These Highlights Do Not Include All The Information Needed To Use Morphine Sulfate Extended-release Capsules Safely And Effectively. See Full Prescribing Information For Morphine Sulfate Extended-release Capsules.

Addiction, Abuse, and Misuse

Because the use of morphine sulfate extended-release capsules exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Manufactured by

UPSHER-SMITH LABORATORIES, LLC

Maple Grove, MN 55369

Revised: 2/2024

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from light and moisture.

Dispense in a sealed, tamper-evident, child-resistant, light-resistant container.

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

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

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.

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 (C ₁₇H ₁₉NO ₃) ₂∙H ₂SO ₄∙5H ₂O 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 pK _bis 7.9 for the tertiary nitrogen (mostly ionized at pH 7.4). Its structural formula is:

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)] .

Do not abruptly discontinue morphine sulfate extended-release capsules in a patient physically dependent on opioids. When discontinuing morphine sulfate extended-release capsules in a physically dependent patient, gradually taper the dosage. Rapid tapering of morphine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5), Drug Abuse and Dependence (9.3)] .

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

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

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.

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)]

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)]

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

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)] .

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)] .

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.

Morphine sulfate extended-release capsules may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)] . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of morphine sulfate extended-release capsules. In patients with circulatory shock, morphine sulfate extended-release capsules may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of morphine sulfate extended-release capsules in patients with circulatory shock.

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.

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

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

• Opioid-Induced Hyperalgesia and Allodynia:Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. ( 5.6)
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate closely, particularly during initiation and titration. ( 5.7)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid. ( 5.9)
• Severe Hypotension: Regularly evaluate during dosage initiation and titration. Avoid use of morphine sulfate extended-release capsules in patients with circulatory shock. ( 5.10)
• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of morphine sulfate extended-release capsules in patients with impaired consciousness or coma. ( 5.11)

• Morphine sulfate extended-release capsules should be prescribed only by healthcare professionals who are knowledgeable about use of extended-release/long-acting opioids and how to mitigate the associated risks. ( 2.1)
• Morphine sulfate extended-release 100 mg capsules, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, are only for use in patients in whom tolerance to an opioid of comparable potency has been established. ( 2.1)
• Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg of morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg of oral oxycodone per day, 8 mg of oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. ( 2.1)
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of morphine sulfate extended-release capsules 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. ( 2.1, 5.1)
• 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. ( 5.1)
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with morphine sulfate extended-release capsules. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1, 5.2)
• Instruct patients to swallow morphine sulfate extended-release capsules intact, or to sprinkle the capsule contents on applesauce and immediately swallow without chewing. ( 2.1, 2.6)
• Instruct patients not to cut, break, chew, crush, or dissolve the pellets in morphine sulfate extended-release capsules to avoid the risk of release and absorption of a potentially fatal dose of morphine. ( 2.1, 2.6, 5.1)
• Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with morphine sulfate extended-release capsules. Consider prescribing naloxone based on the patient's risk factors for overdose. ( 2.2, 5.1, 5.2, 5.3)
• For opioid-naïve patients, initiate treatment using an immediate-release morphine formulation and then convert patients to morphine sulfate extended-release. For opioid non-tolerant patients, initiate with a 30 mg capsule orally every 24 hours. Dosage adjustments may be made every one to two days. ( 2.3, 2.4)
• Do not abruptly discontinue morphine sulfate extended-release capsules in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5, 5.14)

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.

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

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.

• Pregnancy: May cause fetal harm. ( 8.1)
• Lactation: Not recommended. ( 8.2)

Morphine sulfate extended-release capsules contain morphine, a Schedule II controlled substance. As an opioid, morphine sulfate extended-release capsules expose users to the risks of addiction, abuse, and misuse. Because extended-release products such as morphine sulfate extended-release capsules deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of morphine present [see Drug Abuse and Dependence (9)] .

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed morphine sulfate extended-release capsules. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing morphine sulfate extended-release capsules, and reassess all patients receiving morphine sulfate extended-release capsules for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as morphine sulfate extended-release capsules, but use in such patients necessitates intensive counseling about the risks and proper use of morphine sulfate extended-release capsules along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2)] .

Abuse or misuse of morphine sulfate extended-release capsules by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of morphine and can result in overdose and death [see Overdosage (10)] .

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing morphine sulfate extended-release capsules. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

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.

Morphine sulfate extended-release capsules, USP contain white to off-white or tan colored polymer coated pellets of morphine sulfate 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. They are supplied as follows:

20 mg, size 4, yellow, opaque capsule printed with "UPSHER-SMITH" over "0226" and "20 mg" in black ink. They are supplied as follows:

30 mg, size 2, blue violet, opaque capsule printed with "UPSHER-SMITH" over "0227" and "30 mg" in black ink. They are supplied as follows:

50 mg, size 2, blue, opaque capsule printed with "UPSHER-SMITH" over "0228" and "50 mg" in black ink. They are supplied as follows:

60 mg, size 1, pink, opaque capsule printed with "UPSHER-SMITH" over "0229" and "60 mg" in black ink. They are supplied as follows:

80 mg, size 1, light orange, opaque capsule printed with "UPSHER-SMITH" over "0230" and "80 mg" in black ink. They are supplied as follows:

100 mg, size 0, green, opaque capsule printed with "UPSHER-SMITH" over "0233" and "100 mg" in black ink. They are supplied as follows:

Use of morphine sulfate extended-release capsules for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)] .

Individually titrate morphine sulfate extended-release capsules to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving morphine sulfate extended-release capsules to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1, 5.14)] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy, for an extended period of time, periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of morphine sulfate extended-release capsules or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the morphine sulfate extended-release capsules dosage. In patients experiencing inadequate analgesia with once daily dosing of morphine sulfate extended-release capsules, consider a twice daily regimen. Because steady-state plasma concentrations are approximated within 24 hours to 36 hours, morphine sulfate extended-release capsules dosage adjustments may be done every 1 to 2 days.

If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions (5)] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see Overdosage (10)] . Carbon dioxide (CO ₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of morphine sulfate, the risk is greatest during the initiation of therapy or following a dosage increase.

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

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

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 Patient Counseling Information (17)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5)].

Morphine sulfate extended-release capsules may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of morphine sulfate extended-release capsules and know how they will react to the medication [see Patient Counseling Information (17)] .

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)] . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.5); Warnings and Precautions (5.14)] .

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

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

• Complete a REMS-compliant education programoffered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Healthcare Providers Involved in the Management or Support of Patients with Pain.
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG)can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

Morphine sulfate extended-release capsules should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Morphine sulfate extended-release 100 mg capsules, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone daily, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of morphine sulfate extended-release capsules 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.
• 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 [see Warnings and Precautions (5.1)] .

Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with morphine sulfate extended-release capsules. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5)].

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

Instruct patients who are unable to swallow morphine sulfate extended-release capsules to sprinkle the capsule contents on applesauce and immediately swallow without chewing [see Dosage and Administration (2.6)] .

Morphine sulfate extended-release capsules are administered orally at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours).

NDC 0832-0225-00

Morphine Sulfate

Extended-Release Capsules, USP

CII

(Once or twice Daily Formulation)

10 mg

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 Capsules

Rx only

UPSHER-SMITH

NDC 0832-0226-00

Morphine Sulfate

Extended-Release Capsules, USP

CII

(Once or twice Daily Formulation)

20 mg

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 Capsules

Rx only

UPSHER-SMITH

NDC 0832-0227-00

Morphine Sulfate

Extended-Release Capsules, USP

CII

(Once or twice Daily Formulation)

30 mg

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 Capsules

Rx only

UPSHER-SMITH

NDC 0832-0228-00

Morphine Sulfate

Extended-Release Capsules, USP

CII

(Once or twice Daily Formulation)

50 mg

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 Capsules

Rx only

UPSHER-SMITH

NDC 0832-0229-00

Morphine Sulfate

Extended-Release Capsules, USP

CII

(Once or twice Daily Formulation)

60 mg

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 Capsules

Rx only

UPSHER-SMITH

NDC 0832-0230-00

Morphine Sulfate

Extended-Release Capsules, USP

CII

(Once or twice Daily Formulation)

80 mg

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 Capsules

Rx only

UPSHER-SMITH

NDC 0832-0233-00

Morphine Sulfate

Extended-Release Capsules, USP

CII

(Once or twice Daily Formulation)

100 mg

For Use in Opioid-Tolerant Patients Only

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 Capsules

Rx only

UPSHER-SMITH

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

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

Morphine sulfate extended-release capsules must be taken whole. Crushing, chewing, or dissolving the pellets in morphine sulfate extended-release capsules will result in uncontrolled delivery of morphine and can lead to overdose or death [see Warnings and Precautions (5.1)] .

Alternatively, the contents of the morphine sulfate extended-release capsules (pellets) may be sprinkled over applesauce and then swallowed. This method is appropriate only for patients able to reliably swallow the applesauce without chewing. Other foods have not been tested and should not be substituted for applesauce. Instruct the patient to:

• Sprinkle the pellets onto a small amount of applesauce and consume immediately without chewing.
• Rinse the mouth to ensure all pellets have been swallowed.
• Discard any unused portion of the morphine sulfate extended-release capsules after the contents have been sprinkled on applesauce.

The contents of the morphine sulfate extended-release capsules (pellets) may be administered through a French gastrostomy tube.

• Flush the gastrostomy tube with water to ensure that it is wet.
• Sprinkle the morphine sulfate extended-release pellets into 10 mL of water.
• Use a swirling motion to pour the pellets and water into the gastrostomy tube through a funnel.
• Rinse the beaker with a further 10 mL of water and pour this into the funnel.
• Repeat rinsing until no pellets remain in the beaker.

Do not administer morphine sulfate extended-release pellets through a nasogastric tube.

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

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of morphine sulfate with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)] .

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

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)] .

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

Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on morphine sulfate extended-release capsule therapy. The co-ingestion of alcohol with morphine sulfate extended-release capsules may result in increased plasma levels and a potentially fatal overdose of morphine.

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate extended-release capsules [see Warnings and Precautions (5.2), Patient Counseling Information (17)].

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

Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, 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 [see Warnings and Precautions (5.1, 5.2, 5.3)].

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

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

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

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

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.14), Drug Abuse and Dependence (9.3)] .

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF MORPHINE SULFATE EXTENDED-RELEASE CAPSULES

See full prescribing information for complete boxed warning.

• Morphine sulfate extended-release capsules expose users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk before prescribing, and monitor regularly for these behaviors and conditions. ( 5.1)
• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow morphine sulfate extended-release capsules whole to avoid exposure to a potentially fatal dose of morphine. ( 5.3)
• Accidental ingestion of morphine sulfate extended-release capsules, especially by children, can result in fatal overdose of morphine. ( 5.2)
• Instruct patients not to consume alcohol or any products containing alcohol while taking morphine sulfate extended-release capsules because co-ingestion can result in fatal plasma morphine levels. ( 5.3)
• Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.3, 7)
• Prolonged use of morphine sulfate extended-release capsules during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. ( 5.4)
• To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. ( 5.5)

In patients who may be susceptible to the intracranial effects of CO ₂retention (e.g., those with evidence of increased intracranial pressure or brain tumors), morphine sulfate extended-release capsules may reduce respiratory drive, and the resultant CO ₂retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with morphine sulfate extended-release capsules.

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

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

Addiction, Abuse, and Misuse

Because the use of morphine sulfate extended-release capsules exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Manufactured by

UPSHER-SMITH LABORATORIES, LLC

Maple Grove, MN 55369

Revised: 2/2024

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from light and moisture.

Dispense in a sealed, tamper-evident, child-resistant, light-resistant container.

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

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

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.

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 (C ₁₇H ₁₉NO ₃) ₂∙H ₂SO ₄∙5H ₂O 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 pK _bis 7.9 for the tertiary nitrogen (mostly ionized at pH 7.4). Its structural formula is:

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)] .

Do not abruptly discontinue morphine sulfate extended-release capsules in a patient physically dependent on opioids. When discontinuing morphine sulfate extended-release capsules in a physically dependent patient, gradually taper the dosage. Rapid tapering of morphine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5), Drug Abuse and Dependence (9.3)] .

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

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

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.

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)]

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)]

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

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)] .

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)] .

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.

Morphine sulfate extended-release capsules may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)] . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of morphine sulfate extended-release capsules. In patients with circulatory shock, morphine sulfate extended-release capsules may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of morphine sulfate extended-release capsules in patients with circulatory shock.

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.

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

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

• Opioid-Induced Hyperalgesia and Allodynia:Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. ( 5.6)
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate closely, particularly during initiation and titration. ( 5.7)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid. ( 5.9)
• Severe Hypotension: Regularly evaluate during dosage initiation and titration. Avoid use of morphine sulfate extended-release capsules in patients with circulatory shock. ( 5.10)
• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of morphine sulfate extended-release capsules in patients with impaired consciousness or coma. ( 5.11)

• Morphine sulfate extended-release capsules should be prescribed only by healthcare professionals who are knowledgeable about use of extended-release/long-acting opioids and how to mitigate the associated risks. ( 2.1)
• Morphine sulfate extended-release 100 mg capsules, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, are only for use in patients in whom tolerance to an opioid of comparable potency has been established. ( 2.1)
• Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg of morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg of oral oxycodone per day, 8 mg of oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. ( 2.1)
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of morphine sulfate extended-release capsules 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. ( 2.1, 5.1)
• 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. ( 5.1)
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with morphine sulfate extended-release capsules. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1, 5.2)
• Instruct patients to swallow morphine sulfate extended-release capsules intact, or to sprinkle the capsule contents on applesauce and immediately swallow without chewing. ( 2.1, 2.6)
• Instruct patients not to cut, break, chew, crush, or dissolve the pellets in morphine sulfate extended-release capsules to avoid the risk of release and absorption of a potentially fatal dose of morphine. ( 2.1, 2.6, 5.1)
• Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with morphine sulfate extended-release capsules. Consider prescribing naloxone based on the patient's risk factors for overdose. ( 2.2, 5.1, 5.2, 5.3)
• For opioid-naïve patients, initiate treatment using an immediate-release morphine formulation and then convert patients to morphine sulfate extended-release. For opioid non-tolerant patients, initiate with a 30 mg capsule orally every 24 hours. Dosage adjustments may be made every one to two days. ( 2.3, 2.4)
• Do not abruptly discontinue morphine sulfate extended-release capsules in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5, 5.14)

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.

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

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.

• Pregnancy: May cause fetal harm. ( 8.1)
• Lactation: Not recommended. ( 8.2)

Morphine sulfate extended-release capsules contain morphine, a Schedule II controlled substance. As an opioid, morphine sulfate extended-release capsules expose users to the risks of addiction, abuse, and misuse. Because extended-release products such as morphine sulfate extended-release capsules deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of morphine present [see Drug Abuse and Dependence (9)] .

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed morphine sulfate extended-release capsules. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing morphine sulfate extended-release capsules, and reassess all patients receiving morphine sulfate extended-release capsules for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as morphine sulfate extended-release capsules, but use in such patients necessitates intensive counseling about the risks and proper use of morphine sulfate extended-release capsules along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2)] .

Abuse or misuse of morphine sulfate extended-release capsules by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of morphine and can result in overdose and death [see Overdosage (10)] .

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing morphine sulfate extended-release capsules. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

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.

Morphine sulfate extended-release capsules, USP contain white to off-white or tan colored polymer coated pellets of morphine sulfate 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. They are supplied as follows:

20 mg, size 4, yellow, opaque capsule printed with "UPSHER-SMITH" over "0226" and "20 mg" in black ink. They are supplied as follows:

30 mg, size 2, blue violet, opaque capsule printed with "UPSHER-SMITH" over "0227" and "30 mg" in black ink. They are supplied as follows:

50 mg, size 2, blue, opaque capsule printed with "UPSHER-SMITH" over "0228" and "50 mg" in black ink. They are supplied as follows:

60 mg, size 1, pink, opaque capsule printed with "UPSHER-SMITH" over "0229" and "60 mg" in black ink. They are supplied as follows:

80 mg, size 1, light orange, opaque capsule printed with "UPSHER-SMITH" over "0230" and "80 mg" in black ink. They are supplied as follows:

100 mg, size 0, green, opaque capsule printed with "UPSHER-SMITH" over "0233" and "100 mg" in black ink. They are supplied as follows:

Use of morphine sulfate extended-release capsules for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)] .

Individually titrate morphine sulfate extended-release capsules to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving morphine sulfate extended-release capsules to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1, 5.14)] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy, for an extended period of time, periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of morphine sulfate extended-release capsules or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the morphine sulfate extended-release capsules dosage. In patients experiencing inadequate analgesia with once daily dosing of morphine sulfate extended-release capsules, consider a twice daily regimen. Because steady-state plasma concentrations are approximated within 24 hours to 36 hours, morphine sulfate extended-release capsules dosage adjustments may be done every 1 to 2 days.

If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions (5)] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see Overdosage (10)] . Carbon dioxide (CO ₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of morphine sulfate, the risk is greatest during the initiation of therapy or following a dosage increase.

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

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

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 Patient Counseling Information (17)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5)].

Morphine sulfate extended-release capsules may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of morphine sulfate extended-release capsules and know how they will react to the medication [see Patient Counseling Information (17)] .

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)] . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.5); Warnings and Precautions (5.14)] .

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

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

• Complete a REMS-compliant education programoffered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Healthcare Providers Involved in the Management or Support of Patients with Pain.
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG)can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

Morphine sulfate extended-release capsules should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Morphine sulfate extended-release 100 mg capsules, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone daily, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of morphine sulfate extended-release capsules 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.
• 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 [see Warnings and Precautions (5.1)] .

Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with morphine sulfate extended-release capsules. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5)].

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

Instruct patients who are unable to swallow morphine sulfate extended-release capsules to sprinkle the capsule contents on applesauce and immediately swallow without chewing [see Dosage and Administration (2.6)] .

Morphine sulfate extended-release capsules are administered orally at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours).

NDC 0832-0225-00

Morphine Sulfate

Extended-Release Capsules, USP

CII

(Once or twice Daily Formulation)

10 mg

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 Capsules

Rx only

UPSHER-SMITH

NDC 0832-0226-00

Morphine Sulfate

Extended-Release Capsules, USP

CII

(Once or twice Daily Formulation)

20 mg

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 Capsules

Rx only

UPSHER-SMITH

NDC 0832-0227-00

Morphine Sulfate

Extended-Release Capsules, USP

CII

(Once or twice Daily Formulation)

30 mg

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 Capsules

Rx only

UPSHER-SMITH

NDC 0832-0228-00

Morphine Sulfate

Extended-Release Capsules, USP

CII

(Once or twice Daily Formulation)

50 mg

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 Capsules

Rx only

UPSHER-SMITH

NDC 0832-0229-00

Morphine Sulfate

Extended-Release Capsules, USP

CII

(Once or twice Daily Formulation)

60 mg

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 Capsules

Rx only

UPSHER-SMITH

NDC 0832-0230-00

Morphine Sulfate

Extended-Release Capsules, USP

CII

(Once or twice Daily Formulation)

80 mg

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 Capsules

Rx only

UPSHER-SMITH

NDC 0832-0233-00

Morphine Sulfate

Extended-Release Capsules, USP

CII

(Once or twice Daily Formulation)

100 mg

For Use in Opioid-Tolerant Patients Only

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 Capsules

Rx only

UPSHER-SMITH

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

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

Morphine sulfate extended-release capsules must be taken whole. Crushing, chewing, or dissolving the pellets in morphine sulfate extended-release capsules will result in uncontrolled delivery of morphine and can lead to overdose or death [see Warnings and Precautions (5.1)] .

Alternatively, the contents of the morphine sulfate extended-release capsules (pellets) may be sprinkled over applesauce and then swallowed. This method is appropriate only for patients able to reliably swallow the applesauce without chewing. Other foods have not been tested and should not be substituted for applesauce. Instruct the patient to:

• Sprinkle the pellets onto a small amount of applesauce and consume immediately without chewing.
• Rinse the mouth to ensure all pellets have been swallowed.
• Discard any unused portion of the morphine sulfate extended-release capsules after the contents have been sprinkled on applesauce.

The contents of the morphine sulfate extended-release capsules (pellets) may be administered through a French gastrostomy tube.

• Flush the gastrostomy tube with water to ensure that it is wet.
• Sprinkle the morphine sulfate extended-release pellets into 10 mL of water.
• Use a swirling motion to pour the pellets and water into the gastrostomy tube through a funnel.
• Rinse the beaker with a further 10 mL of water and pour this into the funnel.
• Repeat rinsing until no pellets remain in the beaker.

Do not administer morphine sulfate extended-release pellets through a nasogastric tube.

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

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of morphine sulfate with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)] .

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

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)] .

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

Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on morphine sulfate extended-release capsule therapy. The co-ingestion of alcohol with morphine sulfate extended-release capsules may result in increased plasma levels and a potentially fatal overdose of morphine.

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate extended-release capsules [see Warnings and Precautions (5.2), Patient Counseling Information (17)].

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

Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, 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 [see Warnings and Precautions (5.1, 5.2, 5.3)].

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

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

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

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

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.14), Drug Abuse and Dependence (9.3)] .

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF MORPHINE SULFATE EXTENDED-RELEASE CAPSULES

See full prescribing information for complete boxed warning.

• Morphine sulfate extended-release capsules expose users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk before prescribing, and monitor regularly for these behaviors and conditions. ( 5.1)
• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow morphine sulfate extended-release capsules whole to avoid exposure to a potentially fatal dose of morphine. ( 5.3)
• Accidental ingestion of morphine sulfate extended-release capsules, especially by children, can result in fatal overdose of morphine. ( 5.2)
• Instruct patients not to consume alcohol or any products containing alcohol while taking morphine sulfate extended-release capsules because co-ingestion can result in fatal plasma morphine levels. ( 5.3)
• Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.3, 7)
• Prolonged use of morphine sulfate extended-release capsules during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. ( 5.4)
• To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. ( 5.5)

In patients who may be susceptible to the intracranial effects of CO ₂retention (e.g., those with evidence of increased intracranial pressure or brain tumors), morphine sulfate extended-release capsules may reduce respiratory drive, and the resultant CO ₂retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with morphine sulfate extended-release capsules.

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

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