RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

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DESCRIPTION SECTION

11 DESCRIPTION

Morphine sulfate extended-release capsules, USP, an opioid agonist, are for oral use and contain pellets of morphine sulfate.

Each morphine sulfate extended-release capsule, USP contains either 10 mg, 20 mg, 30 mg, 50 mg, 60 mg, 80 mg, or 100 mg of morphine sulfate, USP. The following inactive ingredients are common to all strengths: hypromellose, microcrystalline cellulose, ethylcellulose, methacrylic acid copolymer, polyethylene glycol, diethyl phthalate, and talc. The capsule shells contain gelatin, titanium dioxide, and black ink. In addition, individual capsules contain: FD&C blue #1, FD&C red #40 (10 mg); D&C yellow #10 (20 mg); FD&C blue #1, FD&C red #40 (30 mg); FD&C blue #1, FD&C red #40 (50 mg); FD&C blue #1, FD&C red #40 (60 mg); FD&C red #40, FD&C yellow #6 (80 mg); FD&C yellow #10, FD&C blue #1 (100 mg).

The chemical name of morphine sulfate is 7,8-didehydro-4,5 α-epoxy-17-methyl- morphinan-3,6 α-diol sulfate (2:1) (salt) pentahydrate. The empirical formula is (C17H19NO3)2∙H2SO4∙5H2O and its molecular weight is 758.85.

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 1,000 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 structural formula is:

CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

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

12.2 Pharmacodynamics

CNS Depressant/Alcohol Interaction

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

Effects on the Central Nervous System

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

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and 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.

Effects on the Cardiovascular System

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

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. 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 [see Adverse Reactions (6.2)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration-Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with 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 [see Dosage and Administration (2.1, 2.3)].

Concentration-Adverse Reaction Relationships

There is a relationship between increasing morphine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.3, 2.4)].

12.3 Pharmacokinetics

Absorption

Morphine sulfate extended-release capsules contain polymer coated extended- release pellets of morphine sulfate that release morphine significantly more slowly than oral morphine solution. Following the administration of oral morphine solution, approximately 50% of the morphine absorbed reaches the systemic circulation within 30 minutes compared to 8 hours with an equal amount of morphine sulfate. Because of pre-systemic elimination, only about 20% to 40% of the administered dose reaches the systemic circulation.

Both dose-normalized Cmax and dose-normalized AUC0-48hr values of morphine after a single dose administration of morphine sulfate in healthy volunteers are less than those for morphine oral solution or an extended-release tablet formulation (Table 2).

When morphine sulfate extended-release capsules were given twice daily to 24 patients with chronic pain due to malignancy, steady-state was achieved in about two days. At steady-state, morphine sulfate extended-release capsules have a significantly lower Cmax and a higher Cmin than equivalent doses of oral morphine solution given every 4 hrs and an extended-release tablet given twice daily. When given once daily to 24 patients with malignancy, morphine sulfate extended-release capsules have a similar Cmax and higher Cmin at steady-state when compared to an extended-release morphine tablets, given twice daily at an equivalent total daily dosage (see Table 2).

The single-dose pharmacokinetics of morphine sulfate extended-release capsules are linear over the dosage range of 30 mg to 100 mg.

Table 2: Mean pharmacokinetic parameters (% coefficient variation) resulting from a fasting single dose study in normal volunteers and a multiple-dose study in patients with cancer pain.

Food Effect:

While concurrent administration of food slows the rate of absorption of morphine sulfate extended-release capsules, the extent of absorption is not affected, and morphine sulfate extended-release capsules can be administered without regard to meals.

Distribution

Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. The volume of distribution of morphine is approximately 3 L/kg to 4 L/kg. Morphine is 30% to 35% reversibly bound to plasma proteins. Although the primary site of action of morphine is in the CNS, only small quantities pass the blood-brain barrier. Morphine also crosses the placental membranes [see Use in Specific Populations (8.1)] and has been found in breast milk [see Use in Specific Populations (8.2)].

Elimination

Metabolism

Major pathways of morphine metabolism include glucuronidation in the liver to produce metabolites including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5% to 15%) and sulfation in the liver to produce morphine-3-etheral sulfate. A small fraction (less than 5%) of morphine is demethylated. M3G has no significant contribution to the analgesic activity. Although M6G does not readily cross the blood-brain barrier, it has been shown to have opioid agonist and analgesic activity in humans.

Studies in healthy subjects and cancer patients have shown that the glucuronide metabolite to morphine mean molar ratios (based on AUC) are similar after both single doses and at steady-state for morphine sulfate extended-release capsules, 12-hour extended-release morphine sulfate tablets and morphine sulfate solution.

Excretion

Approximately 10% of a morphine dose is excreted unchanged in the urine. Most of the dose is excreted in the urine as M3G and M6G which are then renally excreted. A small amount of the glucuronide metabolites is excreted in the bile and there is some minor enterohepatic cycling. Seven to 10% of administered morphine is excreted in the feces.

The mean adult plasma clearance of morphine is about 20 to 30 mL/minute/kg. The effective terminal half-life of morphine after IV administration is reported to be approximately 2 hours. The terminal elimination half-life of morphine following a single dose of morphine sulfate extended-release capsules administration is approximately 11 hours to 13 hours.

Specific Populations

Sex

No meaningful differences between male and female patients were demonstrated in the analysis of the pharmacokinetic data from clinical studies.

Race/Ethnicity

Chinese subjects given intravenous morphine in one study had a higher clearance when compared to Caucasian subjects (1852 ± 116 mL/min versus 1495 ± 80 mL/min).

Hepatic Impairment

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

Renal Impairment

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

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INDICATIONS & USAGE SECTION

Highlight: Morphine sulfate extended-release capsules is indicated for the management of severe and persistent pain that requires an extended period with a daily opioid analgesic and for which alternative treatment options are inadequate. (1)

Limitations of Use:

• Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations, reserve morphine sulfate extended-release capsules 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 capsules are not indicated as an as-needed (prn) analgesic. (1)

1 INDICATIONS AND USAGE

Morphine sulfate extended-release capsules are indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate.

Limitations of Use:

• Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, 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 capsules 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 capsules are not indicated as an as-needed (prn) analgesic.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Extended-release capsules: 10 mg, 20 mg, 30 mg, 50 mg, 60 mg, 80 mg, 100 mg (3)

3 DOSAGE FORMS AND STRENGTHS

Morphine sulfate extended-release capsules contain white to off-white or tan colored polymer coated pellets, have an outer opaque capsule with colors as identified below and are available in seven dose strengths:

10 mg, size 4, light blue, opaque capsule printed with "UPSHER-SMITH" over "0225" and "10 mg" in black ink.

20 mg, size 4, yellow, opaque capsule printed with "UPSHER-SMITH" over "0226" and "20 mg" in black ink.

30 mg, size 2, blue violet, opaque capsule printed with "UPSHER-SMITH" over "0227" and "30 mg" in black ink.

50 mg, size 2, blue, opaque capsule printed with "UPSHER-SMITH" over "0228" and "50 mg" in black ink.

60 mg, size 1, pink, opaque capsule printed with "UPSHER-SMITH" over "0229" and "60 mg" in black ink.

80 mg, size 1, light orange, opaque capsule printed with "UPSHER-SMITH" over "0230" and "80 mg" in black ink.

100 mg, size 0, green, opaque capsule printed with "UPSHER-SMITH" over "0233" and "100 mg" in black ink.

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CONTRAINDICATIONS SECTION

Highlight: * Significant respiratory depression (4)

• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment (4)
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (4)
• Known or suspected gastrointestinal obstruction, including paralytic ileus (4)
• Hypersensitivity to morphine (4)

4 CONTRAINDICATIONS

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

• Significant respiratory depression [see Warnings and Precautions (5.2)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.7)]
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.8), Drug Interactions (7)]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.12)]
• Hypersensitivity (e.g., anaphylaxis) to morphine [see Adverse Reactions (6.2)]

BOXED WARNING SECTION

**WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF MORPHINE SULFATE

EXTENDED-RELEASE CAPSULES**

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DRUG INTERACTIONS SECTION

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

• Monoamine Oxidase Inhibitors (MAOIs): Can potentiate effects of morphine. Avoid concomitant use in patients taking MAOIs or within 14 days of stopping treatment with an MAOI. (7)
• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with morphine sulfate extended-release capsules because they may reduce analgesic effect of morphine sulfate extended-release capsules or precipitate withdrawal symptoms. (5.13, 7)

7 DRUG INTERACTIONS

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

Table 1: Clinically Significant Drug Interactions with Morphine Sulfate

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: * Pregnancy: May cause fetal harm. (8.1)

• Lactation: Not recommended. (8.2)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy can cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)]. There are no available data with morphine sulfate extended-release capsules 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 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 [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% to 4% and 15% to 20%, respectively.

Clinical Considerations

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 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 capsules 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 capsules, 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 to 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 to 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 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 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).

8.2 Lactation

Risk Summary

Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with extended-release morphine, including morphine sulfate extended-release capsules.

Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with morphine sulfate extended-release capsules.

Clinical Considerations

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

8.3 Females and Males of Reproductive Potential

Infertility

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

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

8.4 Pediatric Use

The safety and efficacy of morphine sulfate extended-release capsules in patients less than 18 years have not been established.

8.5 Geriatric Use

Clinical studies of morphine sulfate extended-release capsules 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 capsules slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.7)].

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.

8.6 Hepatic Impairment

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

8.7 Renal Impairment

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

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DRUG ABUSE AND DEPENDENCE SECTION

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Morphine sulfate extended-release capsules contain morphine, a Schedule II controlled substance.

9.2 Abuse

Morphine sulfate extended-release capsules contain morphine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of morphine sulfate extended-release capsules increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of morphine sulfate extended-release capsules with alcohol and other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of morphine sulfate extended-release capsules abuse include those with a history of prolonged use of any opioid, including products containing morphine, those with a history of drug or alcohol abuse, or those who use morphine sulfate extended-release capsules in combination with other abused drugs.

"Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Morphine sulfate extended-release capsules, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Morphine Sulfate Extended-Release Capsules

Abuse of morphine sulfate extended-release capsules poses a risk of overdose and death. This risk is increased with concurrent use of morphine sulfate extended-release capsules with alcohol and/or other CNS depressants. Taking cut, broken chewed, crushed, or dissolved morphine sulfate extended-release capsules enhances drug release and increases the risk of overdose and death morphine sulfate extended-release capsules are approved for oral use only. Inappropriate intravenous, intramuscular, or subcutaneous use of morphine sulfate extended-release capsules can result in death, local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, and valvular heart injury, and embolism.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

With parenteral abuse the inactive ingredients can result in local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis and valvular heart injury, embolism, and death.

9.3 Dependence

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

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

When discontinuing morphine sulfate extended-release capsules, gradually taper the dosage using a patient-specific plan that considers the following: the dose of morphine sulfate extended-release capsules the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5), Warnings and Precautions (5.14)].

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

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ADVERSE REACTIONS SECTION

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

To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6 ADVERSE REACTIONS

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

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
• Risks from Concomitant Use with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.3)]
• Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.6)]
• Adrenal Insufficiency [see Warnings and Precautions (5.9)]
• Severe Hypotension [see Warnings and Precautions (5.10)]
• Risks of Use in Patients with Gastrointestinal Conditions [see Warnings and Precautions (5.12)]
• Increased Risk of Seizures in Patients with Seizure Disorders [see Warnings and Precautions (5.13)]
• Withdrawal [see Warnings and Precautions (5.14)]

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the randomized study, the most common adverse reactions with morphine sulfate therapy were drowsiness, constipation, nausea, dizziness, and anxiety. The most common adverse reactions leading to study discontinuation were nausea, constipation (may be severe), vomiting, fatigue, dizziness, pruritus, and somnolence.

In clinical trials in patients with chronic cancer pain, the most common adverse events reported by patients at least once during therapy were drowsiness (9%), constipation (9%), nausea (7%), dizziness (6%), and anxiety (6%). Other less common side effects expected from morphine sulfate extended- release capsules or seen in less than 2% of patients in the clinical trials were:

• Body as a Whole: Headache, chills, flu syndrome, back pain, malaise, withdrawal syndrome
• Cardiovascular: Tachycardia, atrial fibrillation, hypotension, hypertension, pallor, facial flushing, palpitations, bradycardia, syncope
• Central Nervous System: Confusion, anxiety, abnormal thinking, abnormal dreams, lethargy, depression, loss of concentration, insomnia, amnesia, paresthesia, agitation, vertigo, foot drop, ataxia, hypesthesia, slurred speech, hallucinations, vasodilation, euphoria, apathy, seizures, myoclonus
• Endocrine: Hyponatremia due to inappropriate ADH secretion, gynecomastia
• Gastrointestinal: Dysphagia, dyspepsia, stomach atony disorder, gastro-esophageal reflux, delayed gastric emptying, biliary colic
• Hemic and Lymphatic: Thrombocytopenia
• Metabolic and Nutritional: Hyponatremia, edema
• Musculoskeletal: Back pain, bone pain, arthralgia
• Respiratory: Hiccup, rhinitis, atelectasis, asthma, hypoxia, respiratory insufficiency, voice alteration, depressed cough reflex, non-cardiogenic pulmonary edema
• Skin and Appendages: Decubitus ulcer, pruritus, skin flush
• Special Senses: Amblyopia, conjunctivitis, miosis, blurred vision, nystagmus, diplopia
• Urogenital: Urinary abnormality, amenorrhea, urinary retention, urinary hesitancy, reduced libido, reduced potency, prolonged labor

Four-Week Open-Label Safety Study

In the open-label, 4-week safety study, 1,418 patients ages 18 to 85 with chronic, non-malignant pain (e.g., back pain, osteoarthritis, neuropathic pain) were enrolled. The most common adverse events reported at least once during therapy were constipation (12%), nausea (9%), and somnolence (3%). Other less common side effects occurring in less than 3% of patients were vomiting, pruritus, dizziness, sedation, dry mouth, headache, fatigue, and rash.

6.2 Post-Marketing Experience

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

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

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

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

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

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.6)].

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).

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INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

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

Addiction, Abuse, and Misuse

Inform patients that the use of morphine sulfate extended-release capsules, 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 capsules with others and to take steps to protect morphine sulfate extended-release capsules 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 capsules or when the dosage is increased, and that it can occur even at recommended dosages.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.2)].

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)].

Interactions with Alcohol

Instruct patients not to consume alcoholic beverages, or prescription and non- prescription products that contain alcohol, during treatment with morphine sulfate extended-release capsules. The co-ingestion of alcohol with morphine sulfate extended-release capsules may result in increased plasma levels and a potentially fatal overdose of morphine [see Drug Interactions (7)].

Interactions with Benzodiazepines and Other CNS Depressants

Instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter products that contain alcohol, during treatment with morphine sulfate extended-release capsules. The co-ingestion of alcohol with morphine sulfate extended-release capsules may result in increased plasma levels and a potentially fatal overdose of (active opioid) [see Warnings and Precautions (5.3)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with morphine sulfate extended-release capsules. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

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

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

If naloxone is prescribed, also advise patients and caregivers:

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

Hyperalgesia and Allodynia

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.6); Adverse Reactions (6.2)].

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 Warnings and Precautions (5.2), Drug Interactions (7)].

MAOI Interaction

Inform patients not to take morphine sulfate extended-release capsules while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking morphine sulfate extended-release capsules [see Warnings and Precautions (5.8), Drug Interactions (7)].

Important Administration Instructions

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

• Swallow morphine sulfate extended-release capsules whole or sprinkling the capsule contents on applesauce and then swallow immediately without chewing [see Dosage and Administration (2.1, 2.6)].
• Do not crush, chew, or dissolve the pellets contained in the capsules due to a risk of fatal morphine overdose [see Dosage and Administration (2.1)].
• Use morphine sulfate extended-release capsules exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) [see Warnings and Precautions (5.2)].

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue morphine sulfate extended-release capsules without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.5)].

Driving or Operating Heavy Machinery

Inform patients that morphine sulfate extended-release capsules 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 [see Warnings and Precautions (5.15)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].

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 (5.9)].

Hypotension

Inform patients that morphine sulfate extended-release capsules 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 (5.10)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with morphine sulfate extended-release capsules. 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 use of morphine sulfate extended-release capsules for an extended period of time 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 capsules can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

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

Infertility

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2)].

Storage and Disposal

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store morphine sulfate extended-release capsules securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving morphine sulfate extended-release capsules unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)].

SPL MEDGUIDE SECTION

Manufactured by
UPSHER-SMITH LABORATORIES, LLC
Maple Grove, MN 55369

Revised: 2/2024

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INSTRUCTIONS FOR USE SECTION

Instructions For Use
Morphine Sulfate (mor∙feen sul∙fate)
Extended-Release Capsules, CII

If you cannot swallow morphine sulfate extended-release capsules, tell your healthcare provider. There may be another way to take morphine sulfate extended-release capsules that may be right for you. If your healthcare provider tells you that you can take morphine sulfate extended-release capsules using this other way, follow these steps:

Morphine sulfate extended-release capsules can be opened and the pellets inside the capsule can be sprinkled over applesauce, as follows:

You should not receive morphine sulfate extended-release capsules through a nasogastric tube.

This Instructions For Use has been approved by the U.S. Food and Drug Administration.

Manufactured by
UPSHER-SMITH LABORATORIES, LLC
Maple Grove, MN 55369

Revised: 2/2024

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SPL UNCLASSIFIED SECTION

Manufactured by
UPSHER-SMITH LABORATORIES, LLC
Maple Grove, MN 55369

Revised: 2/2024

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