PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL - 100 mg Tablet Bottle Label

PHARMACIST: Dispense the accompanying
** Medication Guide to each patient.**

NDC 51862-188-01

CII

morphine Sulfate
** Extended-Release**
** Tablets**

100mg

For use in opioid tolerant patients only.

Rx Only
100 Tablets

maynepharma

---

CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

CNS Depressant/Alcohol Interaction

Additive pharmacodynamic effects may be expected when morphine sulfate extended-release tablets are 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, 2.3)]

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, 2.3, 2.4)] .

12.3 Pharmacokinetics

Absorption

Morphine sulfate extended-release tablets are 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 are 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 maxand 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.

---

DOSAGE & ADMINISTRATION SECTION

Highlight: * To be prescribed only by healthcare providers knowledgeable in the use of potent opioids for management of chronic pain. ( 2.1)

• Morphine sulfate extended-release tablets 100 mg, 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. ( 2.1)
• Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg of morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg of oral oxycodone per day, 8 mg of oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. ( 2.1)
• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals ( 2.1).
• Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. ( 2.1)
• Instruct patients to swallow morphine sulfate extended-release tablets intact and not to cut, break, chew, crush, or dissolve Morphine sulfate extended-release tablets to avoid the risk of release and absorption of potential fatal dose of morphine. ( 2.1, 5.1)
• Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with Morphine sulfate extended-release tablets. Consider prescribing naloxone based on the patient's risk factors for overdose ( 2.2, 5.1, 5.3, 5.5).
• For opioid-naïve and opioid non-tolerant patients, initiate with 15 mg tablets orally every 8 to 12 hours. ( 2.3)
• Do not abruptly discontinue Morphine sulfate extended-release tablets in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5)

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

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 tablets 100 mg, 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 (5.3)].

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 are administered orally once every 8 or 12 hours.

2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid

Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate extended-release tablets. [see Warnings and Precautions (5.3), Patient Counseling Information (17)] .

Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription directly from a pharmacist, or as part of a community-based program).

Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, and a history of opioid use disorder, or prior opioid overdose. The presence of risk factors of overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1, 5.3, 5.5)] .

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

2.3 Initial Dosage

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 tablets 15 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 tablets 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.

2.4 Titration and Maintenance of Therapy

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.

2.5 Dosage Modifications with Concomitant Use of Central Nervous System

Depressants

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 (5.5), Drug Interactions (7)] .

2.6 Safe Reduction or Discontinuation of Morphine sulfate extended-release

tablets

Do not abruptly discontinue morphine sulfate extended-release tablets in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking morphine sulfate extended-release tablets, there are a variety of factors that should be considered, including the dose of morphine sulfate extended-release tablets the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on morphine sulfate extended- release tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include 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. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.13), Drug Abuse and Dependence (9.3)].

---

DRUG INTERACTIONS SECTION

Highlight: * Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue morphine sulfate extended-release tablets if serotonin syndrome is suspected. ( 7)

• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with morphine sulfate extended-release tablets because they may reduce analgesic effect of morphine sulfate extended-release tablets or precipitate withdrawal symptoms. ( 5.13, 7)

7 DRUG INTERACTIONS

Table 1 includes clinically significant drug interactions with morphine sulfate extended-release tablets.

Table 1: Clinically Significant Drug Interactions with Morphine sulfate extended-release tablets

---

DRUG ABUSE AND DEPENDENCE SECTION

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

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

9.2 Abuse

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 are 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.

9.3 Dependence

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 is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting 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.

Do not abruptly discontinue morphine sulfate extended-release tablets in a patient physically dependent on opioids. Rapid tapering of morphine sulfate extended-release tablets in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing morphine sulfate extended-release tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of morphine sulfate extended-release tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.6), Warnings and Precautions (5.13)].

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)] .

---

ADVERSE REACTIONS SECTION

Highlight: Most common adverse reactions (>10%): constipation, nausea, and sedation. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma Inc. at 1-844-825-8500 or FDA at 1-800-FDA-1088 or****www.fda.gov/medwatch.

6 ADVERSE REACTIONS

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 (5.3)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
• Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.5)]
• Adrenal Insufficiency [see Warnings and Precautions (5.8)]
• Severe Hypotension [see Warnings and Precautions (5.9)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11)]
• Seizures [see Warnings and Precautions (5.12]
• Withdrawal [see Warnings and Precautions (5.13)]

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.

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

6.2 Post-Marketing Experience

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)] .

---

OVERDOSAGE SECTION

10 OVERDOSAGE

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.

Opioid antagonists, such as naloxone , are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist.

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.

---

NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

Mutagenesis

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

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

Impairment of Fertility

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

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

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

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

---

INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

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

Storage and Disposal

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store morphine sulfate extended-release tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2)]. Inform patients that leaving morphine sulfate extended-release tablets unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused morphine sulfate extended-release tablets should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

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.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.3)] .

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with morphine sulfate extended-release tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.3)] .

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

Explain to patients and caregivers that naloxone's effects are temporary, and that they must call 911 to get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)] .

If naloxone is prescribed, also advise patients and caregivers:

• How to treat naloxone in the event of an opioid overdose
• To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency
• To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and care giver will know what to do.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3)] .

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if morphine sulfate extended-release tablets are 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 (5.5), 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 (5.7), 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 (5.8)] .

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 (5.3)]

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue morphine sulfate extended-release tablets without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.6)].

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 (5.9)] .

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 (5.4), 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.

---

HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

Morphine sulfate extended-release 15 mg tablets are round, film-coated, blue tablets, debossed with "15" on one side and "ML" on the other side. They are available as follows:

Morphine sulfate extended-release 30 mg tablets are round, film-coated, purple tablets, debossed with "30" on one side and "ML" on the other side. They are available as follows:

Morphine sulfate extended-release 60 mg tablets are round, film-coated, orange tablets, debossed with "60" on one side and "ML" on the other side. They are available as follows:

Morphine sulfate extended-release 100 mg tablets are round, film-coated, gray tablets, debossed with "100" on one side and "ML" on the other side. They are available as follows:

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Store morphine sulfate extended-release tablets securely and dispose of properly [see Patient Counseling Information (17)].

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Medication Guide with each prescription.

CAUTION

DEA FORM REQUIRED

---