Morphine Sulfate Tablet, Film Coated, Extended Release
FDA Label NDC 43386-541

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Addiction, Abuse, and Misuse

Morphine sulfate extended-release tablets 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 morphine sulfate extended-release tablets, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of morphine sulfate extended-release tablets. Monitor for respiratory depression, especially during initiation of morphine sulfate extended-release tablets or following a dose increase. Instruct patients to swallow morphine sulfate extended-release tablets whole; crushing, chewing, or dissolving morphine sulfate extended-release 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 morphine sulfate extended-release tablets, especially by children, can result in a fatal overdose of morphine [see Warnings and Precautions (5.2)].

Neonatal Opioid Withdrawal Syndrome

Prolonged use of morphine sulfate extended-release tablets 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)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.4), Drug Interactions (7)].

• Reserve concomitant prescribing of morphine sulfate extended-release tablets Injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

Morphine sulfate extended-release tablets 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 [see Warnings and Precautions (5.1)] , reserve morphine sulfate extended-release tablets 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.
• Morphine sulfate extended-release tablets is not indicated as an as-needed (prn) analgesic.
•   Morphine Sulfate Extended-Release Tablets 15 mg

Round, blue-colored, film-coated tablets, debossed "n 15" on one side and plain on the other side.

• Morphine Sulfate Extended-Release Tablets 30 mg

Round, lavender-colored, film-coated tablets, debossed "n 30" on one side and plain on the other side.

• Morphine Sulfate Extended-Release Tablets 60 mg

Round, orange-colored, film-coated tablets, debossed "n 60" on one side and plain on the other side.

• Morphine Sulfate Extended-Release Tablets 100 mg

Round, gray-colored, film-coated tablets, debossed "N 100" on one side and plain on the other side.

• Morphine Sulfate Extended-Release Tablets 200 mg

Capsule-shaped, green-colored, film-coated tablets, debossed "n 200" on one side and plain on the other side.

Morphine sulfate extended-release tablets are contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.2)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.5)]
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.6), Drug Interactions (7)] .
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.10)]
• Hypersensitivity (e.g., anaphylaxis) to morphine [see Adverse Reactions (6.2)]

The following serious adverse reactions are described, or described in greater detail, in other sections:

• 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 Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.4)]
• Adrenal Insufficiency [see Warnings and Precautions (5.7)]
• Severe Hypotension [see Warnings and Precautions (5.8)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.10)]
• Seizures [see Warnings and Precautions (5.11)]
• Withdrawal [see Warnings and Precautions (5.12)]

Morphine sulfate extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Morphine sulfate extended-release tablets100 mg and 200 mg capsules, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, are only for use in patients in whom tolerance to an opioid of comparable potency has been established.

Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone daily, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].
• Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with morphine sulfate extended-release tablets and adjust the dosage accordingly [see Warnings and Precautions (5.2)].

Instruct patients to swallow morphine sulfate extended-release tablets whole [see Patient Counseling Information (17)]. Crushing, chewing, or dissolving morphine sulfate extended-release tablets will result in uncontrolled delivery of morphine and can lead to overdose or death [see Warnings and Precautions (5.1)].

Morphine sulfate extended-release tablets is administered orally once every 8 or 12 hours.

Use of morphine sulfate extended-release tablets as the First Opioid Analgesic (opioid-naïve patients)

Initiate treatment with morphine sulfate extended-release tablets with 15 mg tablets orally every 8 or 12 hours.

Use of morphine sulfate extended-release tablets in Patients who are not Opioid Tolerant (opioid non-tolerant patients)

The starting dose for patients who are not opioid tolerant is morphine sulfate extended-release tablets15 mg orally every 12 hours.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.

Conversion from Other Oral Morphine to Morphine sulfate extended-release tablets

Patients receiving other oral morphine formulations may be converted to morphine sulfate extended-release tablets by administering one-half of the patient's 24-hour requirement as morphine sulfate extended-release tablets on an every-12-hour schedule or by administering one-third of the patient's daily requirement as morphine sulfate extended-release tablets on an every-8-hour schedule.

Conversion from Other Opioids to Morphine sulfate extended-release tablets

Discontinue all other around-the-clock opioid drugs when morphine sulfate extended-release tablets therapy is initiated.

There are no established conversion ratios for conversion from other opioids to morphine sulfate extended-release tablets defined by clinical trials.  Initiate dosing using morphine sulfate extended-release tablets 15 mg orally every 8 to 12 hours.

It is safer to underestimate a patient's 24-hour oral morphine dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral morphine dosage and manage an adverse reaction due to an overdose. While useful tables of opioid equivalents are readily available, there is inter-patient variability in the potency of opioid drugs and opioid formulations. Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to morphine sulfate extended-release tablets.

Conversion from Parenteral Morphine or Other Opioids (Parenteral or Oral) to Morphine sulfate extended-release tablets

When converting from parenteral morphine or other non-morphine opioids (parenteral or oral) to Morphine sulfate extended-release tablets, consider the following general points:

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 Ratios: 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.

Conversion from Methadone to Morphine sulfate extended-release tablets

Close monitoring is of particular importance when converting methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

Individually titrate morphine sulfate extended-release tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving morphine sulfate extended-release tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of morphine sulfate extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the morphine sulfate extended-release tablets dosage. Because steady-state plasma concentrations are approximated in 1 day, morphine sulfate extended-release tablets dosage adjustments may be done every 1 to 2 days.

If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

If the patient is currently taking a central nervous system (CNS) depressant and the decision is made to begin morphine sulfate extended-release tablets, start with the lowest possible dose, 15 mg every 12 hours, monitor patients for signs of respiratory depression, sedation, and hypotension, and consider using a lower dosage of the concomitant CNS depressant [see Warnings and Precautions (5.4), Drug Interactions (7)].

When a patient no longer requires therapy with morphine sulfate extended-release tablets, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue morphine sulfate extended-release tablets [see Warnings and Precautions (5.12), Drug Abuse and Dependence (9.3)].

Morphine sulfate extended-release tablets contains morphine, a Schedule II controlled substance. As an opioid, morphine sulfate extended-release tablets exposes its users to the risks of addiction, abuse, and misuse. Because extended-release products such as morphine sulfate extended-release tablets 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 morphine sulfate extended-release tablets. 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 morphine sulfate extended-release tablets, and monitor all patients receiving morphine sulfate extended-release tablets for development of these behaviors and 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 opioids such as morphine sulfate extended-release tablets, but use in such patients necessitates intensive counseling about the risks of proper use of morphine sulfate extended-release tablets along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of morphine sulfate extended-release tablets 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)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing morphine sulfate extended-release tablets. 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.

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, 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 morphine sulfate extended-release tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression especially within the first 24-72 hours of initiating therapy and following dosage increases of with morphine sulfate extended-release tablets.

To reduce the risk of respiratory depression, proper dosing and titration of morphine sulfate extended-release tablets are essential [see Dosage and Administration (2)]. Overestimating the morphine sulfate extended-release tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of morphine sulfate extended-release tablets, especially by children, can result in respiratory depression and death due to an overdose of morphine.

Prolonged use of morphine sulfate extended-release tablets during pregnancy can result in withdrawal 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. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of morphine sulfate extended-release tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when morphine sulfate extended-release tablets is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7), Patient Counseling Information (17)].

The use of morphine sulfate extended-release tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: Morphine sulfate extended-release tablets-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of morphine sulfate extended-release tablets [see Warnings and Precautions (5.2)].

Elderly, Cachectic, or 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 [see Warnings and Precautions (5.2)].

Monitor such patients closely, particularly when initiating and titrating morphine sulfate extended-release tablets and when morphine sulfate extended-release tablets is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Morphine sulfate extended-release tablets should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Morphine sulfate extended-release tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is 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)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of morphine sulfate extended-release tablets. In patients with circulatory shock, morphine sulfate extended-release tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of morphine sulfate extended-release tablets in patients with circulatory shock.

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), morphine sulfate extended-release tablets may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with morphine sulfate extended-release tablets.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of morphine sulfate extended-release tablets in patients with impaired consciousness or coma.

Morphine sulfate extended-release tablets is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The morphine in morphine sulfate extended-release tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

The morphine in morphine sulfate extended-release tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during morphine sulfate extended-release tablets therapy.

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including morphine sulfate extended-release tablets.  In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)].

When discontinuing morphine sulfate extended-release tablets, gradually taper the dosage [see Dosage and Administration (2.4)]. Do not abruptly discontinue morphine sulfate extended-release tablets [see Drug Abuse and Dependence (9.3)].

Morphine sulfate extended-release tablets 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 morphine sulfate extended-release tablets and know how they will react to the medication [see Patient Counseling Information (17)].

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.

Morphine sulfate extended-release tablets 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 morphine sulfate extended-release tablets 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

The following adverse reactions have been identified during post-approval use of morphine sulfate extended-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in morphine sulfate extended-release tablets

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal withdrawal syndrome [see Warnings and Precautions (5.3)]. There are no available data with morphine sulfate extended-release tablets in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see Human Data]. In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse. Administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3-4 times the HDD; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD [see Animal Data]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

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. 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. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)].

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate.  Morphine sulfate extended-release tablets is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including morphine sulfate extended-release tablets, can 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 dilation, which tends to shorten labor.  Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data

The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design.

Animal Data

Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (HDD).

Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35-322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous

(SC) injection of morphine sulfate to pregnant mice (100-500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD).  No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear.

Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity.

An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10-50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated.

In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social- interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater.

Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD).

Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), 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 at 20 mg/kg/day (3.2 times the HDD).  Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre- gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).

Risk Summary

Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with extended –release morphine, including morphine sulfate extended-release tablets. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with morphine sulfate extended-release tablets.

Clinical Considerations

Monitor infants exposed to morphine sulfate extended-release tablets through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2)].

In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [See Nonclinical Toxicology (13)].

The safety and effectiveness in pediatric patients below the age of 18 have not been established.

The pharmacokinetics of morphine sulfate extended-release tablets have not been studied in elderly patients. Clinical studies of morphine sulfate extended-release tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general, use caution when selecting a dosage for an elderly patient, 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.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of morphine sulfate extended-release tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.5)].

Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than usual dosage of morphine sulfate extended-release tablets and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than usual dosage of morphine sulfate extended-release tablets and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Morphine sulfate extended-release tablets contains morphine, a Schedule II controlled substance.

Morphine sulfate extended-release tablets contains morphine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and tapentadol. Morphine sulfate extended-release tablets can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription 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 addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: 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 in persons with substance use disorders. 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 healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction.

Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers 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.

Morphine sulfate extended-release tablets, 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 and federal 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 limit abuse of opioid drugs.

Risks Specific to Abuse of Morphine sulfate extended-release tablets

Morphine sulfate extended-release tablets is for oral use only. Abuse of morphine sulfate extended-release tablets poses a risk of overdose and death. This risk is increased with concurrent abuse of morphine sulfate extended-release tablets with alcohol and other central nervous system depressants. Taking cut, broken, chewed, crushed, or dissolved morphine sulfate extended-release tablets enhances drug release and increases the risk of overdose and death.

Due to the presence of talc as one of the excipients in Morphine sulfate extended-release tablets, parenteral abuse can be expected to result in local tissue necrosis, infection, pulmonary granulomas, embolism and death, 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 dosage 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 (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Morphine sulfate extended-release tablets should not be abruptly discontinued [see Dosage and Administration (2.5)]. If morphine sulfate extended-release tablets is abruptly discontinued in a physically-dependent patient, withdrawal 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)].

Clinical Presentation

Acute overdosage with morphine sulfate extended-release tablets can be 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, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Treatment of Overdose

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 and 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. For clinically significant respiratory or circulatory depression secondary to morphine overdose, administer and opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose.

Because the duration of reversal would be expected to be less than the duration of action of morphine in morphine sulfate extended-release tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. Morphine sulfate extended-release tablets 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 only brief in nature, administer additional antagonist as directed by the product's prescribing information.

In an individual physically dependent on opioids, administration of the usual dose of the recommended usual dosage 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 initiated with care and by titration with smaller than usual doses of the antagonist.

Morphine sulfate extended-release tablets are for oral use and contains morphine sulfate, an opioid agonist.

Each tablet contains the following inactive ingredients common to all strengths: hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, colloidal silicon dioxide, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.

The tablet strengths describe the amount of morphine per tablet as the pentahydrated sulfate salt (morphine sulfate). The 15 mg tablets also contain: FD &C Blue #2 /Indigo carmine aluminum lake and FD&C Blue #1/Brilliant blue FCF aluminum lake.

The 30 mg tablets also contain: D&C Red # 27/Phloxine aluminum lake and FD&C Blue #.1/Brilliant blue FCF aluminum lake.

The 60 mg tablets also contain: D&C Yellow #10 aluminum lake and FD&C Yellow #6 / Sunset yellow FCF aluminum Lake.

The 100 mg tablets also contain: FD & C Blue # 2/ Indigo carmine aluminum lake, FD & C yellow # 6 /Sunset yellow

FCF aluminum lake and FD & C red # 40/Allura red aluminum lake.

The 200 mg tablets also contain: D&C Yellow #10 aluminum lake and FD&C Blue #1/ Brilliant blue FCF aluminum

lake.

Morphine sulfate is an white to off-white crystalline powder. 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 molecular weight is 758.83 and its structural formula is:

Structure (3251b7fd E1c2 45af B74b 3eecf3495557 01)

Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of morphine is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

CNS Depressant/Alcohol Interaction

Additive pharmacodynamic effects may be expected when morphine sulfate extended-release tablets is used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

Effects on the Central Nervous System

Morphine produces respiratory depression by direct action on brainstem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brainstem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

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 hypoxia in overdose situations.

Effects on the 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 in the small intestine is delayed 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 reduction in biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Morphine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reaction (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)].

Effects on the 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. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration-Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.2)]

Concentration–Adverse Reaction Relationships

There is a relationship between increasing morphine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.2, 2.3)].

Absorption

Morphine sulfate extended-release tablets is an extended-release tablet containing morphine sulfate. Morphine is released from morphine sulfate extended-release tablets 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 morphine sulfate extended-release tablets or an immediate-release formulation. Because of pre-systemic elimination (i.e., metabolism in the gut wall and liver) only about 40% of the administered dose reaches the central compartment.

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

Food Effect

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

Distribution

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

Elimination

Metabolism

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

Excretion

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

Specific Populations

Sex

A sex analysis of pharmacokinetic data from healthy subjects taking morphine sulfate extended-release tablets indicated that morphine concentrations were similar in males and females.

Race/Ethnicity

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

Hepatic Impairment

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

Renal Impairment

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

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of morphine have not been conducted.

Mutagenesis

No formal studies to assess the mutagenic potential of morphine have been conducted.

In the published literature, morphine was found to be mutagenic in vitro increasing DNA fragmentation in human T- cells. Morphine was reported to be mutagenic in the in vivo mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the in vivo clastogenic effects reported with morphine in mice may be related to increases in glucocorticoid levels produced by morphine in this species. In contrast to the above positive findings, in vitro studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in Drosophila.

Impairment of Fertility

No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted. Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. One study in which male rats were administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects including reduction in total pregnancies and higher incidence of pseudopregnancies at 20 mg/kg/day (3.2 times the HDD) were reported.

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

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

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

Morphine sulfate extended-release tablets 15 mg are round, blue-colored, film-coated tablets, debossed "n 15" on one side and plain on the other side. They are supplied as follows:

NDC 43386-540-01 opaque plastic bottles containing 100 tablets

NDC 43386-540-05 opaque plastic bottles containing 500 tablets

Morphine sulfate extended-release tablets 30 mg are round, lavender-colored, film-coated tablets, debossed "n 30" on one side and plain on the other side. They are supplied as follows:

NDC 43386-541-01 opaque plastic bottles containing 100 tablets

NDC 43386-541-05 opaque plastic bottles containing 500 tablets

Morphine sulfate extended-release tablets 60 mg are round, orange-colored, film-coated tablets, debossed "n 60" on one side and plain on the other side.  They are supplied as follows:

NDC 43386-542-01 opaque plastic bottles containing 100 tablets

NDC 43386-542-05 opaque plastic bottles containing 500 tablets

Morphine sulfate extended-release tablets 100 mg are round, gray-colored, film-coated tablets, debossed "N 100" on one side and plain on the other side. They are supplied as follows:

NDC 43386-543-01 opaque plastic bottles containing 100 tablets

NDC 43386-543-05 opaque plastic bottles containing 500 tablets

Morphine sulfate extended-release tablets 200 mg are capsule-shaped, green-colored, film-coated tablets, debossed "n 200" on one side and plain on the other side. They are supplied as follows:

NDC 43386-544-01 opaque plastic bottles containing 100 tablets

NDC 43386-544-05 opaque plastic bottles containing 500 tablets

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

Dispense in a tight, light-resistant container.

CAUTION

DEA FORM REQUIRED

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

Addiction, Abuse, and Misuse

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

Life-Threatening Respiratory Depression

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

Accidental Ingestion

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

Interactions with Benzodiazepines and Other CNS Depressants

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

Serotonin Syndrome

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

MAOI Interaction

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

Adrenal Insufficiency

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

Important Administration Instructions

Instruct patients how to properly take morphine sulfate extended-release tablets, including the following:

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

Hypotension

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

Anaphylaxis

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

Pregnancy

Neonatal Opioid Withdrawal Syndrome

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

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that morphine sulfate extended-release tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Adverse Reactions (6.2)].

Lactation

Advise patients that breastfeeding is not recommended during treatment with morphine sulfate extended-release tablets [see Use in Specific Populations (8.2)]

Infertility

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

Driving or Operating Heavy Machinery

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

Constipation

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

Disposal of Unused Morphine Sulfate Extended-Release tablets

Advise patients to flush the unused tablets down the toilet when morphine sulfate extended-release tablets is no longer needed.

Manufactured by:

Novel Laboratories, Inc.

Somerset, NJ 08873

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, MD 21202

PI5440000204

Rev. 06/2017

Morphine Sulfate (mor' feen  sul' fate) Extended-Release Tablets, CII

Morphine sulfate extended-release tablets are:

• 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 morphine sulfate extended-release tablets:

• Get emergency help right away if you take too much morphine sulfate extended-release tablets (overdose) . When you first start taking morphine sulfate extended-release tablets, 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.
• Taking morphine sulfate extended-release tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
• Never give anyone else your morphine sulfate extended-release tablets. They could die from taking it. Store morphine sulfate extended-release tablets away from children and in a safe place to prevent stealing or abuse. Selling or giving away morphine sulfate extended-release tablets is against the law.

Do not take morphine sulfate extended-release tablets if you have:

• severe asthma, trouble breathing, or other lung problems.
• a bowel blockage or have narrowing of the stomach or intestines.

Before taking morphine sulfate extended-release tablets, 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 morphine sulfate extended-release tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
• breastfeeding. Not recommended during treatment with morphine sulfate extended-release tablets.  It may harm your baby.
• taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking morphine sulfate extended-release tablets with certain other medicines can cause serious side effects.

When taking morphine sulfate extended-release tablets:

• Do not change your dose. Take morphine sulfate extended-release tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest duration.
• 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 morphine sulfate extended-release tablets whole. Do not cut, break, chew, crush, dissolve, snort, or inject morphine sulfate extended-release tablets 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 morphine sulfate extended-release tablets without talking to your healthcare provider.
• After you stop taking morphine sulfate extended-release tablets, flush any unused tablets down the toilet.

While taking morphine sulfate extended-release tablets DO NOT:

• Drive or operate heavy machinery, until you know how morphine sulfate extended-release tablets affects you. Morphine sulfate extended-release tablets 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 morphine sulfate extended-release tablets may cause you to overdose and die.

The possible side effects of morphine sulfate extended-release tablets 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, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

These are not all the possible side effects of morphine sulfate extended-release tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov

Manufactured by: Novel Laboratories, Inc., Somerset, NJ 08873 or call 1- 866-403-7592

This Medication Guide has been approved by the U.S. Food and Drug Administration.

PI5440000204

Rev. 06/2017

Morphine Sulfate Extended-Release Tablets, 15 mg

Container Label

NDC  43386-540-01

15 mg- 100 Ct (3251b7fd E1c2 45af B74b 3eecf3495557 02)

Morphine Sulfate Extended-Release Tablets, 30 mg

Container Label

NDC 43386-541-01

30 (3251b7fd E1c2 45af B74b 3eecf3495557 03)

Morphine Sulfate Extended-Release Tablets, 60 mg

Container Label

NDC  43386-542-01

60 mg (3251b7fd E1c2 45af B74b 3eecf3495557 04)

Morphine Sulfate Extended-Release Tablets, 100 mg

Container Label

NDC 43386-543-01

100 mg (3251b7fd E1c2 45af B74b 3eecf3495557 05)

Morphine Sulfate Extended-Release Tablets, 200 mg

Container Label

NDC  43386-544-01

200 mg (3251b7fd E1c2 45af B74b 3eecf3495557 06)