MS 60 MG Extended Release Oral Tablet

Generic Name: MORPHINE SULFATE
Brand Name: Morphine Sulfate
  • Substance Name(s):
  • MORPHINE SULFATE

DRUG INTERACTIONS

7 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 Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Limit dosages and durations to the minimum required.

Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].

Examples: Benzodiazepines and other sedative hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.

Discontinue Morphine sulfate extended-release tablets if serotonin syndrome is suspected.

Example: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.7)].

Intervention: Do not use Morphine sulfate extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.

Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Morphine sulfate extended-release tablets and/or precipitate withdrawal symptoms.

Intervention: Avoid concomitant use.

Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine sulfate extended-release tablets and/or the muscle relaxant as necessary.

Cimetidine Clinical Impact: The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.

Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine sulfate extended-release tablets and/or cimetidine as necessary.

Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Morphine sulfate extended-release tablets are used concomitantly with anticholinergic drugs.

P-Glycoprotein (P-gp) Inhibitors Clinical Impact: The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.

Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine sulfate extended-release tablets and/or the PGP-inhibitor as necessary.

Example: Quinidine 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)

OVERDOSAGE

10 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.

DESCRIPTION

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

Each tablet contains the following inactive ingredients common to all strengths: lactose monohydrate, hypromellose, magnesium stearate, colloidal silicon dioxide, polyethylene glycol, titanium dioxide, polydextrose, and triacetin.

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 No.

2 The 30 mg tablets also contain: D&C Red No.

7, FD&C Blue No.

2 The 60 mg tablets also contain: D&C Yellow No.

6 and red iron oxide.

The 100 mg tablets also contain: black iron oxide Morphine sulfate is an odorless, white, crystalline powder with a bitter taste.

It has a solubility of 1 in 21 parts of water and 1 in 1000 parts of alcohol, but is practically insoluble in chloroform or ether.

The octanol: water partition coefficient of morphine is 1.42 at physiologic pH and the pKb is 7.9 for the tertiary nitrogen (mostly ionized at pH 7.4).

Its molecular weight is 758.83 and its structural formula is: Chemical Structure

HOW SUPPLIED

16 /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: NDC 51862-185-01 bottles of 100 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: NDC 51862-186-01 bottles of 100 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: NDC 51862-187-01 bottles of 100 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: NDC 51862-188-01 bottles of 100 Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.] 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

RECENT MAJOR CHANGES

Boxed Warning 09/2018 Warnings and Precautions (5.2) 09/2018

GERIATRIC USE

8.5 Geriatric Use 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 (5.6)].

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.

DOSAGE FORMS AND STRENGTHS

3 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 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 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 Morphine sulfate extended-release 100 mg tablets100 mg tablets are for use in opioid-tolerant patients only are round, film-coated, gray tablets, debossed with “100” on one side and “ML” on the other side Extended-release tablets: 15 mg, 30 mg, 60 mg, and 100 mg (3)

MECHANISM OF ACTION

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.

INDICATIONS AND USAGE

1 Morphine sulfate extended-release tablets are 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.

Morphine sulfate extended-release tablets are an opioid agonist indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

(1) Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve 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.

(1) Morphine sulfate extended-release tablets are not indicated as an as-needed (prn) analgesic.

(1) Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations [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 are not indicated as an as-needed (prn) analgesic.

PEDIATRIC USE

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

PREGNANCY

8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal withdrawal syndrome [see Warnings and Precautions (5.4)].

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 (5.4)].

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 are 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).

BOXED WARNING

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE- THREATENING RESPIRATORY DEPRESSION, ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning.

Morphine sulfate extended-release tablets exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death.

Assess patient’s risk before prescribing, and monitor regularly for these behaviors and conditions.

(5.1) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products.

(5.2) Serious, life-threatening, or fatal respiratory depression may occur.

Monitor closely, especially upon initiation or following a dose increase.

Instruct patients to swallow Morphine sulfate extended-release tablets whole to avoid exposure to a potentially fatal dose of morphine.

(5.3) Accidental ingestion of Morphine sulfate extended-release tablets, especially by children, can result in a fatal overdose of morphine.

(5.3) 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.

If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

(5.4) 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.

Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation.

(5.5, 7) 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)].

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS): To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products [see Warnings and Precautions (5.2)].

Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers.

Healthcare providers are strongly encouraged to complete a REMS-compliant education program, counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products, emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and consider other tools to improve patient, household, and community safety.

Life-Threatening Respiratory Depress ion 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 (5.3)].

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 (5.3)].

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 (5.4)].

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 (5.5), Drug Interactions (7)].

Reserve concomitant prescribing of Morphine sulfate extended-release tablets 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.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration.

(5.6) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.

(5.7) Severe Hypotension: Monitor during dosage initiation and titration.

Avoid use in patients with circulatory shock.

(5.8) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression.

Avoid use of Morphine sulfate extended-release tablets in patients with impaired consciousness or coma.

(5.9) 5.1 Addiction, Abuse, and Misuse 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.

5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products.

Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers.

Healthcare providers are strongly encouraged to do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.

Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed.

The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.

Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.

Consider using other tools to improve patient, household, and community safety, such as patient- prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com.

The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

5.3 Life-Threatening Respiratory Depression 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.

5.4 Neonatal Opioid Withdrawal Syndrome 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)].

5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants 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 are 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)].

5.6 Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients 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 (5.3)].

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 (5.3)].

Monitor such patients closely, particularly when initiating and titrating Morphine sulfate extended-release tablets and when Morphine sulfate extended-release tablets are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3)].

Alternatively, consider the use of non-opioid analgesics in these patients.

5.7 Interaction with Monoamine Oxidase Inhibitors 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.

5.8 Adrenal Insufficiency 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.

5.9 Severe Hypotension 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.

5.10 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness 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.

5.11 Risks of Use in Patients with Gastrointestinal Conditions Morphine sulfate extended-release tablets are 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.

5.12 Increased Risk of Seizures in Patients with Seizure Disorders 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.

5.13 Withdrawal 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)].

5.14 Risks of Driving and Operating Machinery 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)].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION 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 (5.3)].

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 (5.3)].

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 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)] 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 (5.9)].

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.

Disposal of Unused Morphine sulfate extended-release tablets Advise patients to flush the unused tablets down the toilet when Morphine sulfate extended-release tablets are no longer needed.

Healthcare professionals can call Mayne Pharma at 1-844-825-8500 for information on this product.

DOSAGE AND ADMINISTRATION

2 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 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.

(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) For opioid-naïve and opioid non-tolerant patients, initiate with 15 mg tablets orally every 8 to 12 hours.

(2.2) Do not abruptly discontinue Morphine sulfate extended-release tablets in a physically dependent patient.

(2.4) 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 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 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.

2.3 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.

2.4 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)].

2.5 Discontinuation of Morphine sulfate extended-release tablets 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 (5.13), Drug Abuse and Dependence (9.3)].