Label: MS CONTIN- morphine sulfate tablet, film coated, extended release
view more59011-262-10, 59011-263-05, 59011-263-10, 59011-264-10
- Packager: Purdue Pharma LP
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: CII
- Marketing Status: New Drug Application
If you are a consumer or patient please visit this version.
- BOXED WARNING(What is this?)
WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; and NEONATAL OPIOID WITHDRAWAL SYNDROMEClose
- HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use MS CONTIN ® safely and effectively. See full prescribing information for MS CONTIN.
MS CONTIN ® (morphine sulfate extended-release tablets), for oral use CII
Initial U.S. Approval: 1941
WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION, ACCIDENTAL INGESTION; and NEONATAL OPIOID WITHDRAWAL SYNDROME
See full prescribing information for complete boxed warning.
- MS CONTIN exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors and conditions. (5.1)
- Serious, life-threatening or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow MS CONTIN tablets whole to avoid exposure to a potentially fatal dose of morphine. (5.2)
- Accidental ingestion of MS CONTIN, especially in children, can result in fatal overdose of morphine. (5.2)
- Prolonged use of MS CONTIN during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.3)
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
MS CONTIN is an opioid agonist product indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. (1)
Limitations of Use
- Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve MS CONTIN for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. (1)
- MS CONTIN is not indicated as an as-needed (prn) analgesic. (1)
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Extended-release tablets: 15 mg, 30 mg, 60 mg, 100 mg, 200 mg (3)
WARNINGS AND PRECAUTIONS
- Interaction with CNS depressants: Concomitant use may cause profound sedation, respiratory depression, and death. If coadministration is required, consider dose reduction of one or both drugs because of additive pharmacologic effects. (5.4)
- Elderly, cachectic, debilitated patients, and those with chronic pulmonary disease: Monitor closely because of increased risk for life-threatening respiratory depression. (5.5, 5.6)
- Hypotensive effect: Monitor during dose initiation and titration. (5.7)
- Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of MS CONTIN in patients with impaired consciousness or coma susceptible to intracranial effects of CO2 retention. (5.8)
- Mixed agonist/antagonist and partial agonist opioid analgesics: Avoid use with MS CONTIN because they may reduce analgesic effect of MS CONTIN or precipitate withdrawal symptoms. (5.11, 7.2)
- Monoamine oxidase inhibitors (MAOIs): Avoid MS CONTIN in patients taking MAOIs or within 14 days of stopping such treatment. (7.4)
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
- FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; and NEONATAL OPIOID WITHDRAWAL SYNDROME
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS AND USAGE
- 2 DOSAGE AND ADMINISTRATION
2.1 Initial Dosing
Patients receiving other oral morphine formulations may be converted to MS CONTIN by administering one-half of the patient's 24-hour requirement as MS CONTIN on an every-12-hour schedule or by administering one-third of the patient's daily requirement as MS CONTIN on an every-8-hour schedule.
Parenteral to oral morphine ratio: Between 2 to 6 mg of oral morphine may be required to provide analgesia equivalent to 1 mg of parenteral morphine. Typically, a dose of morphine that is approximately three times the previous daily parenteral morphine requirement is sufficient.
- Other parenteral or oral non-morphine opioids to oral morphine sulfate: Specific recommendations are not available because of a lack of systematic evidence for these types of analgesic substitutions. Published relative potency data are available, but such ratios are approximations. In general, begin with half of the estimated daily morphine requirement as the initial dose, managing inadequate analgesia by supplementation with immediate-release morphine.
2.3 Discontinuation of MS CONTIN
When the patient no longer requires therapy with MS CONTIN tablets, use a gradual downward titration of the dose to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue MS CONTIN.
- 3 DOSAGE FORMS AND STRENGTHS
- MS CONTIN® (morphine sulfate extended-release tablets) 15 mg
Round, blue-colored, film-coated tablets bearing the symbol PF on one side and M 15 on the other
- MS CONTIN® (morphine sulfate extended-release tablets) 30 mg
Round, lavender-colored, film-coated tablets bearing the symbol PF on one side and M 30 on the other
- MS CONTIN® (morphine sulfate extended-release tablets) 60 mg
Round, orange-colored, film-coated tablets bearing the symbol PF on one side and M 60 on the other
- MS CONTIN® (morphine sulfate extended-release tablets) 100 mg*
Round, gray-colored, film-coated tablets bearing the symbol PF on one side and 100 on the other
- MS CONTIN® (morphine sulfate extended-release tablets) 200 mg*
Capsule-shaped, green-colored, film-coated tablets bearing the symbol PF on one side and M 200 on the other
- MS CONTIN® (morphine sulfate extended-release tablets) 15 mg
- 4 CONTRAINDICATIONS
- Significant respiratory depression
- Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
- Known or suspected paralytic ileus
- Hypersensitivity (e.g., anaphylaxis) to morphine [see Adverse Reactions (6.2)]
- 5 WARNINGS AND PRECAUTIONS
5.7 Hypotensive Effects
MS CONTIN may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7.1)]. Monitor these patients for signs of hypotension after initiating or titrating the dose of MS CONTIN. In patients with circulatory shock, MS CONTIN may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of MS CONTIN in patients with circulatory shock.
5.8 Use in Patients with Head Injury or Increased Intracranial Pressure
Monitor patients taking MS CONTIN who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with MS CONTIN. MS CONTIN may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury.
5.9 Use in Patients with Gastrointestinal Conditions
The morphine in MS CONTIN may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase.
5.10 Use in Patients with Convulsive or Seizure Disorders
The morphine in MS CONTIN may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during MS CONTIN therapy.
5.12 Driving and Operating Machinery
MS CONTIN may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of MS CONTIN and know how they will react to the medication.
- 6 ADVERSE REACTIONS
- Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
- Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
- Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)]
- Interactions with Other CNS Depressants [see Warnings and Precautions (5.4)]
- Hypotensive Effect [see Warnings and Precautions (5.7)]
- Gastrointestinal Effects [see Warnings and Precautions (5.9)]
- Seizures [see Warnings and Precautions (5.10)]
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
MS CONTIN may increase the risk of serious adverse reactions such as those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, or shock [see Overdosage (10)].
6.2 Post-Marketing Experience
The following adverse reactions have been identified during postapproval use of MS CONTIN: amenorrhea, asthenia, bronchospasm, confusional state, drug hypersensitivity, fatigue, hyperalgesia, hypertonia, ileus, increased hepatic enzymes, intestinal obstruction, lethargy, malaise, pulmonary edema, thinking disturbances, somnolence, and vertigo.
- 7 DRUG INTERACTIONS
7.1 CNS Depressants
The concomitant use of MS CONTIN with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma, and death. Monitor patients receiving CNS depressants and MS CONTIN for signs of respiratory depression, sedation, and hypotension.
7.2 Interactions with Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonist (buprenorphine) analgesics may reduce the analgesic effect of MS CONTIN or precipitate withdrawal symptoms. Avoid the use of agonist/antagonist and partial agonist analgesics in patients receiving MS CONTIN.
7.3 Muscle Relaxants
Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and MS CONTIN for signs of respiratory depression that may be greater than otherwise expected.
7.4 Monoamine Oxidase Inhibitors (MAOIs)
The effects of morphine may be potentiated by MAOIs. Monitor patients on concurrent therapy with an MAOI and MS CONTIN for increased respiratory and central nervous system depression. MAOIs have been reported to potentiate the effects of morphine anxiety, confusion, and significant depression of respiration or coma. MS CONTIN should not be used in patients taking MAOIs or within 14 days of stopping such treatment.
Cimetidine can potentiate morphine-induced respiratory depression. There is a report of confusion and severe respiratory depression when a patient undergoing hemodialysis was concurrently administered morphine and cimetidine. Monitor patients for respiratory depression when MS CONTIN and cimetidine are used concurrently.
Morphine can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Morphine may also lead to acute retention of urine by causing spasm of the sphincter of the bladder, particularly in men with enlarged prostates.
Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when MS CONTIN is used concurrently with anticholinergic drugs.
7.8 P-Glycoprotein (PGP) Inhibitors
PGP-inhibitors (e.g., quinidine) may increase the absorption/exposure of morphine sulfate by about two-fold. Therefore, monitor patients for signs of respiratory and central nervous system depression when MS CONTIN is used concurrently with PGP inhibitors.
- 8 USE IN SPECIFIC POPULATIONS
Fetal/neonatal adverse reactions
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see Warnings and Precautions (5.3)].
In humans, the frequency of congenital anomalies has been reported to be no greater than expected among the children of 70 women who were treated with morphine during the first four months of pregnancy or in 448 women treated with morphine anytime during pregnancy. Furthermore, no malformations were observed in the infant of a woman who attempted suicide by taking an overdose of morphine and other medication during the first trimester of pregnancy.
Several literature reports indicate that morphine administered subcutaneously during the early gestational period in mice and hamsters produced neurological, soft tissue and skeletal abnormalities. With one exception, the effects that have been reported were following doses that were maternally toxic and the abnormalities noted were characteristic of those observed when maternal toxicity is present. In one study, following subcutaneous infusion of doses greater than or equal to 0.15 mg/kg to mice, exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted in the absence of maternal toxicity. In the hamster, morphine sulfate given subcutaneously on gestation day 8 produced exencephaly and cranioschisis. In rats treated with subcutaneous infusions of morphine during the period of organogenesis, no teratogenicity was observed. No maternal toxicity was observed in this study, however, increased mortality and growth retardation were seen in the offspring. In two studies performed in the rabbit, no evidence of teratogenicity was reported at subcutaneous doses up to 100 mg/kg.
Infants born to mothers who have taken opioids chronically may exhibit neonatal withdrawal syndrome [see Warnings and Precautions (5.3)], reversible reduction in brain volume, small size, decreased ventilatory response to CO2 and increased risk of sudden infant death syndrome. Morphine sulfate should be used by a pregnant woman only if the need for opioid analgesia clearly outweighs the potential risks to the fetus.
Controlled studies of chronic in utero morphine exposure in pregnant women have not been conducted. Published literature has reported that exposure to morphine during pregnancy in animals is associated with reduction in growth and a host of behavioral abnormalities in the offspring. Morphine treatment during gestational periods of organogenesis in rats, hamsters, guinea pigs and rabbits resulted in the following treatment-related embryotoxicity and neonatal toxicity in one or more studies: decreased litter size, embryo-fetal viability, fetal and neonatal body weights, absolute brain and cerebellar weights, delayed motor and sexual maturation, and increased neonatal mortality, cyanosis and hypothermia. Decreased fertility in female offspring, and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed. Decreased litter size and viability were observed in the offspring of male rats administered morphine (25 mg/kg, IP) for 1 day prior to mating. Behavioral abnormalities resulting from chronic morphine exposure of fetal animals included altered reflex and motor skill development, mild withdrawal, and altered responsiveness to morphine persisting into adulthood.
8.2 Labor and Delivery
Opioids cross the placenta and may produce respiratory depression in neonates. MS CONTIN is not for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.
8.3 Nursing Mothers
Morphine is excreted in breast milk, with a milk to plasma morphine AUC ratio of approximately 2.5:1. The amount of morphine received by the infant varies depending on the maternal plasma concentration, the amount of milk ingested by the infant, and the extent of first pass metabolism.
Because of the potential for adverse reactions in nursing infants from MS CONTIN, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
8.5 Geriatric Use
The pharmacokinetics of MS CONTIN have not been studied in elderly patients. Clinical studies of MS CONTIN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- 9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
MS CONTIN contains morphine, a Schedule II controlled substance with a high potential for abuse similar to other opioids including fentanyl, hydromorphone, methadone, oxycodone, and oxymorphone. MS CONTIN can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].
All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high”, or the use of steroids for performance enhancement and muscle build up.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
"Drug-seeking" behavior is very common to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
MS CONTIN, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests as required by state law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to reduce abuse of opioid drugs.
MS CONTIN is for oral use only. Abuse of MS CONTIN poses a risk of overdose and death. This risk is increased with concurrent abuse of MS CONTIN with alcohol and other substances. Taking cut, broken, chewed, crushed, or dissolved MS CONTIN enhances drug release and increases the risk of overdose and death.
Due to the presence of talc as one of the excipients in MS CONTIN, parenteral abuse can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
MS CONTIN should not be abruptly discontinued [see Dosage and Administration (2.3)]. If MS CONTIN is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].
- 10 OVERDOSAGE
Acute overdosage with morphine is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations.
In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.
The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose. Such agents should be administered cautiously to persons who are known, or suspected to be physically dependent on MS CONTIN. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.
Because the duration of reversal would be expected to be less than the duration of action of morphine in MS CONTIN, carefully monitor the patient until spontaneous respiration is reliably re-established. MS CONTIN will continue to release morphine and add to the morphine load for 24 to 48 hours or longer following ingestion necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be administered as directed in the product’s prescribing information.
In an individual physically dependent on opioids, administration of the usual dose of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.Close
- 11 DESCRIPTION
Each tablet contains the following inactive ingredients common to all strengths: cetostearyl alcohol, hydroxyethyl cellulose, hypromellose, magnesium stearate, polyethylene glycol, talc and titanium dioxide.
Morphine sulfate is an odorless, white, crystalline powder with a bitter taste. It has a solubility of 1 in 21 parts of water and 1 in 1000 parts of alcohol, but is practically insoluble in chloroform or ether. The octanol: water partition coefficient of morphine is 1.42 at physiologic pH and the pKb is 7.9 for the tertiary nitrogen (mostly ionized at pH 7.4). Its structural formula is:
- 12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Morphine sulfate, an opioid agonist, is relatively selective for the mu receptor, although it can interact with other opioid receptors at higher doses. In addition to analgesia, the widely diverse effects of morphine sulfate include analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal motility, altered circulatory dynamics, histamine release, physical dependence, and alterations of the endocrine and autonomic nervous systems.
Morphine produces both its therapeutic and its adverse effects by interaction with one or more classes of specific opioid receptors located throughout the body. Morphine acts as a full agonist, binding with and activating opioid receptors at sites in the peri-aqueductal and peri-ventricular grey matter, the ventro-medial medulla and the spinal cord to produce analgesia.
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. 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.
The principal actions of therapeutic value of morphine are analgesia and sedation. 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 brainstem respiratory centers. The mechanism of respiratory depression involves a reduction in the responsiveness of the brainstem 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. 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.
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. The end result is constipation. Morphine can cause a marked reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.
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.
Opioids inhibit the secretion of ACTH, cortisol, testosterone, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
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. Overall, the effects of opioids appear to be modestly immunosuppressive.
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 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.
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.
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.
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.
Morphine pharmacokinetics are altered in individuals 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 subjects, indicating diminished metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.
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
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, 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
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:Close
- 17 PATIENT COUNSELING INFORMATION
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 or 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.
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting MS CONTIN or when the dose 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.
Inform patients that accidental ingestion, especially in 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.
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)].
- Swallowing MS CONTIN tablets whole
- Not crushing, chewing, or dissolving the tablets
- Using MS CONTIN exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression)
- Not discontinuing MS CONTIN without first discussing the need for a tapering regimen with the prescriber
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).
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.
- MEDICATION GUIDE
This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: April 2014 Medication Guide
MS CONTIN® (MS-KON-tin) (morphine sulfate extended-release tablets), CII
MS CONTIN is:
- A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily around-the-clock, long-term treatment with an opioid, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them.
- A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.
- Not for use to treat pain that is not around-the-clock.
Important information about MS CONTIN:
- Get emergency help right away if you take too much MS CONTIN (overdose). When you first start taking MS CONTIN, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
- Never give anyone else your MS CONTIN. They could die from taking it. Store MS CONTIN away from children and in a safe place to prevent stealing or abuse. Selling or giving away MS CONTIN is against the law.
Do not take MS CONTIN if you have:
- severe asthma, trouble breathing, or other lung problems.
- a bowel blockage or have narrowing of the stomach or intestines.
Before taking MS CONTIN, tell your healthcare provider if you have a history of:
- head injury, seizures
- liver, kidney, thyroid problems
- problems urinating
- pancreas or gallbladder problems
- abuse of street or prescription drugs, alcohol addiction, or mental health problems.
Tell your healthcare provider if you are:
- pregnant or planning to become pregnant. Prolonged use of MS CONTIN during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
- breastfeeding. MS CONTIN passes into breast milk and may harm your baby.
- taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking MS CONTIN with certain other medicines can cause serious side effects.
When taking MS CONTIN:
- Do not change your dose. Take MS CONTIN exactly as prescribed by your healthcare provider.
- Take your prescribed dose every 8 to 12 hours, as directed by your healthcare provider. Do not take more than your prescribed dose. If you miss a dose, take your next dose at the usual time.
- Swallow MS CONTIN whole. Do not cut, break, chew, crush, dissolve, snort, or inject MS CONTIN because this may cause you to overdose and die.
- Call your healthcare provider if the dose you are taking does not control your pain.
- Do not stop taking MS CONTIN without talking to your healthcare provider.
- After you stop taking MS CONTIN, flush any unused tablets down the toilet.
While taking MS CONTIN DO NOT:
- Drive or operate heavy machinery, until you know how MS CONTIN affects you. MS CONTIN can make you sleepy, dizzy, or lightheaded.
- Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with MS CONTIN may cause you to overdose and die.
The possible side effects of MS CONTIN are:
- constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.
Get emergency medical help if you have:
- trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, light-headedness when changing positions, or you are feeling faint.
Manufactured by: Purdue Pharma L.P., Stamford, CT 06901-3431, www.purduepharma.com or call 1-888-726-7535
- PRINCIPAL DISPLAY PANEL
- PRINCIPAL DISPLAY PANEL
- PRINCIPAL DISPLAY PANEL
- PRINCIPAL DISPLAY PANEL
- PRINCIPAL DISPLAY PANEL
- INGREDIENTS AND APPEARANCE
morphine sulfate tablet, film coated, extended release
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:59011-260 Route of Administration ORAL DEA Schedule CII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength morphine sulfate (UNII: X3P646A2J0) (morphine - UNII:76I7G6D29C) morphine sulfate 15 mg Inactive Ingredients Ingredient Name Strength cetostearyl alcohol (UNII: 2DMT128M1S) hydroxyethyl cellulose (140 MPA.S at 5%) (UNII: 8136Y38GY5) hypromelloses (UNII: 3NXW29V3WO) magnesium stearate (UNII: 70097M6I30) polyethylene glycols (UNII: 3WJQ0SDW1A) talc (UNII: 7SEV7J4R1U) titanium dioxide (UNII: 15FIX9V2JP) FD&C Blue No. 2 (UNII: L06K8R7DQK) Lactose (UNII: J2B2A4N98G) Polysorbate 80 (UNII: 6OZP39ZG8H) Product Characteristics Color BLUE Score no score Shape ROUND Size 7mm Flavor Imprint Code PF;M15 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59011-260-10 100 in 1 BOTTLE, PLASTIC Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA019516 07/01/1987 MS CONTIN
morphine sulfate tablet, film coated, extended release
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:59011-261 Route of Administration ORAL DEA Schedule CII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength morphine sulfate (UNII: X3P646A2J0) (morphine - UNII:76I7G6D29C) morphine sulfate 30 mg Inactive Ingredients Ingredient Name Strength cetostearyl alcohol (UNII: 2DMT128M1S) hydroxyethyl cellulose (140 MPA.S at 5%) (UNII: 8136Y38GY5) hypromelloses (UNII: 3NXW29V3WO) magnesium stearate (UNII: 70097M6I30) polyethylene glycols (UNII: 3WJQ0SDW1A) talc (UNII: 7SEV7J4R1U) titanium dioxide (UNII: 15FIX9V2JP) D&C Red No. 7 (UNII: ECW0LZ41X8) FD&C Blue No. 1 (UNII: H3R47K3TBD) Lactose (UNII: J2B2A4N98G) Polysorbate 80 (UNII: 6OZP39ZG8H) Product Characteristics Color PURPLE (Lavender) Score no score Shape ROUND Size 7mm Flavor Imprint Code PF;M30 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59011-261-25 100 in 1 BOTTLE, PLASTIC 2 NDC:59011-261-05 500 in 1 BOTTLE, PLASTIC Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA019516 07/01/1987 MS CONTIN
morphine sulfate tablet, film coated, extended release
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:59011-262 Route of Administration ORAL DEA Schedule CII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength morphine sulfate (UNII: X3P646A2J0) (morphine - UNII:76I7G6D29C) morphine sulfate 60 mg Inactive Ingredients Ingredient Name Strength cetostearyl alcohol (UNII: 2DMT128M1S) hydroxyethyl cellulose (140 MPA.S at 5%) (UNII: 8136Y38GY5) hypromelloses (UNII: 3NXW29V3WO) magnesium stearate (UNII: 70097M6I30) polyethylene glycols (UNII: 3WJQ0SDW1A) talc (UNII: 7SEV7J4R1U) titanium dioxide (UNII: 15FIX9V2JP) D&C Red No. 30 (UNII: 2S42T2808B) D&C Yellow No. 10 (UNII: 35SW5USQ3G) hydroxypropyl cellulose (UNII: RFW2ET671P) lactose (UNII: J2B2A4N98G) Product Characteristics Color ORANGE Score no score Shape ROUND Size 7mm Flavor Imprint Code PF;M60 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59011-262-10 100 in 1 BOTTLE, PLASTIC 2 NDC:59011-262-05 500 in 1 BOTTLE, PLASTIC Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA019516 07/01/1987 MS CONTIN
morphine sulfate tablet, film coated, extended release
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:59011-263 Route of Administration ORAL DEA Schedule CII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength morphine sulfate (UNII: X3P646A2J0) (morphine - UNII:76I7G6D29C) morphine sulfate 100 mg Inactive Ingredients Ingredient Name Strength cetostearyl alcohol (UNII: 2DMT128M1S) hydroxyethyl cellulose (140 MPA.S at 5%) (UNII: 8136Y38GY5) hypromelloses (UNII: 3NXW29V3WO) magnesium stearate (UNII: 70097M6I30) polyethylene glycols (UNII: 3WJQ0SDW1A) talc (UNII: 7SEV7J4R1U) titanium dioxide (UNII: 15FIX9V2JP) Ferrosoferric oxide (UNII: XM0M87F357) Product Characteristics Color GRAY Score no score Shape ROUND Size 7mm Flavor Imprint Code PF;100 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59011-263-10 100 in 1 BOTTLE, PLASTIC 2 NDC:59011-263-05 500 in 1 BOTTLE, PLASTIC Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA019516 07/01/1987 MS CONTIN
morphine sulfate tablet, film coated, extended release
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:59011-264 Route of Administration ORAL DEA Schedule CII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength morphine sulfate (UNII: X3P646A2J0) (morphine - UNII:76I7G6D29C) morphine sulfate 200 mg Inactive Ingredients Ingredient Name Strength cetostearyl alcohol (UNII: 2DMT128M1S) hydroxyethyl cellulose (140 MPA.S at 5%) (UNII: 8136Y38GY5) hypromelloses (UNII: 3NXW29V3WO) magnesium stearate (UNII: 70097M6I30) polyethylene glycols (UNII: 3WJQ0SDW1A) talc (UNII: 7SEV7J4R1U) titanium dioxide (UNII: 15FIX9V2JP) D&C Yellow No. 10 (UNII: 35SW5USQ3G) FD&C Blue No. 1 (UNII: H3R47K3TBD) hydroxypropyl cellulose (UNII: RFW2ET671P) Product Characteristics Color GREEN Score no score Shape CAPSULE Size 14mm Flavor Imprint Code PF;M200 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59011-264-10 100 in 1 BOTTLE, PLASTIC Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA019516 07/01/1987 Labeler - Purdue Pharma LP (932323652) Registrant - Purdue Pharma LP (932323652) Establishment Name Address ID/FEI Business Operations The PF Laboratories Inc. 098258726 MANUFACTURE(59011-263, 59011-264, 59011-261, 59011-262) Establishment Name Address ID/FEI Business Operations Purdue Pharmaceuticals L.P. 132080875 MANUFACTURE(59011-263, 59011-264, 59011-261, 59011-262)