SKENAN LP

Morphine sulfate tablets are an opioid agonist, available in 15 mg and 30 mg for oral administration: 15 mg tablet: Each tablet contains 15 mg morphine sulfate, USP (equivalent to 11.25 mg morphine). 30 mg tablet: Each tablet contains 30 mg morphine sulfate, USP (equivalent to 22.5 mg morphine).

Chemically, morphine sulfate is 7,8-didehydro-4,5α-epoxy-17-methylmorphinan-3,6α-diol sulfate (2:1) (salt) pentahydrate.

Morphine sulfate, USP is a white to off-white crystalline solid.

It is soluble in water and slightly soluble in alcohol, but is practically insoluble in chloroform.

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

Its molecular formula is (C 17 H 19 NO 3 ) 2.

• H 2 SO 4.

• 5H 2 O, and it has the following chemical structure: Each tablet contains 15 or 30 mg of morphine sulfate, USP and the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose and pregelatinised starch.

Morphine sulfate tablets are indicated for the management of: adult and pediatric patients weighing at least 50 kg and above with acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. adults with chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, , reserve morphine sulfate tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): Have not been tolerated or are not expected to be tolerated, Have not provided adequate analgesia or are not expected to provide adequate analgesia Morphine sulfate tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

Morphine sulfate tablets are opioid agonists indicated for the management of: adults and pediatric patients weighing 50 kg and above with acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. adults with chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, reserve morphine sulfate tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): Have not been tolerated or are not expected to be tolerated, Have not provided adequate analgesia or are not expected to provide adequate analgesia Morphine sulfate tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

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 Effects on the Central Nervous System: Morphine produces respiratory depression by direct action on brain stem respiratory centers.

The respiratory depression involves a reduction in the responsiveness of the brain stem 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 opioid 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 due to 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 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 a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

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.

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans.

They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Use of opioids for an extended period of time 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.

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 opioid agonists.

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.

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. 12.3 Pharmacokinetics Absorption: Morphine, when administered as morphine sulfate is about two-thirds absorbed from the gastrointestinal tract with the maximum analgesic effect occurring 60 minutes post-administration.

The oral bioavailability of morphine sulfate is less than 40% and shows large inter-individual variability due to extensive pre-systemic metabolism.

Administration of the 30 mg morphine sulfate tablet and 30 mg of Morphine Sulfate Oral Solution every six hours for 5 days resulted in a comparable 24-hour exposure (AUC).

The steady-state levels were achieved within 48 hours for both tablets and solution.

The mean steady state

C max values were about and 58 ng/mL for tablets and solution, respectively.

When morphine sulfate 30 mg tablet was administered 30 minutes after ingesting a high fat/high calorie meal, there was no change in the extent of absorption (AUC) of morphine sulfate.

There was, however, an increase in the median T max from 0.5 to 0.75 hours and an 11% decrease in C max.

The tablet can be administered without regard to meals.

Once absorbed, morphine sulfate is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain.

Although the primary site of action is the CNS, only small quantities cross the blood-brain barrier.

Morphine sulfate also crosses the placental membranes and has been found in breast milk.

The volume of distribution of morphine sulfate is approximately to 6 L/kg, and morphine sulfate is 20% to 35% reversibly bound to plasma proteins.

Metabolism: The major pathway of morphine sulfate detoxification is conjugation, either with D-glucuronic acid to produce glucuronides or with sulfuric acid to produce morphine-3-etheral sulfate.

While a small fraction (less than 5%) of morphine sulfate is demethylated, virtually all morphine sulfate is converted by hepatic metabolism to the 3.

• and 6.

• glucuronide metabolites (M3G and M6G; about 50% and 15%, respectively).

M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.

Most of a dose of morphine sulfate is excreted in urine as M3G and M6G, with elimination of morphine sulfate occurring primarily as renal excretion of M3G.

Approximately 10% of the dose is excreted unchanged in urine.

A small amount of glucuronide conjugates are excreted in bile, with minor enterohepatic recycling.

Seven to 10% of administered morphine sulfate is excreted in the feces.

The mean adult plasma clearance is approximately to 30 mL/min/kg. The effective terminal half-life of morphine sulfate after IV administration is reported to be approximately 2 hours.

In some studies involving longer periods of plasma sampling, a longer terminal half-life of morphine sulfate of about 15 hours was reported.

Pediatric Patients: Morphine pharmacokinetics were analyzed in a population pharmacokinetic analysis of 66 pediatric patients aged 2 years to 17 years.

Initially after dosing, the geometric mean plasma half-life of morphine was up to 1.8 hours.

The geometric mean terminal elimination plasma half-life of morphine was 18.6 hours.

For both the

M3G metabolite and M6G metabolite, the single-dose geometric mean C max in pediatric patients was not greater than in adults.

Race/ Ethnicity: There may be some pharmacokinetic differences associated with race.

In one published study, Chinese subjects given intravenous morphine sulfate had a higher clearance when compared to Caucasian subjects (1852 +/ - 116 mL/min compared to 1495 +/ - 80 mL/min).

While evidence of greater post-operative morphine sulfate consumption in men compared to women is present in the literature, clinically significant differences in analgesic outcomes and pharmacokinetic parameters have not been consistently demonstrated.

Some studies have shown an increased sensitivity to the adverse effects of morphine sulfate, including respiratory depression, in women compared to men.

Morphine pharmacokinetics are altered in patients with cirrhosis.

Clearance was found to decrease with a corresponding increase in half-life.

M3G and M6G to morphine AUC ratios also decreased in these subjects, indicating diminished metabolic activity.

Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.

Morphine pharmacokinetics are altered in patients with renal failure.

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.

The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse Life-Threatening Respiratory Depression Interactions with Benzodiazepine or Other CNS Depressants Neonatal Opioid Withdrawal Syndrome Opioid-Induced Hyperalgesia and Allodynia Adrenal Insufficiency Severe Hypotension Gastrointestinal Adverse Reactions Seizures Withdrawal The following adverse reactions associated with the use of morphine were identified in clinical studies or postmarketing reports.

Because some of these reactions were 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.

Serious adverse reactions associated with morphine use included: respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.

The common adverse reactions seen on initiation of therapy with morphine in adults were dose-dependent and were typical opioid-related adverse reactions.

The most frequent of these included: constipation, nausea, and somnolence.

Other commonly observed adverse reactions included: lightheadedness, dizziness, sedation, vomiting, and sweating.

The frequency of these events depended upon several factors including clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual.

Other less frequently observed adverse reactions from opioid analgesics, including morphine sulfate included: Body as a Whole: malaise, withdrawal syndrome Cardiovascular System: bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia Digestive System: biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst Endocrine: hypogonadism Hemic and Lymphatic System: anemia, thrombocytopenia Metabolic and Nutritional.

Disorders : edema, weight loss Musculoskeletal: skeletal muscle rigidity, decreased bone mineral density Nervous System: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, depression, dry mouth, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo, headache Respiratory System: hiccup, hypoventilation, voice alteration Skin and Appendages: dry skin, urticaria, pruritus Special Senses: amblyopia, eye pain, taste perversion Urogenital System: abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention or hesitancy, anti-diuretic effect, amenorrhea Serotonin Syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

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

Anaphylaxis has been reported with ingredients contained in morphine sulfate tablets.

Cases of androgen deficiency have occurred with chronic use of opioids for an extended period of time. .

Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids.

Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Clinical Trial Experience in Pediatric Patients

The safety of morphine sulfate was evaluated in 81 pediatric patients with acute pain.

Tablets are not recommended for use in pediatric patients weighing less than 50 kg. The adverse reaction profile in pediatric patients is similar to adults.

The most common adverse reactions reported on initiation of therapy in at least 5% of patients were: nausea (17%), vomiting (10%), constipation (6%), decreased oxygen saturation (5%), and flatulence (5%).

Most Common Adverse Reactions Seen on Initiation of Therapy are: Adults: constipation, nausea, somnolence, lightheadedness, dizziness, sedation, vomiting, and sweating.

Pediatrics (>5%): nausea, vomiting, constipation, decreased oxygen saturation, and flatulence.fda.gov/medwatch.

Acute overdose with morphine 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, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death.

Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

In case of overdose, priorities are the reestablishment 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 measures.

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 opioid reversal is expected to be less than the duration of action of morphine in morphine sulfate tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished.

If the response to an opioid antagonist 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 recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome.

The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered.

If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

Morphine sulfate tablets are contraindicated in patients with: Significant respiratory depression.

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.

Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days.

Known or suspected gastrointestinal obstruction, including paralytic ileus.

Hypersensitivity to morphine (e.g., anaphylaxis) .

Significant respiratory depression.

Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment.

Hypersensitivity to morphine.

Morphine sulfate tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals.

Reserve titration to higher doses of morphine sulfate tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic.

Clinical guidelines on opioid prescribing for some acute pain conditions are available.

Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse.

Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with morphine sulfate tablets.

Consider this risk when selecting an initial dose and when making dose adjustments.

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 tablets.

Consider prescribing naloxone based on the patient’s risk factors for overdose.

Initiate treatment with morphine sulfate tablets in adults and pediatric patients 50 kg and above: 15 to 30 mg every 4 hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia.

Do not exceed 30 mg as an initial dose in pediatric patients.

Titrate the dose based upon the individual patient’s response to their initial dose of morphine sulfate tablets Do not abruptly discontinue morphine sulfate tablets in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. 2.1 Important Dosage and Administration Instructions Morphine sulfate tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.

Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of morphine sulfate tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors.

Consider this risk when selecting an initial dose and when making dose adjustments. 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 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).

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose.

The presence of risk factors for overdose should not prevent the proper management of pain in any given patient.

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 tablets as the First Opioid Analgesic (Opioid-naïve or Opioid-non - tolerant Patients): Adults: The recommended dosage to initiate treatment in adults is 15 mg to 30 mg every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia.

Titrate the dose based upon the individual patient’s response to their initial dose of morphine sulfate tablets.

Pediatric Patients Weighing at

Least 50 kg: The recommended dosage to initiate treatment in pediatric patients weighing at least 50 kg and who are able to swallow oral tablets is 15 mg every 4 hours as needed for pain, and the lowest dose necessary to achieve adequate analgesia.

Do not exceed 30 mg as an initial dose.

Morphine sulfate tablets are not recommended for use in pediatric patients who weigh less than 50 kg as the recommended dosage cannot be achieved with available tablet strengths.

Consider use of another morphine sulfate product in patients who cannot swallow oral tablets or who weigh less than 50 kg. Conversion from Parenteral Morphine to Morphine sulfate tablets For conversion from parenteral morphine to morphine sulfate tablets, anywhere from to 6 mg of oral morphine sulfate may be required to provide pain relief equivalent to 1 mg of parenteral morphine.

Conversion from Other Opioids to Morphine sulfate tablets There is inter-patient variability in the potency of opioid drugs and opioid formulations.

Therefore, a conservative approach is advised when determining the total daily dosage of morphine sulfate tablets.

It is safer to underestimate a patient’s 24-hour morphine sulfate tablets dosage than to overestimate the 24-hour morphine sulfate tablets dosage and manage an adverse reaction due to overdose.

Initiate dosing using morphine sulfate tablets 15 mg to 30 mg every 4 hours.

Conversion from Morphine sulfate tablets to Extended-Release Morphine For a given dose, the same total amount of morphine sulfate is available from morphine sulfate tablets, and extended.

• release morphine formulations.

The extended duration of release of morphine sulfate from extended-release formulations results in reduced maximum and increased minimum plasma morphine sulfate concentrations than with shorter acting morphine sulfate products.

Conversion from morphine sulfate tablets to the same total daily dose of an extended-release formulation could lead to excessive sedation at peak serum levels.

Therefore, conversion to extended-release morphine may lead to increased risk of excessive sedation and respiratory depression. 2.4 Titration and Maintenance of Therapy Individually titrate morphine sulfate tablets to a dose that provides adequate analgesia and minimizes adverse reactions.

Continually reevaluate patients receiving morphine sulfate tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions as well as to reassess for the development of addiction, abuse, or misuse.

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.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the morphine sulfate tablets dosage.

If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage.

Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of Morphine Sulfate Tablets Do not abruptly discontinue morphine sulfate 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 tablets, there are a variety of factors that should be considered, including the total daily dose of opioids (including morphine sulfate 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 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 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, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When ma.

Morphine sulfate tablets 15 mg: Each tablet contains 15 mg morphine sulfate, USP (equivalent to 11.25 mg morphine) and is a white, round, biconvex tablet, scored on one side and debossed “M 15” on other side.

NDC 67877-670-01: Bottle of 100 Tablets 30 mg: Each tablet contains 30 mg morphine sulfate, USP (equivalent to 22.5 mg morphine) and is a white, round, biconvex tablet, scored on one side and debossed “M 30” on other side.

NDC 67877-671-01: Bottle of 100 Tablets Storage Store at 20° to 25°C (68° to 77°F).

Protect from moisture.

Store morphine sulfate tablets securely and dispose of properly.

U se of opioid analgesics for an extended period of time during pregnancy can cause neonatal opioid withdrawal syndrome.

There are no available data with morphine sulfate 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.

In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 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 to 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.

Based on animal data, advise pregnant women of the potential risk to a fetus.

The 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% to 4% and 15% to 20%, respectively.

Fetal/Neonatal Adverse Reactions: Use of opioid analgesics for an extended period of time 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 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 signs of neonatal opioid withdrawal syndrome and manage accordingly.

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 tablets are not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate.

Opioid analgesics, including morphine sulfate tablets, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions.

However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.

Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

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.

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 to 322 mg/kg) on Gestation Day 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 to 500 mg/kg) on Gestation Day 8 or 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 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 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 to 10.

In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10 to 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 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 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 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 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).

The safety and effectiveness of morphine sulfate tablets have been established for the management of pediatric patients weighing at least 50 kg with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate.

Use of morphine sulfate tablets in this is supported by clinical evidence in adults and supportive data from an open-label, safety and pharmacokinetic study in pediatric patients 2 through 17 years of age with post-operative acute pain.

Patients were excluded if they had used opioids for more than 7 days within the previous 30 days prior to surgery or had received opioids in any form in the previous 7 days prior to surgery.

Initial dosing was approximately 0.15 mg/kg to 0.3 mg/kg. Pharmacokinetic modeling and simulation indicate that an initial dose of 15 mg morphine sulfate tablets to pediatric patients weighing at least 50 kg is expected to produce a maximum systemic exposure (C max ) similar to that achieved after single dose administration of 10 mg morphine sulfate oral solution to adults.

Safety data were available in 81 patients who received single and multiple doses (63 patients aged to 17 years received the oral solution; 18 patients aged 12 years to 17 years received the tablets).

The median duration of treatment was 20 hours (range 4 hours to 36 hours).

Opioid and non-opioid rescue analgesics were allowed.

The safety profile in pediatric patients consisted primarily of opioid-related adverse reactions and is similar to that observed in adults.

The safety and effectiveness of morphine sulfate tablets have not been established for the management of pediatric patients weighing less than 50 kg with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate because the recommended dosage cannot be achieved with available tablet strengths.

Consider use of another morphine sulfate product in patients who cannot swallow oral tablets or who weigh less than 50 kg.

The safety and effectiveness of morphine sulfate tablets have not been established for the management of pediatric patients with chronic pain severe enough to require an opioid analgesic when alternative treatments are inadequate.

Elderly patients (aged 65 years or older) may have increased sensitivity to morphine.

In general, use caution when selecting a dose 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 tablets slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression.

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 regularly evaluate renal function.