NDA 019516/S-034
`Page 3
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` MS CONTIN®
`
`(morphine sulfate controlled-release) Tablets
`
`
`
`
`
`CII
`
`15 mg 30 mg 60 mg 100 mg* 200 mg*
`
`*100 mg and 200 mg are for use in opioid-tolerant patients only
`
`
`
`
`
`WARNING:
`
`
`MS CONTIN contains morphine sulfate, an opioid agonist and a Schedule II controlled
`substance, with an abuse liability similar to other opioid analgesics.
`
`Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. This
`
`should be considered when prescribing or dispensing MS CONTIN in situations where the
`
`physician or pharmacist is concerned about an increased risk of misuse, abuse, or
`diversion.
`
` MS CONTIN Tablets are a controlled-release oral formulation of morphine sulfate
`
`
` indicated for the management of moderate to severe pain when a continuous, around-the­
`clock opioid analgesic is needed for an extended period of time.
`
`
` MS CONTIN Tablets are NOT intended for use as a prn analgesic.
`
`
`MS CONTIN 100 and 200 mg Tablets ARE FOR USE IN OPIOID-TOLERANT
`
`
`PATIENTS ONLY. These tablet strengths may cause fatal respiratory depression when
`administered to patients not previously exposed to opioids.
`
`
`MS CONTIN TABLETS ARE TO BE SWALLOWED WHOLE AND ARE NOT TO BE
`BROKEN, CHEWED, DISSOLVED, OR CRUSHED. TAKING BROKEN, CHEWED,
`DISSOLVED, OR CRUSHED MS CONTIN TABLETS LEADS TO RAPID RELEASE
`AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF MORPHINE.
`
`
`
`1
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`NDA 019516/S-034
`Page 4
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`
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`DESCRIPTION
`Chemically, morphine sulfate is 7,8-didehydro-4,5α-epoxy-17-methylmorphinan-3,6α-diol
`sulfate (2:1) (salt) pentahydrate and has the following structural formula:
`
`
`
`
`
`
`
`
`MS CONTIN® (morphine sulfate controlled-release) Tablets are opiate analgesics supplied in 15,
`30, 60, 100 and 200 mg tablet strengths. The tablet strengths describe the amount of morphine
`per tablet as the pentahydrated sulfate salt (morphine sulfate, USP). MS CONTIN® Controlled-
`release Tablets 15 mg, 30 mg, 60 mg, 100 mg, and 200 mg contain the following inactive
`
`
` ingredients: cetostearyl alcohol, hydroxyethyl cellulose, hypromellose, magnesium stearate,
` polyethylene glycol, talc and titanium dioxide.
`
`
`
`
`
`MS CONTIN Controlled-release Tablets 15 mg also contains FD&C Blue No. 2, lactose and
`polysorbate 80.
`
`MS CONTIN Controlled-release Tablets 30 mg also contains D&C Red No. 7, FD&C Blue No.
`1, lactose and polysorbate 80.
`
`
`MS CONTIN Controlled-release Tablets 60 mg also contains D&C Red No. 30, D&C Yellow
`No. 10, hydroxypropyl cellulose, and lactose.
`
` MS CONTIN Controlled-release Tablets 100 mg also contains black iron oxide.
`
` MS CONTIN Controlled-release Tablets 200 mg also contains D&C Yellow No. 10, FD&C Blue
`No. 1, and hydroxypropyl cellulose.
`
`
`
`
`
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`2
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`NDA 019516/S-034
`Page 5
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`
` CLINICAL PHARMACOLOGY
`
` Morphine is a pure opioid agonist whose principal therapeutic action is analgesia. Other
`
`members of the class known as opioid agonists include substances such as oxycodone,
`hydromorphone, fentanyl, codeine, and hydrocodone. Pharmacological effects of opioid agonists
`include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis,
`cough suppression, and analgesia. Like all pure opioid agonist analgesics, with increasing doses
`there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics,
`where there is a limit to the analgesic effect with increasing doses. With pure opioid agonist
`
`analgesics, there is no defined maximum dose; the ceiling to analgesic effectiveness is imposed
`
`only by side effects, the more serious which may include somnolence and respiratory depression.
`
`
`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 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.
`
`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.
`
`
`Gastrointestinal Tract and Other Smooth Muscle
`
`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 resulting in constipation. Other
`
`
`opioid induced-effects may include a reduction in gastric, biliary and pancreatic secretions,
`spasm of the sphincter of Oddi, and transient elevations in serum amylase.
`
`
`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.
`
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`NDA 019516/S-034
`Page 6
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`
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`Endocrine System
`Opioids have been shown to have a variety of effects on the secretion of hormones. Opioids
`inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also
`stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and
`glucagons in humans and other species, rats and dogs. Thyroid stimulating hormone (TSH) has
`been shown to be both inhibited and stimulated by opioids.
`
`Immune System
`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.
`
`Pharmacodynamics
`As with all opioids, the minimum effective plasma concentration for analgesia varies widely
`
`among patients, especially among patients who have been previously treated with potent agonist
`
`
`opioids. As a result, patients must be treated with individualized titration of dosage to the
`
`desired effect. The minimum effective analgesic concentration of morphine for any individual
`patient may increase over time due to an increase in pain, the development of new pain
`syndrome and/or the development of analgesic tolerance.
`
`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.
`
`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 significantly
`
`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, MS CONTIN® will have at steady-state, a lower Cmax and
`
`a higher Cmin than conventional morphine.
`
`
`Concentration - Adverse Experience Relationships
`MS CONTIN® Tablets are associated with typical opioid-related adverse experiences. There is a
`general relationship between increasing morphine plasma concentration and increasing
`
`
`frequency of dose-related opioid adverse experiences such as nausea, vomiting, CNS effects, and
`
`4
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`NDA 019516/S-034
`Page 7
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`
`
` respiratory depression. In opioid-tolerant patients, the situation is altered by the development of
`
`tolerance to opioid-related side effects, and the relationship is not clinically relevant.
`
`As with all opioids, the dose must be individualized (see DOSAGE AND
`ADMINISTRATION), because the effective analgesic dose for some patients will be too high
`
`to be tolerated by other patients.
`
`
`
`PHARMACOKINETICS AND METABOLISM
`
`MS CONTIN is a controlled-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.
`
`
`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 (ka). The
`formulation employed in MS CONTIN has not been shown to affect morphine's oral
`bioavailability, but does decrease its apparent ka. Other basic pharmacokinetic parameters (e.g.,
`volume of distribution [Vd], elimination rate constant [ke], 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 MS CONTIN is 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 (Cmax) and minimum (Cmin) blood levels and the
`times of their occurrence.
`
`
`Absorption
`Following the administration of immediate-release 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 MS CONTIN to normal
`volunteers, however, this extent of absorption occurs, on average, after 1.5 hours.
`
`Food Effects
`The possible 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.
`
`5
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`NDA 019516/S-034
`Page 8
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`
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`Distribution
` The volume of distribution (Vd) for morphine is approximately 4 liters per kilogram. 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.
`
`Metabolism
`Although a small fraction (less than 5%) of morphine is demethylated, for all practical purposes,
`virtually all morphine is converted to the 3- and 6- (M3G and M6G) glucuronide metabolites.
`
`
`M3G is present in the highest plasma concentration following oral administration and possesses
`no significant analgesic activity. M6G, while possessing analgesic activity, is present in the
`
`
`
`plasma in low concentrations.
`
`Excretion
`The elimination of morphine occurs primarily as renal excretion of morphine-3- glucuronide and
`
`its terminal elimination half-life after intravenous administration is normally 2 to 4 hours. 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. As with any drug, caution should be taken to guard
`against unanticipated accumulation if renal and/or hepatic function is seriously impaired.
`
`Special Populations
`
`Renal Impairment
`Morphine pharmacokinetics are altered in patients with renal failure. Clearance is decreased and
`the metabolites, M3G and M6G, may accumulate to much higher plasma levels in these patients
`
`
`as compared to patients with normal renal function.
`
`
`Drug-Drug Interactions
`
`Known drug-drug interactions involving morphine are pharmacodynamic not pharmacokinetic.
`
`INDICATIONS AND USAGE
`
`
`MS CONTIN Tablets are a controlled-release oral formulation of morphine sulfate indicated for
`
`the management of moderate to severe pain when a continuous, around-the-clock opioid
`analgesic is needed for an extended period of time.
`
`
`
`MS CONTIN Tablets are NOT intended for use as a prn analgesic.
`
`The MS CONTIN 100 and 200 mg tablet strengths are high dose, controlled-release, oral
`morphine formulations indicated for the relief of pain in opioid-tolerant patients only.
`
`
`
`6
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`NDA 019516/S-034
`Page 9
`
`
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` MS CONTIN is not indicated for pain in the immediate postoperative period (the first 12-24
`
`
`
` hours following surgery) for patients not previously taking the drug, because its safety in this
`setting has not been established.
`
`MS CONTIN is not indicated for pain in the postoperative period if the pain is mild, or not
`expected to persist for an extended period of time.
`
`
`
`MS CONTIN is only indicated for postoperative use if the patient is already receiving the drug
`
`
`prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for
`
`an extended period of time. Physicians should individualize treatment, moving from parenteral
`to oral analgesics as appropriate. (See American Pain Society guidelines.)
`
`
`
`CONTRAINDICATIONS
`
`MS CONTIN is contraindicated in patients with known hypersensitivity to morphine or in any
`
`situation where opioids are contraindicated. This includes patients with respiratory depression
`(in the absence of resuscitative equipment or in unmonitored settings), and in patients with acute
`
`or severe bronchial asthma or hypercarbia.
`
`MS CONTIN is contraindicated in any patient who has or is suspected of having a paralytic
`
`ileus.
`
`WARNINGS (See also: CLINICAL PHARMACOLOGY)
`
`
`MS CONTIN (MORPHINE SULFATE CONTROLLED-RELEASE) TABLETS ARE TO
`BE SWALLOWED WHOLE AND ARE NOT TO BE BROKEN, CHEWED,
`DISSOLVED, OR CRUSHED. TAKING BROKEN, CHEWED, DISSOLVED, OR
`CRUSHED MS CONTIN® TABLETS LEADS TO RAPID RELEASE AND
`ABSORPTION OF A POTENTIALLY FATAL DOSE OF MORPHINE.
`
`
`
`MS CONTIN 100 AND 200 mg Tablets ARE FOR USE IN OPIOID-TOLERANT
`PATIENTS ONLY. These tablet strengths may cause fatal respiratory depression when
`
`
`administered to patients not previously exposed to opioids.
`
`
`MS CONTIN 100 AND 200 mg Tablets are for use only in opioid-tolerant patients
`requiring daily morphine equivalent dosages of 200 mg or more for the 100 mg tablet and
`400 mg or more for the 200 mg tablet. Care should be taken in the prescribing of these
`
`
`tablet strengths. Patients should be instructed against use by individuals other than the
`patient for whom it was prescribed, as such inappropriate use may have severe medical
`
`
`consequences, including death.
`
`Misuse, Abuse and Diversion of Opioids
`
` Morphine is an opioid agonist and a Schedule II controlled substance. Such drugs are sought by
`drug abusers and people with addiction disorders and are subject to criminal diversion.
`
`
`
`
`7
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`NDA 019516/S-034
`Page 10
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`
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`Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. This should
`
` be considered when prescribing or dispensing MS CONTIN® in situations where the physician or
`pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
`
` MS CONTIN can be abused by crushing, chewing, snorting or injecting the dissolved product.
`
`
`These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to
`the abuser that could result in overdose and death (see WARNINGS: Drug Abuse and
`
`Addiction).
`
`
`
`
`Concerns about abuse, addiction, and diversion should not prevent the proper management of
`pain.
`
`Healthcare professionals should contact their State Professional Licensing Board, or State
`
`Controlled Substances Authority for information on how to prevent and detect abuse or diversion
`of this product.
`
`Interactions with Alcohol and Drugs of Abuse
`Morphine may be expected to have additive effects when used in conjunction with alcohol, other
`opioids, or illicit drugs that cause central nervous system depression because respiratory
`
`depression, hypotension, and profound sedation or coma may result. (See WARNINGS:
`
`Interactions with other CNS Depressants.)
`
`Drug Abuse and Addiction
`MS CONTIN is a mu-agonist opioid with an abuse liability similar to other opioid agonists
`and is a Schedule II controlled substance. MS CONTIN and other opioids used in
`
`analgesia, can be abused and are subject to criminal diversion.
`
`
`Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued
`
`use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi­
`
`
`disciplinary approach, but relapse is common.
`
`
`“Drug-seeking” behavior is very common in 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 “loss” of prescriptions, tampering with prescriptions
` and reluctance to provide prior medical records or contact information for other treating
`
`
` physician(s). “Doctor shopping” 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 and is characterized by misuse for non-medical purposes, often in
`
`combination with other psychoactive substances. MS CONTIN®, like other opioids, has been
`diverted for non-medical use. Careful record keeping of prescribing information, including
`
`
`quantity, frequency, and renewal requests is strongly advised.
`
`
`
`8
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`NDA 019516/S-034
`Page 11
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`
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` Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy,
`
`
`
` and proper dispensing and storage are appropriate measures that help to limit abuse of opioid
`drugs.
`
`MS CONTIN is intended for oral use only as an intact tablet. Abuse of the crushed tablet
`poses a hazard of overdose and death. This risk is increased with concurrent abuse of
`
`alcohol and other substances. Due to the presence of talc as one of the excipients in tablets,
`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.
`
`
`Respiratory Depression
`Respiratory depression is the chief hazard of all morphine preparations. Respiratory depression
`
`occurs most frequently in the elderly and debilitated patients as well as in those suffering from
`
`conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may
`
`dangerously decrease pulmonary ventilation.
`
`Morphine should be used with extreme caution in patients with chronic obstructive pulmonary
`
`disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve,
`
`hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual
`therapeutic doses of morphine may decrease respiratory drive while simultaneously increasing
`
`airway resistance to the point of apnea.
`
`
`Head Injury and Increased Intracranial Pressure
`The respiratory depressant effects of morphine with carbon dioxide retention and secondary
`elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head
`injury, other intracranial lesions, or pre-existing increase in intracranial pressure. Morphine
`produces effects which may obscure neurologic signs of further increases in pressure in patients
`with head injuries.
`
`
`
`Hypotensive Effect
`
`MS CONTIN®, like all opioid analgesics, may cause severe hypotension in an individual whose
`ability to maintain his blood pressure has already been compromised by a depleted blood
`volume, or a concurrent administration of drugs such as phenothiazines or general anesthetics.
`
`MS CONTIN may produce orthostatic hypotension in ambulatory patients.
`
`MS CONTIN, like all opioid analgesics, should be administered with caution to patients in
`circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and
`blood pressure.
`
`
`
`9
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`NDA 019516/S-034
`Page 12
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`
` Interactions with other CNS Depressants
`
`MS CONTIN, like all opioid analgesics, should be used with great caution and in reduced dosage
`in patients who are concurrently receiving other central nervous system depressants including
`
`sedatives or hypnotics, general anesthetics, phenothiazines, other tranquilizers, and alcohol
`because respiratory depression, hypotension, and profound sedation or coma may result.
`
`
`Other
`Although extremely rare, cases of anaphylaxis have been reported.
`
`PRECAUTIONS (See also: CLINICAL PHARMACOLOGY)
`
`Special precautions regarding MS CONTIN 100 mg and 200 mg Tablets
`
`MS CONTIN 100 mg and 200 mg Tablets are for use only in opioid-tolerant patients
`requiring daily morphine equivalent dosages of 200 or more for the 100 mg tablet and 400
`
`mg or more for the 200 mg tablet. Care should be taken in its prescription and patients
`
`
`should be instructed against use by individuals other than the patient for whom it was
`prescribed, as this may have severe medical consequences for that individual.
`
`
`General
`MS CONTIN Tablets are a controlled-release oral formulation of morphine sulfate indicated for
`
`
`the management of moderate to severe pain when a continuous, around-the-clock analgesic is
`needed for an extended period of time. MS CONTIN does not release morphine continuously
`
`over the course of a dosing interval. The administration of single doses of MS CONTIN 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. (See DOSAGE AND
`
`ADMINISTRATION.)
`
`Selection of patients for treatment with MS CONTIN® should be governed by the same
`
`principles that apply to the use of morphine or other potent opioid analgesics. Specifically, the
`increased risks associated with its use in the following populations should be considered: the
`elderly or debilitated and those with severe impairment of hepatic, pulmonary, or renal function;
`myxedema or hypothyroidism; adrenocortical insufficiency (e.g., Addison's Disease); CNS
`
`
`depression or coma; toxic psychosis; prostatic hypertrophy or urethral stricture; acute
`
`alcoholism; delirium tremens; kyphoscoliosis or inability to swallow.
`
`The administration of morphine, like all opioid analgesics, may obscure the diagnosis or clinical
`course in patients with acute abdominal conditions.
`
`
`
`Morphine may aggravate convulsions in patients with convulsive disorders, and all opioids may
`
`induce or aggravate seizures in some clinical settings.
`
`10
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`NDA 019516/S-034
`Page 13
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`
`
` Interactions with Mixed Agonist/Antagonist Opioid Analgesics
`
`Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should be
`administered with caution to a patient who has received or is receiving a course of therapy with a
`pure opioid agonist analgesic such as morphine sulfate. In this situation, mixed
`
`agonist/antagonist analgesics may reduce the analgesic effect of morphine sulfate and/or may
`
`
`
`precipitate withdrawal symptoms in these patients.
`
`Use in Pancreatic/Biliary Tract Disease
`Morphine should be used with caution in patients about to undergo surgery of the biliary tract
`since it may cause spasm of the sphincter of Oddi. Similarly, morphine should be used with
`
`caution in patients with acute pancreatitis secondary to biliary tract disease.
`
`
`Tolerance
`
`Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a
`diminution of one or more of the drug’s effects over time. Tolerance may occur to both the
`
`desired and undesired effects of drugs, and may develop at different rates for different effects.
`
`Physical Dependence
`Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal
`
`syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level
`of the drug, and/or administration of an antagonist.
`
`
`The opioid abstinence or withdrawal syndrome is characterized by some or all of the following:
`restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia,
`
`
`mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia,
`
`nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
`
`
`
`In general, opioids should not be abruptly discontinued (see DOSAGE AND
`
`
`ADMINISTRATION: Cessation of Therapy).
`
`
`Information for Patients/Caregivers
`If clinically advisable, patients receiving MS CONTIN® or their caregivers should be given the
`following information by the physician, nurse, or pharmacist:
`
`
`
`1. Patients should be advised that MS CONTIN Tablets contain morphine and should be taken
`only as directed.
`
`
`
`
`2. Patients should be advised that MS CONTIN Tablets were designed to work properly only if
`
`swallowed whole. MS CONTIN Tablets will release all of their morphine if split, divided,
`
`broken, chewed, dissolved, or crushed resulting in the risk of a fatal overdose.
`
`
`
`3. Patients should be advised not to change the dose of MS CONTIN without consulting their
`physician.
`
`11
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`NDA 019516/S-034
`Page 14
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`4. Patients should be advised to report episodes of breakthrough pain and adverse experiences
`
` occurring during therapy. Individualization of dosage is essential to make optimal use of this
`medication.
`
`
`5.
`
`
`
`
`6.
`
`
`
` MS CONTIN may impair mental and/or physical ability required for the performance of potentially hazardous
`tasks (e.g., driving, operating machinery). Patients started on MS CONTIN or whose dose has been changed
`
`should refrain from dangerous activity until it is established that they are not adversely affected.
`
` MS CONTIN should not be taken with alcohol or other CNS depressants (sleep aids, tranquilizers) except by the
`
`
`orders of the prescribing physician because dangerous additive effects may occur resulting in serious injury or
`
`death.
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`7. Women of childbearing potential who become or are planning to become pregnant should be advised to consult
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`their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their
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`unborn child.
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`8.
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` Patients should be advised that if they have been receiving treatment with MS CONTIN for more than a few
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`weeks and cessation of therapy is indicated, it may be appropriate to taper the MS CONTIN dose, rather than
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`abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a
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`dose schedule to accomplish a gradual discontinuation of the medication.
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`9.
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` MS CONTIN 100 mg and 200 mg Tablets are for use only in opioid-tolerant patients requiring daily morphine
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`equivalent dosages of 200 mg or more for the 100 mg tablet and 400 mg or more for the 200 mg tablet. Special
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`care must be taken to avoid accidental ingestion or the use by individuals (including children) other than the
`patient for whom it was originally prescribed, as such unsupervised use may have severe, even fatal,
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`consequences.
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`10. Patients should be advised that MS CONTIN® is a potential drug of abuse. They should
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`protect it from theft, and it should never be given to anyone other than the individual for
`whom it was prescribed.
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`11. Patients should be advised that they may pass empty matrix "ghosts" (tablets) via colostomy
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`or in the stool, and that this is of no concern since the active medication has already been
`absorbed.
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`12. Patients should be instructed to keep MS CONTIN in a secure place out of the reach of
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`children. When MS CONTIN is no longer needed, the unused tablets should be destroyed by
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`flushing down the toilet.
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`Use in Drug and Alcohol Addiction
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`MS CONTIN is an opioid with no approved use in the management of addiction disorders. Its
`proper usage in individuals with drug or alcohol dependence, either active or in remission, is for
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`the management of pain requiring opioid analgesia.
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`12
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`NDA 019516/S-034
`Page 15
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`Drug Interactions (See also: WARNINGS)
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` Use with CNS Depressants
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`The concomitant use of other central nervous system depressants including sedatives or
`hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol may produce additive
`depressant effects. Respiratory depression, hypotension, and profound sedation or coma may
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`occur. When such combined therapy is contemplated, the dose of one or both agents should be
`reduced. Opioid analgesics, including MS CONTIN, may enhance the neuromuscular blocking
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`action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
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`Carcinogenicity/Mutagenicity/Impairment of Fertility
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`Studies of morphine sulfate in animals to evaluate the drug's carcinogenic and mutagenic
`potential or the effect on fertility have not been conducted.
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`Pregnancy
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`Teratogenic Effects - CATEGORY C
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`Adequate animal studies on reproduction have not been performed to determine whether
`morphine affects fertility in males or females. There are no well-controlled studies in women,
`but marketing experience does not include any evidence of adverse effects on the fetus following
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`routine (short-term) clinical use of morphine sulfate products. Although there is no clearly
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`defined risk, such experience cannot exclude the possibility of infrequent or subtle damage to the
`human fetus.
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`MS CONTIN® should be used in pregnant women only if the need for strong opioid analgesia
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`clearly outweighs the potential risk to the fetus. (See also: PRECAUTIONS: Labor and
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`Delivery, and WARNINGS: DRUG ABUSE AND ADDICTION.)
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`Labor and Delivery
`MS CONTIN is not recommended for use in women during and immediately prior to labor.
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`Occasionally, opioid analgesics may prolong labor through actions which 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.
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`Neonates whose mothers received opioid analgesics during labor should be observed closely for
`signs of respiratory depression. A specific narcotic antagonist, naloxone, should be av