WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; and NEONATAL OPIOID WITHDRAWAL SYNDROME Addiction, Abuse, and Misuse MS CONTIN® exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing MS CONTIN, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of MS CONTIN. Monitor for respiratory depression, especially during initiation of MS CONTIN or following a dose increase. Instruct patients to swallow MS CONTIN tablets whole; crushing, chewing, or dissolving MS CONTIN tablets can cause rapid release and absorption of a potentially fatal dose of morphine [see Warnings and Precautions (5.2)]. Accidental Ingestion Accidental ingestion of even one dose of MS CONTIN, especially by children, can result in a fatal overdose of morphine [see Warnings and Precautions (5.2)]. Neonatal Opioid Withdrawal Syndrome Prolonged use of MS CONTIN during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. 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 [see Warnings and Precautions (5.3)]. 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)
|Boxed Warning ||04/2014 |
|Indications and Usage (1) ||04/2014 |
|Dosage and Administration (2) ||04/2014 |
|Warnings and Precautions (5) ||04/2014 |
1 INDICATIONS AND USAGE MS CONTIN is 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. 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. MS CONTIN is not indicated as an as-needed (prn) analgesic. 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)
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 *100 mg and 200 mg tablets are for use in opioid-tolerant patients only Extended-release tablets: 15 mg, 30 mg, 60 mg, 100 mg, 200 mg (3)
4 CONTRAINDICATIONS MS CONTIN is contraindicated in patients with: 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)] Significant respiratory depression (4) Acute or severe bronchial asthma (4) Known or suspected paralytic ileus (4) Hypersensitivity to morphine (4)
5 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) 5.1 Addiction, Abuse, and Misuse MS CONTIN contains morphine, a Schedule II controlled substance. As an opioid, MS CONTIN exposes its users to the risks of addiction, abuse, and misuse. As modified-release products such as MS CONTIN deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of morphine present [see Drug Abuse and Dependence (9)]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed MS CONTIN and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing MS CONTIN, and monitor all patients receiving opioids for development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as MS CONTIN, but use in such patients necessitates intensive counseling about the risks of proper use of MS CONTIN along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of MS CONTIN by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of morphine and can result in overdose and death [see Overdosage (10)]. Opioid agonists such as MS CONTIN are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing MS CONTIN. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of MS CONTIN, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with MS CONTIN and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of MS CONTIN are essential [see Dosage and Administration (2)]. Overestimating the MS CONTIN dose when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of MS CONTIN, especially by children, can result in respiratory depression and death due to an overdose of morphine. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of MS CONTIN during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. 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. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. 5.4 Interactions with Central Nervous System Depressants Hypotension, and profound sedation, coma or respiratory depression may result if MS CONTIN is used concomitantly with other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of MS CONTIN in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol and/or illicit drugs that cause CNS depression. If the decision to begin MS CONTIN is made, start with the lowest possible dose, 15 mg every 12 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.1)]. 5.5 Use in Elderly, Cachectic, and Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating MS CONTIN and when MS CONTIN is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. 5.6 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with MS CONTIN, as in these patients, even usual therapeutic doses of MS CONTIN may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible. 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. Avoid the use of MS CONTIN in patients with impaired consciousness or coma. 5.9 Use in Patients with Gastrointestinal Conditions MS CONTIN is contraindicated in patients with paralytic ileus. Avoid the use of MS CONTIN in patients with other GI obstruction. 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. 5.11 Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including MS CONTIN. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing MS CONTIN, gradually taper the dose [see Dosage and Administration (2.3)]. Do not abruptly discontinue MS CONTIN. 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 The following serious adverse reactions are described elsewhere in the labeling: 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)] Most common adverse reactions: constipation, nausea, and sedation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Purdue Pharma L.P. at 1-888-726-7535 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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)]. Most Frequently Observed Reactions In clinical trials, the most common adverse reactions with MS CONTIN were constipation, dizziness, sedation, nausea, vomiting, sweating, dysphoria, and euphoric mood. Some of these effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain. Less Frequently Observed Reactions Cardiovascular disorders: tachycardia, bradycardia, palpitations Eye disorders: visual impairment, vision blurred, diplopia, miosis Gastrointestinal disorders: dry mouth, diarrhea, abdominal pain, constipation, dyspepsia General disorders and administration site conditions: chills, feeling abnormal, edema, edema peripheral, weakness Hepatobiliary disorders: biliary colic Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: muscle rigidity, muscle twitching Nervous system disorders: presyncope, syncope, headache, tremor, uncoordinated muscle movements, convulsion, intracranial pressure increased, taste alteration, paresthesia, nystagmus Psychiatric disorders: agitation, mood altered, anxiety, depression, abnormal dreams, hallucination, disorientation, insomnia Renal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effects Reproductive system and breast disorders: reduced libido and/or potency Respiratory, thoracic and mediastinal disorders: laryngospasm Skin and subcutaneous tissue disorders: pruritus, urticaria, rash Vascular disorders: flushing, hypotension, hypertension 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. Anaphylaxis has been reported with ingredients contained in MS CONTIN. Advise patients how to recognize such a reaction and when to seek medical attention.
7 DRUG INTERACTIONS 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) 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. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)]. 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. 7.5 Cimetidine 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. 7.6 Diuretics 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. 7.7 Anticholinergics 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 Pregnancy: Based on animal data, may cause fetal harm. (8.1) Nursing mothers: Morphine has been detected in human milk. Closely monitor infants of nursing women receiving MS CONTIN. (8.3) 8.1 Pregnancy Clinical Considerations 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)]. Teratogenic Effects -Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. MS CONTIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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. Non-Teratogenic Effects 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. Withdrawal signs can occur in breast-feeding infants when maternal administration of morphine is stopped. 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 The safety and effectiveness in pediatric patients below the age of 18 have not been established. 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.