MS Contin (Page 8 of 9)

12.3 Pharmacokinetics

Absorption

MS CONTIN is an extended-release tablet containing morphine sulfate. Morphine is released from MS CONTIN somewhat more slowly than from immediate-release oral preparations. Following oral administration of a given dose of morphine, the amount ultimately absorbed is essentially the same whether the source is MS CONTIN or an immediate-release formulation. 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.

The oral bioavailability of morphine is approximately 20 to 40%. When MS CONTIN is given on a fixed dosing regimen, steady-state is achieved in about a day.

Food Effect

The effect of food upon the systemic bioavailability of MS CONTIN has not been systematically evaluated for all strengths. One study, conducted with the 30 mg MS CONTIN tablets, showed no significant differences in Cmax and AUC (0-24h) values, whether the tablet was taken while fasting or with a high-fat breakfast.

Distribution

Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen, and brain. Morphine also crosses placental membranes and has been found in breast milk. The volume of distribution (Vd) for morphine is approximately 3 to 4 liters per kilogram and morphine is 30 to 35% reversibly bound to plasma proteins.

Elimination

Metabolism

The major pathways of morphine metabolism include glucuronidation to produce metabolites including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5 to 15%) and sulfation in the liver to produce morphine-3-etheral sulfate. A small fraction (less than 5%) of morphine is demethylated. M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.

Excretion

The elimination of morphine occurs primarily as renal excretion of M3G and its effective half-life after intravenous administration is normally 2 to 4 hours. Approximately 10% of the dose is excreted unchanged in urine. In some studies involving longer periods of plasma sampling, a longer terminal half-life of about 15 hours was reported. A small amount of the glucuronide conjugate is excreted in the bile, and there is some minor enterohepatic recycling.

Specific Populations

Sex

A sex analysis of pharmacokinetic data from healthy subjects taking MS CONTIN indicated that morphine concentrations were similar in males and females.

Race/Ethnicity

Chinese subjects given intravenous morphine had a higher clearance when compared to Caucasian subjects (1852 +/- 116 ml/min compared to 1495 +/- 80 ml/min).

Hepatic Impairment

Morphine pharmacokinetics are altered in patients with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine plasma AUC ratios also decreased in these patients, indicating diminished metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.

Renal Impairment

Morphine pharmacokinetics are altered in patients with renal failure. The AUC is increased and clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of morphine 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 in vitro increasing DNA fragmentation in human T-cells. Morphine was reported to be mutagenic in the in vivo mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the in vivo 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, in vitro studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in 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 and higher incidence of pseudopregnancies at 20 mg/kg/day (3.2 times the HDD) were reported.

Studies from the literature have also reported changes in hormonal levels in male rats (i.e. testosterone, luteinizing hormone) following treatment with morphine at 10 mg/kg/day or greater (1.6 times the HDD).

Female rats that were administered morphine sulfate intraperitoneally prior to mating exhibited prolonged estrous cycles at 10 mg/kg/day (1.6 times the HDD).

Exposure of adolescent male rats to morphine has been associated with delayed sexual maturation and following mating to untreated females, smaller litters, increased pup mortality, and/or changes in reproductive endocrine status in adult male offspring have been reported (estimated 5 times the plasma levels at the HDD).

16 HOW SUPPLIED/STORAGE AND HANDLING

MS CONTIN® (morphine sulfate extended-release tablets) 15 mg are round, blue-colored, film-coated tablets bearing the symbol PF on one side and M 15 on the other. They are supplied as follows:

NDC 59011-260-10: opaque plastic bottles containing 100 tablets

MS CONTIN® (morphine sulfate extended-release tablets) 30 mg are round, lavender-colored, film-coated tablets bearing the symbol PF on one side and M 30 on the other. They are supplied as follows:

NDC 59011-261-25: opaque plastic bottles containing 100 tablets

MS CONTIN® (morphine sulfate extended-release tablets) 60 mg are round, orange-colored, film-coated tablets bearing the symbol PF on one side and M 60 on the other. They are supplied as follows:

NDC 59011-262-10: opaque plastic bottles containing 100 tablets

MS CONTIN® (morphine sulfate extended-release tablets) 100 mg are round, gray-colored, film-coated tablets bearing the symbol PF on one side and 100 on the other. They are supplied as follows:

NDC 59011-263-10: opaque plastic bottles containing 100 tablets

MS CONTIN® (morphine sulfate extended-release tablets) 200 mg are capsule-shaped, green-colored, film-coated tablets bearing the symbol PF on one side and M 200 on the other. They are supplied as follows:

NDC 59011-264-10: opaque plastic bottles containing 100 tablets

Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Addiction, Abuse, and Misuse

Inform patients that the use of MS CONTIN, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share MS CONTIN with others and to take steps to protect MS CONTIN from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting MS CONTIN or when the dosage is increased, and that it can occur even at recommended doses [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store MS CONTIN securely and to dispose of unused MS CONTIN by flushing the tablets down the toilet.

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if MS CONTIN is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.4), Drug Interactions (7)].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see Drug Interactions (7)].

MAOI Interaction

Inform patients not to take MS CONTIN while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking MS CONTIN [see Warnings and Precautions (5.6), Drug Interactions (7)].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.7)].

Important Administration Instructions

Instruct patients how to properly take MS CONTIN, including the following:

  • Swallow MS CONTIN tablets whole [see Dosage and Administration (2.1)]
  • Do not crush, chew, or dissolve the tablets [see Dosage and Administration (2.1)]
  • Use MS CONTIN exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) [see Warnings and Precautions (5.2)]
  • Do not discontinue MS CONTIN without first discussing the need for a tapering regimen with the prescriber [see Dosage and Administration (2.5)]

Hypotension

Inform patients that MS CONTIN may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.8)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in MS CONTIN. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of MS CONTIN during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that MS CONTIN can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Adverse Reactions (6.2)].

Lactation

Advise patients that breastfeeding is not recommended during treatment with MS CONTIN [see Use in Specific Populations (8.2)]

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [Use in Specific Populations (8.3)].

Driving or Operating Heavy Machinery

Inform patients that MS CONTIN may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

Disposal of Unused MS CONTIN

Advise patients to flush the unused tablets down the toilet when MS CONTIN is no longer needed.

Healthcare professionals can telephone Purdue Pharma’s Medical Services Department (1-888-726-7535) for information on this product.

Purdue Pharma L.P.Stamford, CT 06901-3431

©2016, Purdue Pharma L.P.

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