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Oramorph SR (Morphine Sulfate) - Description and Clinical Pharmacology

 
 



ORAMORPH® SR
(MORPHINE SULFATE)
Sustained Release Tablets
15 mg, 30 mg, 60 mg, 100 mg

NOTE
THIS IS A SUSTAINED RELEASE DOSAGE FORM. PATIENT SHOULD BE INSTRUCTED TO SWALLOW THE TABLET AS A WHOLE; THE TABLET SHOULD NOT BE BROKEN IN HALF, NOR SHOULD IT BE CRUSHED OR CHEWED.
THE SUSTAINED RELEASE OF MORPHINE FROM ORAMORPH SR SHOULD BE TAKEN INTO CONSIDERATION IN EVENT OF ADVERSE REACTIONS OR OVERDOSAGE.

DESCRIPTION

Each tablet for oral administration contains:

Morphine sulfate . . . . . . . . . .  15 mg, 30 mg, 60 mg, or 100 mg in a tablet that provides for sustained release of the medication.

Morphine sulfate occurs as white, feathery, silky crystals, cubical masses of crystals, or white crystalline powder; it is soluble in water and slightly soluble in alcohol. Morphine has a pKa of 7.9, with an octanol/water partition coefficient of 1.42 at pH 7.4. At this pH, the tertiary amino group is mostly ionized, making the molecule water-soluble. Morphine is significantly more water-soluble than any other opioid in clinical use.

Chemically, morphine sulfate is 7,8-didehydro-4,5α-epoxy-17-methyl-morphinian-3,6α-diol sulfate (2:1)(salt) pentahydrate, and has the following structural formula:

Each ORAMORPH SR Tablet contains 15 mg, 30 mg, 60 mg, or 100 mg Morphine Sulfate USP. Inactive ingredients: Lactose, Hydroxypropyl Methylcellulose, Colloidal Silicon Dioxide, and Stearic Acid.

CLINICAL PHARMACOLOGY

Morphine is the prototype of many narcotic drugs that interact predominantly with the opioid μ-receptor. These μ-binding sites are discretely distributed in the human brain, with high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve.

In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system and gastrointestinal tract. Its primary actions of therapeutic value are analgesia and sedation. Morphine appears to increase the patient's tolerance for pain and to decrease discomfort, although the presence of the pain itself may still be recognized. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur.

Morphine depresses various respiratory centers, depresses the cough reflex, and constricts the pupils. Analgesically effective blood levels of morphine may cause nausea and vomiting directly by stimulating the chemoreceptor trigger zone, but nausea and vomiting are significantly more common in ambulatory than in recumbent patients, as is postural syncope.

Morphine increases the tone and decreases the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time is responsible for the constipating effect of morphine. Because morphine may increase biliary-tract pressure, some patients with biliary colic may experience worsening rather than relief of pain.

While morphine generally increases the tone of urinary-tract smooth muscle, the net effect tends to be variable, in some cases producing urinary urgency, in others, difficulty in urination.

In therapeutic doses, morphine does not usually exert major effects on the cardiovascular system. Some patients, however, exhibit a propensity to develop orthostatic hypotension and fainting. Rapid intravenous injection is more likely to precipitate a fall in blood pressure than oral dosing.

Morphine can cause histamine release, which appears to be responsible for dilation of cutaneous blood vessels, with resulting flushing of the face and neck, pruritus, and sweating.

PHARMACOKINETICS

ORAMORPH SR Tablets are a sustained release oral dosage form of morphine sulfate. Only about 40% of the administered dose reaches the central compartment because of first-pass effect (i.e., metabolism in the gut wall and liver). Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. Morphine also crosses the placental membrane and has been found in breast milk.

For all practical purposes, virtually all morphine is converted to glucuronide metabolites; only a small fraction (less than 5%) of absorbed morphine is demethylated. Among these glucuronide metabolites, morphine-3-glucuronide is present in the highest plasma concentration following oral administration; a smaller fraction is converted to morphine-6-glucuronide, which has the greater analgesic activity of these two metabolites.

The glucuronide system has a high capacity and is not easily saturated, even in disease. Therefore, the rate of delivery of morphine to the gut and liver does not influence the total and/or the relative quantities of the various metabolites formed.

The pharmacokinetic parameters following oral administration of ORAMORPH SR, presented in the table below, 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 (L/kg), and the terminal elimination half-life is approximately 2 to 4 hours.

TABLE OF APPROXIMATE1 AVERAGE PHARMACOKINETIC PARAMETERS FOLLOWING ORAL DOSING OF ORAMORPH SR
Pharmacokinetic Parameter
    {scientific notation}
            (unit)
Dose of ORAMORPH SR
Dose of
2 x 15 mg
30 mg 60 mg 100 mg

Dose metabolized = approximately 90%

Morphine metabolites (%) = morphine-3-glucuronide (55-75%),

morphine-6-glucuronide (1-5%)

1Derived from pharmacokinetic studies in 24 normal volunteers

Bioavailability
(oral compared to injectable)
approximately 40%
    Time-to-peak plasma concentration {Tmax} (h)mean
(range)
3.7
(1-6)
3.8
(1-7)
3.8
(2-7)
3.6
(1.5-12)
    Peak plasma concentration {Cmax}
(ng/mL) [single dose]
mean
(range)
11.1
(6.5-16.2)
9.9
(5.0-18.6)
16.1
(10.0-25.3)
27.4
(14.1-46.1)
Volume of distribution (calculated from mean clearance and terminal half-life) {Vd(β)} (L/kg)mean- - - - - - - 4 L/kg - - - - - - -

Following the administration of conventional, immediate-release, oral morphine products, approximately 50% of the morphine, that will ever reach the central compartment, reaches it within 30 minutes. Following the administration of an equal amount of ORAMORPH SR to normal volunteers, however, 50% of absorption occurs, on average, after 1.5 hours.

A pharmacokinetic study in normal volunteers indicates that there is little to no effect on the systemic bioavailability of ORAMORPH SR when administered with food.

Although variation in the physico-mechanical properties of a formulation of an oral morphine drug product can affect both its absolute bioavailability and its absorption rate constant (ka), morphine distribution and clearance are unchanged, as they are fundamental properties of morphine in the organism. However, in chronic use, the possibility of shifts in metabolite-to-parent drug ratios cannot be excluded.

When immediate-release oral morphine or ORAMORPH SR is given on a fixed dosing regimen, steady-state is achieved in about one to two days.

For a given dose and dosing interval, the Area-Under-the-Curve (AUC) and average blood concentration of morphine at steady-state (Css) will be independent of the type of oral formulation administered, as long as the formulations have the same absolute bioavailability. The absorption rate of a formulation will, however, affect the maximum (Cmax) and minimum (Cmin) plasma concentrations and the time between administration and their occurrence. For any fixed dose and dosing interval, ORAMORPH SR will have, at steady-state, a lower Cmax and a higher Cmin than conventional immediate-release morphine, which might be a therapeutic advantage in chronic pain control (see also PHARMACODYNAMICS).

The clearance of morphine occurs primarily as renal excretion of morphine-3-glucuronide. A small amount of the glucuronide conjugate is excreted in the bile, and there is some minor enterohepatic recycling; about 10% of the glucuronide conjugate is excreted in the feces. Because morphine is essentially metabolized in the liver, the effects of renal disease on morphine's clearance are not likely to be pronounced. As with any drug, however, caution should be taken to guard against unanticipated accumulation if renal and/or hepatic function is seriously impaired.

PHARMACODYNAMICS

In clinical settings, morphine's primary actions of therapeutic value are analgesia and sedation. Opiate analgesia involves at least three anatomical areas of the central nervous system: the periaqueductal-periventricular gray matter, the ventromedial medulla, and the spinal cord. Morphine appears to increase the patient's tolerance for pain, and to decrease the discomfort, although the presence of pain itself may still be recognized.

While there is considerable variability in the relationship between morphine blood concentration and analgesic response, effective analgesia probably will not occur below some minimum blood level in a given patient. The minimum effective blood level for analgesia will vary among patients, especially among patients who have been previously treated with potent μ-agonist opioids. Similarly, there is considerable variability in the relationship between morphine plasma concentration and untoward clinical responses, but higher concentrations are more likely to be toxic.

In contrast to immediate-release morphine, after dosing with ORAMORPH SR, the morphine blood levels show reduced fluctuation between peak and trough plasma levels; that means that they are more centered within the theoretical 'therapeutic window'. On the other hand, the reduced fluctuation in morphine plasma concentration might conceivably affect other phenomena, as for example, the rate of tolerance induction.

ORAMORPH SR is an analgesic intended for patients who require chronic morphine analgesia and who will have, in consequence, markedly different degrees of pharmacodynamic tolerance for opioid drugs. Morphine and similar opioids induce tolerance to their effects, so that a shortening of the duration of satisfactory analgesia may be the first sign of an increase in tolerance.

Once patients are started on morphine, the dose required for satisfactory analgesia will rise, with the rate of development of tolerance varying, depending on the patient's prior narcotic use, level of pain, degree of anxiety, use of other CNS-active drugs, circulatory status, total daily dose, and the dosing interval.

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