioavailability of morphine sulfate extended-release tablets have not been systematically evaluated for all strengths. Data from at least one study suggests that concurrent administration of morphine sulfate extended-release tablets with a fatty meal may cause a slight decrease in peak plasma concentration. Variation in the physical/mechanical properties of a formulation of an oral morphine drug product can affect both its absolute bioavailability and its absorption rate constant (k). The formulation employed in morphine sulfate extended-release tablets have not been shown to affect morphine's oral bioavailability, but does decrease its apparent k. Other basic pharmacokinetic parameters (e.g., volume of distribution [Vd], elimination rate constant [k], clearance [Cl]), are unchanged as they are fundamental properties of morphine in the organism. However, in chronic use, the possibility that shifts in metabolite to parent drug ratios may occur cannot be excluded. When immediate-release oral morphine or morphine sulfate extended-release tablets are given on a fixed dosing regimen, steady-state is achieved in about a day. For a given dose and dosing interval, the AUC and average blood concentration of morphine at steady state (Css) will be independent of the specific type of oral formulation administered so long as the formulations have the same absolute bioavailability. The absorption rate of a formulation will, however, affect the maximum (C) and minimum (C) blood levels and the times of their occurrence.<br/>Pharmacodynamics: The effects described below are common to all morphine-containing products.<br/>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 and endogenous compounds with morphine-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.<br/>Gastrointestinal Tract and Other Smooth Muscle: Gastric, biliary, and pancreatic secretions are decreased by morphine. Morphine causes a reduction in motility associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm. The end result is constipation. Morphine can cause a marked increase in biliary tract pressure as a result of spasm of sphincter of Oddi.<br/>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.<br/>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. In general, the minimum effective analgesic concentration in the plasma of non-tolerant patients ranges from approximately 5 to 20 ng/mL. 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 10 to 50 times as great (or 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 Cand a higher Cthan conventional morphine. This is a potential advantage; a reduced fluctuation in morphine concentration during the dosing interval should keep morphine blood levels more centered within the theoretical "therapeutic window." (Fluctuation for a dosing interval is defined as [C- C]/[Css-average].) On the other hand, the degree of fluctuation in serum morphine concentration might conceivably affect other phenomena. For example, reduced fluctuations in blood morphine concentrations might influence the rate of tolerance induction. The elimination of morphine occurs primarily as renal excretion of 3-morphine glucuronide. A small amount of the glucuronide conjugate is excreted in the bile, and there is some minor enterohepatic recycling. Because morphine is primarily metabolized to inactive metabolites, the effects of renal disease on morphine's elimination are not likely to be pronounced. However, as with any drug, caution should be taken to guard against unanticipated accumulation if renal and/or hepatic function is seriously impaired.
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Morphine sulfate extended-release tablets, 30 mg: Oval tablet, film-coated pink, debossed���E���on one side and���30���on the other side. Morphine sulfate extended-release tablets, 60 mg: Oval tablet, film-coated white, debossed���E���on one side and���60���on the other side. Store at 25��C (77��F); excursions permitted to 15��C to 30��C (59��F to 86��F). [See USP Controlled Room Temperature.] Dispense in tight, light-resistant and child-resistant containers as defined in the USP. CAUTIONDEA Order Form Required. Manufactured byKV Pharmaceutical Co. forETHEX CorporationSt. Louis, MO 63044
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Morphine Sulfate
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Morphine Sulfate Extended-Release (Tablet)
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The adverse reactions caused by morphine are essentially those observed with other opioid analgesics. They include the following major hazards: respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest.<br/>Most Frequently Observed: Constipation, lightheadedness, dizziness, sedation, nausea, vomiting, sweating, dysphoria, and euphoria. Some of these effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain. Some adverse reactions in ambulatory patients may be alleviated if the patient lies down.<br/>Less Frequently Observed Reactions: Central Nervous System: Weakness, headache, agitation, tremor, uncoordinated muscle movements, seizure, alterations of mood (nervousness, apprehension, depression, floating feelings), dreams, muscle rigidity, transient hallucinations and disorientation, visual disturbances, insomnia, increased intracranial pressure. Gastrointestinal: Dry mouth, biliary tract spasm, laryngospasm, anorexia, diarrhea, cramps, taste alteration, constipation, ileus, intestinal obstruction, increases in hepatic enzymes. Cardiovascular: Flushing of the face, chills, tachycardia, bradycardia, palpitation, faintness, syncope, hypotension, hypertension. Genitourinary: Urine retention or hesitance, reduced libido and/or potency. Dermatologic: Pruritus, urticaria, other skin rashes, edema, diaphoresis. Other: Antidiuretic effect, paresthesia, muscle tremor, blurred vision, nystagmus, diplopia, miosis, anaphylaxis.
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Morphine sulfate extended-release tablets are a controlled-release oral morphine formulation 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.
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Morphine Sulfate Extended-Release