Morphine Sulfate (Page 5 of 7)

12.2 Pharmacodynamics

Morphine sulfate concentrations are not predictive of analgesic response, especially in patients previously treated with opioids. The minimum effective concentration varies widely and is influenced by a variety of factors, including the extent of previous opioid use, age and general medical condition. Effective doses in tolerant patients may be significantly higher than in opioid-naïve patients.

12.3 Pharmacokinetics

Absorption

Morphine sulfate is about two-thirds absorbed from the gastrointestinal tract with the maximum analgesic effect occurring 60 minutes post-administration. The oral bioavailability of morphine sulfate is less than 40% and shows large inter-individual variability due to extensive pre-systemic metabolism.

Food Effects

Although the presence of a food effect was not assessed with morphine sulfate oral solution, significant food effect is not expected with a solution formulation.

Steady-State

Administration of the 30 mg Morphine Sulfate Tablet and 30 mg of Morphine Sulfate Oral Solution every six hours for 5 days resulted in a comparable 24-hour exposure (AUC). The steady-state levels were achieved within 48 hours for both tablets and solution. The mean steady state Cmax values were about 78 and 58 ng/mL for tablet and solution, respectively.

Distribution

Once absorbed, morphine sulfate is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. Although the primary site of action is the CNS, only small quantities cross the blood-brain barrier. Morphine sulfate also crosses the placental membranes and has been found in breast milk. The volume of distribution of morphine sulfate is approximately 1 to 6 L/kg, and morphine sulfate is 20 to 35% reversibly bound to plasma proteins.

Metabolism

The major pathway of morphine sulfate detoxification is conjugation, either with D-glucuronic acid to produce glucuronides or with sulfuric acid to produce morphine-3-etheral sulfate. While a small fraction (less than 5%) of morphine sulfate is demethylated, virtually all morphine sulfate is converted by hepatic metabolism to the 3- and 6-glucuronide metabolites (M3G and M6G; about 50% and 15%, respectively). M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.

Excretion

Most of a dose of morphine sulfate is excreted in urine as M3G and M6G, with elimination of morphine sulfate occurring primarily as renal excretion of M3G. Approximately 10% of the dose is excreted unchanged in urine. A small amount of glucuronide conjugates are excreted in bile, with minor enterohepatic recycling. Seven to 10% of administered morphine sulfate is excreted in the feces.

The mean adult plasma clearance is approximately 20 to 30 mL/min/kg. The effective terminal half-life of morphine sulfate after IV administration is reported to be approximately 2 hours. In some studies involving longer periods of plasma sampling, a longer terminal half-life of morphine sulfate of about 15 hours was reported.

Race

There may be some pharmacokinetic differences associated with race. In one published study, Chinese subjects given intravenous morphine sulfate had a higher clearance when compared to Caucasian subjects (1852 +/- 116 mL/min compared to 1495 +/- 80 mL/min).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Studies in animals to evaluate the carcinogenic potential of morphine sulfate have not been conducted.

Mutagenesis

No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, morphine was found to be mutagenic increasing DNA fragmentation in human T-cells. Morphine was reported to be mutagenic in the mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the clastogenic effects reported with morphine in mice may be related to increases in glucocorticoid levels produced by morphine in this species. In contrast to the above positive findings, studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in . in vitro in vivo in vivo in vitro Drosophila

Impairment of Fertility

No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted. Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. One study in which male rats were administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects including reduction in total pregnancies, higher incidence of pseudopregnancies, and reduction in implantation sites were seen. Studies from the literature have also reported changes in hormonal levels (i.e. testosterone, luteinizing hormone, serum corticosterone) following treatment with morphine. These changes may be associated with the reported effects on fertility in the rat.

16 HOW SUPPLIED/STORAGE AND HANDLING

NDC:17856-0238-5 in a CUP, UNIT-DOSE of 5 SOLUTIONS

17 PATIENT COUNSELING INFORMATION

See Medication Guide

Provide the following information to patients receiving morphine sulfate or their caregivers:

•Advise patients that morphine sulfate is a narcotic pain reliever, and should be taken only as directed.•Advise patients that Morphine Sulfate Oral Solution is available in three concentrations: 10 mg per 5 mL, 20 mg per 5 mL and 100 mg per 5 mL (20 mg/mL). Carefully instruct patients about which concentration they have been prescribed and how to measure and take the correct dose of Morphine Sulfate Oral Solution. Advise patients whenever the prescribed concentration is changed to avoid dosing errors which could result in accidental overdose and death.•Advise patients to always use the enclosed calibrated oral syringe when administering Morphine Oral Solution 100 mg per 5 mL (20 mg/mL) to ensure the dose is measured and administered accurately.•The 100 mg per 5 mL (20 mg/mL) formulation is only for patients who are already receiving opioid-therapy and have demonstrated opioid-tolerance. Use of this formulation may cause fatal respiratory depression when administered to patients who have not had previous exposure to opioids.•Advise patients not to adjust the dose of morphine sulfate without consulting with a physician or other healthcare professional.•Advise patients that morphine sulfate may cause drowsiness, dizziness, or lightheadedness and may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Advise patients started on morphine sulfate or patients whose dose has been adjusted to refrain from any potentially dangerous activity until it is established that they are not adversely affected.•Instruct patients not to combine morphine sulfate with central nervous system depressants (such as sleep aids, tranquilizers, antihistamines, general anesthetics, phenothiazines, other opioids, and monoamine oxidase [MAO] inhibitors) except by the orders of the prescribing physician, and not to combine with alcohol because dangerous additive effects may occur, resulting in serious injury or death.•Instruct women of childbearing potential who become or are planning to become pregnant to consult a physician prior to initiating or continuing therapy with morphine sulfate.•Advise patients that safe use in pregnancy has not been established and that prolonged use of opioid analgesics during pregnancy may cause fetal-neonatal physical dependence, Neonatal withdrawal may also occur.•If patients have been receiving treatment with morphine sulfate for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose as abrupt discontinuation of the medication could precipitate withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the medication.•Advise patients that morphine sulfate is a potential drug of abuse. They must protect it from theft. It should never be given to anyone other than the individual for whom it was prescribed.•Instruct patients to keep morphine sulfate in a secure place out of the reach of children. When morphine sulfate is no longer needed, the unused oral solution should be destroyed by flushing down the toilet.•Advise patients taking morphine sulfate of the potential for severe constipation; appropriate laxatives and/or stool softeners as well as other appropriate treatments should be initiated from the onset of opioid therapy.•Advise patients of the most common adverse events that may occur while taking morphine sulfate: constipation, nausea, somnolence, lightheadedness, dizziness, sedation, vomiting, and sweating.

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