Morphine Sulfate Oral Solution

Risk of Medication Errors

Ensure accuracy when prescribing, dispensing, and administering Morphine Sulfate Oral Solution. Dosing errors due to confusion between mg and mL, and other morphine solutions of different concentrations can result in accidental overdose and death [ see Dosage and Administration ( 2.1), Warnings and Precautions ( 5.1 )].

Storage

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

Protect from moisture.



Store Morphine Sulfate Oral Sulfate Solution securely and dispose of properly [ see Patient Counseling Information ( 17) ].

Morphine Sulfate Oral Solution contains morphine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and tapentadol. Morphine Sulfate Oral Solution can be abused and is subject to misuse, addiction, and criminal diversion [ see Warnings and Precautions (5.2) ].

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

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

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Morphine Sulfate Oral Solution, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

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

Morphine Sulfate Oral Solution is an opioid agonist, available in the following concentrations for oral administration:

• 10 mg per 5 mL (2 mg/mL): Each 1 mL of oral solution contains 2 mg of morphine sulfate, USP (equivalent to 1.5 mg morphine).
• 20 mg per 5 mL (4 mg/mL): Each 1 mL of oral solution contains 4 mg of morphine sulfate, USP (equivalent to 3 mg morphine).
• 100 mg per 5 mL (20 mg/mL): Each 1 mL of oral solution contains 20 mg of morphine sulfate, USP (equivalent to 15 mg morphine).

The chemical name is 7,8-didehydro-4,5 alpha-epoxy-17 methyl-morphinan-3,6 alpha-diol sulfate (2:1) (salt) pentahydrate. The molecular weight is 758.83. Its molecular formula is (C ₁₇H ₂₁NO ₃)2•H ₂SO ₄•5Η ₂Ο, and it has the following chemical structure.

Morphine sulfate, USP is a white to off-white crystalline powder or a fine white to light yellow powder. It is soluble in water and slightly soluble in 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 _a is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4).

For the 10 mg per 5 mL (2 mg/mL) concentration: Each 5 mL of oral solution contains 10 mg of morphine sulfate, USP and the following inactive ingredients: citric acid anhydrous, disodium edetate, FD&C Green No. 3, glycerin, sodium benzoate, sorbitol, sucralose, and purified water.

For the 20 mg per 5 mL (4 mg/mL) concentration: Each 5 mL of oral solution contains 20 mg of morphine sulfate, USP and the following inactive ingredients: citric acid anhydrous, disodium edetate, FD&C Green No. 3, glycerin, sodium benzoate, sorbitol, sucralose, and purified water.

For the 100 mg per 5 mL (20 mg/mL) concentration (only for opioid tolerant adults): Each 5 mL of oral solution contains 100 mg of morphine sulfate, USP and the following inactive ingredients: citric acid anhydrous, D&C Red No. 33, disodium edetate, glycerin, sodium benzoate, sorbitol, sucralose, and purified water.

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Do not abruptly discontinue Morphine Sulfate Oral Solution in a patient physically dependent on opioids. Rapid tapering of Morphine Sulfate Oral Solution 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 Oral Solution, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Morphine Sulfate Oral Solution the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.6) and  Warnings and Precautions ( 5.4, 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 Oral Solution in a patient physically dependent on opioids. When discontinuing Morphine Sulfate Oral Solution 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 ( 2.6) and Drug Abuse and Dependence ( 9.3)] .



Additionally, avoid the use of mixed agonist/antagonist (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 Oral Solution. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions ( 7) ]

This Medication Guide has been approved by the U.S. Food and Drug Administration

RLS.106.99-1.0

Revised Feb 2022

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.'s morphine sulfate oral solution. However, due to Hikma Pharmaceuticals USA Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

The safety and effectiveness of Morphine Sulfate Oral Solution (2 mg/mL and 4mg/mL) have not been established for the management of pediatric patients 2 to 17 years of age with chronic pain severe enough to require an opioid analgesic when alternative treatments are inadequate.



The safety and effectiveness of Morphine Sulfate Oral Solution (2 mg/mL and 4mg/mL ) have not been established in pediatric patients less than 2 years of age.



The safety and effectiveness of Morphine Sulfate Oral Solution 20 mg/mL have not been established in pediatric patients.

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.'s morphine sulfate oral solution. However, due to Hikma Pharmaceuticals USA Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general, use caution when selecting a dose for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Morphine Sulfate Oral Solution slowly in geriatric patients and monitor closely 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 monitor renal function.

Initiating Treatment with Morphine Sulfate Oral Solution

Adults: The recommended dosage to initiate treatment with Morphine Sulfate Oral Solution 2 mg/mL and 4 mg/mL in adults is 10 mg to 20 mg every 4 hours as needed for pain.



Do not initiate treatment with Morphine Sulfate Oral Solution 20 mg/mL in adult patients who are opioid naïve. The recommended dosage to initiate treatment with Morphine Sulfate Oral Solution 20 mg/mL in opioid tolerant adults is 10 mg to 20 mg every 4 hours as needed for pain.

Conversion from Parenteral Morphine to Morphine Sulfate Oral Solution

For conversion from parenteral morphine to Morphine Sulfate Oral Solution, anywhere from 3 to 6 mg of oral morphine sulfate may be required to provide pain relief equivalent to 1 mg of parenteral morphine.

Conversion from Other Opioids to Morphine Sulfate Oral Solution

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Morphine Sulfate Oral Solution. It is safer to underestimate a patient’s 24-hour Morphine Sulfate Oral Solution dosage than to overestimate the 24-hour Morphine Sulfate Oral Solution dosage and manage an adverse reaction due to overdose. Initiate treatment in adults a dosage range of 10 to 20 mg every 4 hours as needed for pain.

Conversion from Morphine Sulfate Oral Solution to Extended-Release Morphine

For a given dose, the same total amount of morphine sulfate is available from Morphine Sulfate Oral Solution and extended-release morphine formulations. The extended duration of release of morphine sulfate from extended-release formulations results in reduced maximum and increased minimum plasma morphine sulfate concentrations than with shorter acting morphine sulfate products. Conversion from Morphine Sulfate Oral Solution to the same total daily dose of an extended-release formulation could lead to excessive sedation at peak serum levels. Therefore, conversion to extended-release morphine formulations must be accompanied by close observation for signs of excessive sedation and respiratory depression.

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.'s morphine sulfate oral solution. However, due to Hikma Pharmaceuticals USA Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Morphine Sulfate Oral Solution is contraindicated in patients with:

• Significant respiratory depression [ see Warnings and Precautions ( 5.4 ) ].
  
  
  
  
• 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 to morphine (e.g., anaphylaxis) [ see Adverse Reactions ( 6) ].

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

• Addiction, Abuse, and Misuse [ see Warnings and Precautions (5.2) ]
• Life-Threatening Respiratory Depression [ see Warnings and Precautions (5.4) ]
• Neonatal Opioid Withdrawal Syndrome [ see Warnings and Precautions (5.5) ]
• Interactions with Benzodiazepine or Other CNS Depressants [ see Warnings and Precautions (5.6) ]
• Adrenal Insufficiency [ see Warnings and Precautions (5.9) ]
• Severe Hypotension [ see Warnings and Precautions (5.10) ]
• Gastrointestinal Adverse Reactions [ see Warnings and Precautions (5.12) ]
• Seizures [ see Warnings and Precautions (5.13) ]
• Withdrawal [ see Warnings and Precautions (5.14) ]

The following adverse reactions associated with the use of morphine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

The common adverse reactions seen on initiation of therapy with morphine in adults were dose-dependent and were typical opioid-related adverse reactions. The most frequent of these included constipation, nausea, and somnolence. Other commonly observed adverse reactions included: lightheadedness, dizziness, sedation, vomiting, and sweating. The frequency of these events depended upon several factors including clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual.

Other less frequently observed adverse reactions from opioid analgesics, including morphine sulfate included:

Body as a Whole: malaise, withdrawal syndrome

Cardiovascular System: bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia

Digestive System: anorexia, biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst

Endocrine : hypogonadism

Hemic and Lymphatic System : anemia, thrombocytopenia

Metabolic and Nutritional Disorders : edema, weight loss

Musculoskeletal : skeletal muscle rigidity, decreased bone mineral density

Nervous System : abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, depression, dry mouth, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo, headache

Respiratory System : hiccup, hypoventilation, voice alteration

Skin and Appendages : dry skin, urticaria, pruritus

Special Senses : amblyopia, eye pain, taste perversion

Urogenital System : abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention or hesitancy, anti-diuretic effect, amenorrhea

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

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

Anaphylaxis : Anaphylaxis has been reported with ingredients contained in Morphine Sulfate Oral Solution.

Androgen Deficiency : Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)] .

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.'s morphine sulfate oral solution. However, due to Hikma Pharmaceuticals USA Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Table 1 includes clinically significant drug interactions with Morphine Sulfate Oral Solution.

Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than usual dosage of Morphine Sulfate Oral Solution and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)] .

Morphine Sulfate Oral Solution, CII

20 mg/mL

Important Information You Need to Know Before Using Morphine Sulfate Oral Solution:

• The Morphine Sulfate Oral Solution 20 mg/mL should only be used in adults who have received opioids in the past or who are currently receiving opioids.
• Always use the oral syringe that comes with your Morphine Sulfate Oral Solution to measure your prescribed dose.
• Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose.

Each Morphine Sulfate Oral Solution carton contains:

• 1 Morphine Sulfate Oral Solution bottle
• 1 Oral syringe

How should I store Morphine Sulfate Oral Solution?

• Store Morphine Sulfate Oral Solution at room temperature 68°F to 77°F (20°C to 25°C).
• Protect from moisture.
• Keep Morphine Sulfate Oral Solution and all medicines out of the reach of children.

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 Oral Solution and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)] .

Morphine Sulfate Oral Solution 2 mg/mL and 4 mg/mL is indicated for the management of:

• adults with acute and chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Morphine Sulfate Oral Solution 20 mg/mL is indicated for the relief of acute and chronic pain in opioid-tolerant adult patients.

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

• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. ( 5.7)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.9)
• Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Morphine Sulfate Oral Solution 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 Oral Solution in patients with impaired consciousness or coma. ( 5.11)

• Morphine Sulfate Oral Solution 20 mg/mL is only for opioid-tolerant adult patients. ( 2.1 ) 
• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. ( 2.1 )
• Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. ( 2.1 ) 
• 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 Oral Solution. Consider prescribing naloxone based on the patient’s risk factors for overdose. ( 2.2, 5.2, 5.4, 5.6 ). 
• Adults: Initiate treatment with Morphine Sulfate Oral Solution 10 mg to 20 mg every 4 hours as needed. ( 2.3 ) 
• Do not abruptly discontinue Morphine Sulfate Oral Solution in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5 )

Morphine Sulfate Oral Solution:

• 10 mg per 5 mL (2 mg/mL): Each 1 mL of clear, blue-green oral solution contains 2 mg of morphine sulfate, USP (equivalent to 1.5 mg morphine).
• 20 mg per 5 mL (4 mg/mL): Each 1 mL of clear, blue-green oral solution contains 4 mg of morphine sulfate, USP (equivalent to 3 mg morphine).
• 100 mg per 5 mL (20 mg/mL) (only for opioid tolerant adults) : Each 1 mL of clear, pink oral solution contains 20 mg of morphine sulfate, USP (equivalent to 15 mg morphine).
  
  

Pregnancy: May cause fetal harm. ( 8.1)

Morphine Sulfate Oral Solution contains morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Oral Solution exposes users to the risks of addiction, abuse, and misuse [ 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. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Morphine Sulfate Oral Solution, and monitor all patients receiving Morphine Sulfate Oral Solution 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 Oral Solution, but use in such patients necessitates intensive counseling about the risks and proper use of Morphine Sulfate Oral Solution along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Morphine Sulfate Oral Solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug.



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 patients or caregivers to read the FDA-approved patient labeling (Medication Guide and Instruction for Use).

Storage and Disposal

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Morphine Sulfate Oral Solution securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions ( 5.4, 5.14) and Drug Abuse and Dependence ( 9.2)]. Inform patients that leaving Morphine Sulfate Oral Solution unsecured can pose a deadly risk to others in the home.



Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused Morphine Sulfate Oral Solution 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 Oral Solution

10 mg per 5 mL (2 mg/mL) Oral Solution is supplied as a clear, blue-green solution. Each 1 mL clear, blue green oral solution contains 2 mg morphine sulfate, USP (equivalent to 1.5 morphine).

• NDC 75826-129-05: Bottle of 100 mL
• NDC 75826-129-17: Bottle of 500 mL

20 mg per 5 mL (4 mg/ mL) Oral Solution is supplied as a clear, blue-green solution. Each 1 mL of clear, blue-green oral solution contains 4 mg of morphine sulfate, USP (equivalent to 3 mg morphine).

• NDC 75826-130-05: Bottle of 100 mL
• NDC 75826-130-17: Bottle of 500 mL
  
  
  
  

100 mg per 5 mL (20 mg/mL) Oral Solution (color added)  (only for opioid tolerant adults) is supplied as a clear, pink solution.  Each 1 mL of clear, pink oral solution contains 20 mg of morphine sulfate, USP (equivalent to 15 mg morphine).

• NDC 75826-131-15: Bottle of 15 mL with an Oral Syringe
• NDC 75826-131-01: Bottle of 30 mL with an Oral Syringe
• NDC 75826-131-04: Bottle of 120 mL with an Oral Syringe

Morphine Sulfate Oral Solution is available in three concentrations: 2 mg/mL, 4 mg/mL, and 20 mg/mL [ see Dosage Forms and Strengths ( 3) ]

• Morphine Sulfate Oral Solution 2 mg/mL and 4 mg/mL is indicated for use in adults.
  • Always use an appropriately graduated oral syringe with metric units of measurement (i.e., mL) when administering Morphine Sulfate Oral Solution 2 mg/mL and 4 mg/mL to correctly measure the prescribed amount of medication.

• Morphine Sulfate Oral Solution 20 mg/mL is only indicated for use in opioid-tolerant adult patients who have already been receiving opioid therapy. This concentration is to be used only in adult patients who have already been titrated to a stable analgesic regimen using lower concentrations of morphine sulfate and who can benefit from use of a higher concentration (smaller volume) of oral solution. 
  • Adult patients considered to be opioid tolerant are those who are receiving, 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 per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
  • Always use the enclosed calibrated oral syringe when administering Morphine Sulfate Oral Solution 20 mg/mL to ensure the dose is measured and administered accurately.

• Ensure accuracy when prescribing, dispensing, and administering Morphine Sulfate Oral Solution to avoid dosing errors due to confusion between mg and mL, and with other morphine solutions of different concentrations, which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose (in mg) and the total dose in volume (mL).
• Instruct patients on how to accurately measure and take the correct dose of Morphine Sulfate Oral Solution.
• Instruct patients to never use household teaspoons or tablespoons to measure Morphine Sulfate Oral Solution.

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.'s morphine sulfate oral solution. However, due to Hikma Pharmaceuticals USA Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Prolonged use of Morphine Sulfate Oral Solution during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [ see Use in Specific Populations ( 8.1) ].

Individually titrate Morphine Sulfate Oral Solution to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Morphine Sulfate Oral Solution to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.2)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.



If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Morphine Sulfate Oral Solution dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

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 Oral Solution, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Morphine Sulfate Oral Solution.

To reduce the risk of respiratory depression, proper dosing and titration of Morphine Sulfate Oral Solution are essential [ see Dosage and Administration ( 2 ) ]. Overestimating the Morphine Sulfate Oral Solution dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Morphine Sulfate Oral Solution 20 mg/mL is for use only in opioid-tolerant adult patients. Administration of this formulation may cause fatal respiratory depression when administered to patients who are not tolerant to the respiratory depressant effects of opioids.

Accidental ingestion of even one dose of Morphine Sulfate Oral Solution, 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 (2.6)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose:

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Morphine Sulfate Oral Solution. 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). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].



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. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Warnings and Precautions (5.2, 5.6), Patient Counseling Information (17)].

NDC 75826-131-15

15mL

Morphine Sulfate

Oral Solution ^†

CII

100 mg / 5 mL

(20 mg/mL) ^†Color Added

ONLY FOR USE IN PATEINTS

WHO ARE OPIOID TOLERANT

PHARMACIST: Dispense the

Enclosed Medication Guide to

each patient.

Rx Only

PRINCIPAL DISPLAY PANEL - 30 ml Bottle Label

NDC 75826-131-01

30ml



Morphine Sulfate Oral Solution ^†

CII

100 mg / 5 ml

(20 mg/ml) ^†Color Added



ONLY FOR USE IN PATEINTS WHO ARE OPIOD TOLERANT



PHARMACIST: Dispense the Enclosed Medication Guide to each patient



Rx Only

Morphine Sulfate Oral Solution 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 Oral Solution and know how they will react to the medication.

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

NDC 75826-129-05

100 mL

Morphine Sulfate

Oral Solution

CII

10 mg / 5 mL

PHARMACIST: Dispense the

Enclosed Medication Guide to

each patient.

Rx Only

NDC 75826-130-05

100 mL

Morphine Sulfate

Oral Solution

CII

20 mg / 5 mL

PHARMACIST: Dispense the

Enclosed Medication Guide to

each patient.

Rx Only

Morphine Sulfate Oral Solution is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The morphine in Morphine Sulfate Oral Solution may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with morphine solutions of different concentrations, when prescribing, dispensing, and administering Morphine Sulfate Oral Solution. Ensure that the dose is communicated clearly and dispensed accurately. Always use the enclosed calibrated oral syringe or dosing cup when administering Morphine Sulfate Oral Solution to ensure the dose is measured and administered accurately. A household teaspoon or tablespoon is not an adequate measuring device. Given the inexactitude of the household spoon measure and the possibility of using a tablespoon instead of a teaspoon, which could lead to overdosage, it is strongly recommended that caregivers obtain and use a calibrated measuring device. Health care providers should recommend a calibrated device that can measure and deliver the prescribed dose accurately, and instruct caregivers to use extreme caution in measuring the dosage.

The morphine in Morphine Sulfate Oral Solution may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Morphine Sulfate Oral Solution therapy.

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

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

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

Do not abruptly discontinue Morphine Sulfate Oral Solution 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 Oral Solution, there are a variety of factors that should be considered, including the dose of Morphine Sulfate Oral Solution 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 Oral Solution who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.



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



When managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.4), Drug Abuse and Dependence ( 9.3)].

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Morphine Sulfate Oral Solution with benzodiazepines or other CNS depressants (e.g., non- benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [ see Drug Interactions ( 7) ]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.



If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when Morphine Sulfate Oral Solution is 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) ].

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 Oral Solution [see Warnings and Precautions ( 5.4), 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 ( 5.2, 5.4, 5.6)].



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

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

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Morphine Sulfate Oral Solution in patients with impaired consciousness or coma.

The use of Morphine Sulfate Oral Solution in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

See full prescribing information for complete boxed warning.

• Ensure accuracy when prescribing, dispensing, and administering Morphine Sulfate Oral Solution. Dosing errors due to confusion between mg and mL, and other morphine solutions of different concentrations can result in accidental overdose and death. ( 2.1, 5.1)
• Morphine Sulfate Oral Solution exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and monitor regularly for these behaviors and conditions. ( 5.2)
• 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. ( 5.3)
• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. ( 5.4)
• Accidental ingestion of Morphine Sulfate Oral Solution, especially by children, can result in a fatal overdose of morphine. ( 5.4)
• Prolonged use of Morphine Sulfate Oral Solution 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. ( 5.5)
• 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. ( 5.6, 7)

Risk of Medication Errors

Ensure accuracy when prescribing, dispensing, and administering Morphine Sulfate Oral Solution. Dosing errors due to confusion between mg and mL, and other morphine solutions of different concentrations can result in accidental overdose and death [ see Dosage and Administration ( 2.1), Warnings and Precautions ( 5.1 )].

Storage

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

Protect from moisture.



Store Morphine Sulfate Oral Sulfate Solution securely and dispose of properly [ see Patient Counseling Information ( 17) ].

Morphine Sulfate Oral Solution contains morphine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and tapentadol. Morphine Sulfate Oral Solution can be abused and is subject to misuse, addiction, and criminal diversion [ see Warnings and Precautions (5.2) ].

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

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

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Morphine Sulfate Oral Solution, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

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

Morphine Sulfate Oral Solution is an opioid agonist, available in the following concentrations for oral administration:

• 10 mg per 5 mL (2 mg/mL): Each 1 mL of oral solution contains 2 mg of morphine sulfate, USP (equivalent to 1.5 mg morphine).
• 20 mg per 5 mL (4 mg/mL): Each 1 mL of oral solution contains 4 mg of morphine sulfate, USP (equivalent to 3 mg morphine).
• 100 mg per 5 mL (20 mg/mL): Each 1 mL of oral solution contains 20 mg of morphine sulfate, USP (equivalent to 15 mg morphine).

The chemical name is 7,8-didehydro-4,5 alpha-epoxy-17 methyl-morphinan-3,6 alpha-diol sulfate (2:1) (salt) pentahydrate. The molecular weight is 758.83. Its molecular formula is (C ₁₇H ₂₁NO ₃)2•H ₂SO ₄•5Η ₂Ο, and it has the following chemical structure.

Morphine sulfate, USP is a white to off-white crystalline powder or a fine white to light yellow powder. It is soluble in water and slightly soluble in 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 _a is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4).

For the 10 mg per 5 mL (2 mg/mL) concentration: Each 5 mL of oral solution contains 10 mg of morphine sulfate, USP and the following inactive ingredients: citric acid anhydrous, disodium edetate, FD&C Green No. 3, glycerin, sodium benzoate, sorbitol, sucralose, and purified water.

For the 20 mg per 5 mL (4 mg/mL) concentration: Each 5 mL of oral solution contains 20 mg of morphine sulfate, USP and the following inactive ingredients: citric acid anhydrous, disodium edetate, FD&C Green No. 3, glycerin, sodium benzoate, sorbitol, sucralose, and purified water.

For the 100 mg per 5 mL (20 mg/mL) concentration (only for opioid tolerant adults): Each 5 mL of oral solution contains 100 mg of morphine sulfate, USP and the following inactive ingredients: citric acid anhydrous, D&C Red No. 33, disodium edetate, glycerin, sodium benzoate, sorbitol, sucralose, and purified water.

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Do not abruptly discontinue Morphine Sulfate Oral Solution in a patient physically dependent on opioids. Rapid tapering of Morphine Sulfate Oral Solution 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 Oral Solution, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Morphine Sulfate Oral Solution the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.6) and  Warnings and Precautions ( 5.4, 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 Oral Solution in a patient physically dependent on opioids. When discontinuing Morphine Sulfate Oral Solution 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 ( 2.6) and Drug Abuse and Dependence ( 9.3)] .



Additionally, avoid the use of mixed agonist/antagonist (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 Oral Solution. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions ( 7) ]

This Medication Guide has been approved by the U.S. Food and Drug Administration

RLS.106.99-1.0

Revised Feb 2022

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.'s morphine sulfate oral solution. However, due to Hikma Pharmaceuticals USA Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

The safety and effectiveness of Morphine Sulfate Oral Solution (2 mg/mL and 4mg/mL) have not been established for the management of pediatric patients 2 to 17 years of age with chronic pain severe enough to require an opioid analgesic when alternative treatments are inadequate.



The safety and effectiveness of Morphine Sulfate Oral Solution (2 mg/mL and 4mg/mL ) have not been established in pediatric patients less than 2 years of age.



The safety and effectiveness of Morphine Sulfate Oral Solution 20 mg/mL have not been established in pediatric patients.

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.'s morphine sulfate oral solution. However, due to Hikma Pharmaceuticals USA Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general, use caution when selecting a dose for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Morphine Sulfate Oral Solution slowly in geriatric patients and monitor closely 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 monitor renal function.

Initiating Treatment with Morphine Sulfate Oral Solution

Adults: The recommended dosage to initiate treatment with Morphine Sulfate Oral Solution 2 mg/mL and 4 mg/mL in adults is 10 mg to 20 mg every 4 hours as needed for pain.



Do not initiate treatment with Morphine Sulfate Oral Solution 20 mg/mL in adult patients who are opioid naïve. The recommended dosage to initiate treatment with Morphine Sulfate Oral Solution 20 mg/mL in opioid tolerant adults is 10 mg to 20 mg every 4 hours as needed for pain.

Conversion from Parenteral Morphine to Morphine Sulfate Oral Solution

For conversion from parenteral morphine to Morphine Sulfate Oral Solution, anywhere from 3 to 6 mg of oral morphine sulfate may be required to provide pain relief equivalent to 1 mg of parenteral morphine.

Conversion from Other Opioids to Morphine Sulfate Oral Solution

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Morphine Sulfate Oral Solution. It is safer to underestimate a patient’s 24-hour Morphine Sulfate Oral Solution dosage than to overestimate the 24-hour Morphine Sulfate Oral Solution dosage and manage an adverse reaction due to overdose. Initiate treatment in adults a dosage range of 10 to 20 mg every 4 hours as needed for pain.

Conversion from Morphine Sulfate Oral Solution to Extended-Release Morphine

For a given dose, the same total amount of morphine sulfate is available from Morphine Sulfate Oral Solution and extended-release morphine formulations. The extended duration of release of morphine sulfate from extended-release formulations results in reduced maximum and increased minimum plasma morphine sulfate concentrations than with shorter acting morphine sulfate products. Conversion from Morphine Sulfate Oral Solution to the same total daily dose of an extended-release formulation could lead to excessive sedation at peak serum levels. Therefore, conversion to extended-release morphine formulations must be accompanied by close observation for signs of excessive sedation and respiratory depression.

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.'s morphine sulfate oral solution. However, due to Hikma Pharmaceuticals USA Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Morphine Sulfate Oral Solution is contraindicated in patients with:

• Significant respiratory depression [ see Warnings and Precautions ( 5.4 ) ].
  
  
  
  
• 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 to morphine (e.g., anaphylaxis) [ see Adverse Reactions ( 6) ].

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

• Addiction, Abuse, and Misuse [ see Warnings and Precautions (5.2) ]
• Life-Threatening Respiratory Depression [ see Warnings and Precautions (5.4) ]
• Neonatal Opioid Withdrawal Syndrome [ see Warnings and Precautions (5.5) ]
• Interactions with Benzodiazepine or Other CNS Depressants [ see Warnings and Precautions (5.6) ]
• Adrenal Insufficiency [ see Warnings and Precautions (5.9) ]
• Severe Hypotension [ see Warnings and Precautions (5.10) ]
• Gastrointestinal Adverse Reactions [ see Warnings and Precautions (5.12) ]
• Seizures [ see Warnings and Precautions (5.13) ]
• Withdrawal [ see Warnings and Precautions (5.14) ]

The following adverse reactions associated with the use of morphine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

The common adverse reactions seen on initiation of therapy with morphine in adults were dose-dependent and were typical opioid-related adverse reactions. The most frequent of these included constipation, nausea, and somnolence. Other commonly observed adverse reactions included: lightheadedness, dizziness, sedation, vomiting, and sweating. The frequency of these events depended upon several factors including clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual.

Other less frequently observed adverse reactions from opioid analgesics, including morphine sulfate included:

Body as a Whole: malaise, withdrawal syndrome

Cardiovascular System: bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia

Digestive System: anorexia, biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst

Endocrine : hypogonadism

Hemic and Lymphatic System : anemia, thrombocytopenia

Metabolic and Nutritional Disorders : edema, weight loss

Musculoskeletal : skeletal muscle rigidity, decreased bone mineral density

Nervous System : abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, depression, dry mouth, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo, headache

Respiratory System : hiccup, hypoventilation, voice alteration

Skin and Appendages : dry skin, urticaria, pruritus

Special Senses : amblyopia, eye pain, taste perversion

Urogenital System : abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention or hesitancy, anti-diuretic effect, amenorrhea

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

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

Anaphylaxis : Anaphylaxis has been reported with ingredients contained in Morphine Sulfate Oral Solution.

Androgen Deficiency : Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)] .

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.'s morphine sulfate oral solution. However, due to Hikma Pharmaceuticals USA Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Table 1 includes clinically significant drug interactions with Morphine Sulfate Oral Solution.

Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than usual dosage of Morphine Sulfate Oral Solution and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)] .

Morphine Sulfate Oral Solution, CII

20 mg/mL

Important Information You Need to Know Before Using Morphine Sulfate Oral Solution:

• The Morphine Sulfate Oral Solution 20 mg/mL should only be used in adults who have received opioids in the past or who are currently receiving opioids.
• Always use the oral syringe that comes with your Morphine Sulfate Oral Solution to measure your prescribed dose.
• Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose.

Each Morphine Sulfate Oral Solution carton contains:

• 1 Morphine Sulfate Oral Solution bottle
• 1 Oral syringe

How should I store Morphine Sulfate Oral Solution?

• Store Morphine Sulfate Oral Solution at room temperature 68°F to 77°F (20°C to 25°C).
• Protect from moisture.
• Keep Morphine Sulfate Oral Solution and all medicines out of the reach of children.

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 Oral Solution and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)] .

Morphine Sulfate Oral Solution 2 mg/mL and 4 mg/mL is indicated for the management of:

• adults with acute and chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Morphine Sulfate Oral Solution 20 mg/mL is indicated for the relief of acute and chronic pain in opioid-tolerant adult patients.

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

• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. ( 5.7)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.9)
• Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Morphine Sulfate Oral Solution 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 Oral Solution in patients with impaired consciousness or coma. ( 5.11)

• Morphine Sulfate Oral Solution 20 mg/mL is only for opioid-tolerant adult patients. ( 2.1 ) 
• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. ( 2.1 )
• Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. ( 2.1 ) 
• 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 Oral Solution. Consider prescribing naloxone based on the patient’s risk factors for overdose. ( 2.2, 5.2, 5.4, 5.6 ). 
• Adults: Initiate treatment with Morphine Sulfate Oral Solution 10 mg to 20 mg every 4 hours as needed. ( 2.3 ) 
• Do not abruptly discontinue Morphine Sulfate Oral Solution in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5 )

Morphine Sulfate Oral Solution:

• 10 mg per 5 mL (2 mg/mL): Each 1 mL of clear, blue-green oral solution contains 2 mg of morphine sulfate, USP (equivalent to 1.5 mg morphine).
• 20 mg per 5 mL (4 mg/mL): Each 1 mL of clear, blue-green oral solution contains 4 mg of morphine sulfate, USP (equivalent to 3 mg morphine).
• 100 mg per 5 mL (20 mg/mL) (only for opioid tolerant adults) : Each 1 mL of clear, pink oral solution contains 20 mg of morphine sulfate, USP (equivalent to 15 mg morphine).
  
  

Pregnancy: May cause fetal harm. ( 8.1)

Morphine Sulfate Oral Solution contains morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Oral Solution exposes users to the risks of addiction, abuse, and misuse [ 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. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Morphine Sulfate Oral Solution, and monitor all patients receiving Morphine Sulfate Oral Solution 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 Oral Solution, but use in such patients necessitates intensive counseling about the risks and proper use of Morphine Sulfate Oral Solution along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Morphine Sulfate Oral Solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug.



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 patients or caregivers to read the FDA-approved patient labeling (Medication Guide and Instruction for Use).

Storage and Disposal

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Morphine Sulfate Oral Solution securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions ( 5.4, 5.14) and Drug Abuse and Dependence ( 9.2)]. Inform patients that leaving Morphine Sulfate Oral Solution unsecured can pose a deadly risk to others in the home.



Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused Morphine Sulfate Oral Solution 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 Oral Solution

10 mg per 5 mL (2 mg/mL) Oral Solution is supplied as a clear, blue-green solution. Each 1 mL clear, blue green oral solution contains 2 mg morphine sulfate, USP (equivalent to 1.5 morphine).

• NDC 75826-129-05: Bottle of 100 mL
• NDC 75826-129-17: Bottle of 500 mL

20 mg per 5 mL (4 mg/ mL) Oral Solution is supplied as a clear, blue-green solution. Each 1 mL of clear, blue-green oral solution contains 4 mg of morphine sulfate, USP (equivalent to 3 mg morphine).

• NDC 75826-130-05: Bottle of 100 mL
• NDC 75826-130-17: Bottle of 500 mL
  
  
  
  

100 mg per 5 mL (20 mg/mL) Oral Solution (color added)  (only for opioid tolerant adults) is supplied as a clear, pink solution.  Each 1 mL of clear, pink oral solution contains 20 mg of morphine sulfate, USP (equivalent to 15 mg morphine).

• NDC 75826-131-15: Bottle of 15 mL with an Oral Syringe
• NDC 75826-131-01: Bottle of 30 mL with an Oral Syringe
• NDC 75826-131-04: Bottle of 120 mL with an Oral Syringe

Morphine Sulfate Oral Solution is available in three concentrations: 2 mg/mL, 4 mg/mL, and 20 mg/mL [ see Dosage Forms and Strengths ( 3) ]

• Morphine Sulfate Oral Solution 2 mg/mL and 4 mg/mL is indicated for use in adults.
  • Always use an appropriately graduated oral syringe with metric units of measurement (i.e., mL) when administering Morphine Sulfate Oral Solution 2 mg/mL and 4 mg/mL to correctly measure the prescribed amount of medication.

• Morphine Sulfate Oral Solution 20 mg/mL is only indicated for use in opioid-tolerant adult patients who have already been receiving opioid therapy. This concentration is to be used only in adult patients who have already been titrated to a stable analgesic regimen using lower concentrations of morphine sulfate and who can benefit from use of a higher concentration (smaller volume) of oral solution. 
  • Adult patients considered to be opioid tolerant are those who are receiving, 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 per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
  • Always use the enclosed calibrated oral syringe when administering Morphine Sulfate Oral Solution 20 mg/mL to ensure the dose is measured and administered accurately.

• Ensure accuracy when prescribing, dispensing, and administering Morphine Sulfate Oral Solution to avoid dosing errors due to confusion between mg and mL, and with other morphine solutions of different concentrations, which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose (in mg) and the total dose in volume (mL).
• Instruct patients on how to accurately measure and take the correct dose of Morphine Sulfate Oral Solution.
• Instruct patients to never use household teaspoons or tablespoons to measure Morphine Sulfate Oral Solution.

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.'s morphine sulfate oral solution. However, due to Hikma Pharmaceuticals USA Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Prolonged use of Morphine Sulfate Oral Solution during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [ see Use in Specific Populations ( 8.1) ].

Individually titrate Morphine Sulfate Oral Solution to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Morphine Sulfate Oral Solution to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.2)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.



If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Morphine Sulfate Oral Solution dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

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 Oral Solution, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Morphine Sulfate Oral Solution.

To reduce the risk of respiratory depression, proper dosing and titration of Morphine Sulfate Oral Solution are essential [ see Dosage and Administration ( 2 ) ]. Overestimating the Morphine Sulfate Oral Solution dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Morphine Sulfate Oral Solution 20 mg/mL is for use only in opioid-tolerant adult patients. Administration of this formulation may cause fatal respiratory depression when administered to patients who are not tolerant to the respiratory depressant effects of opioids.

Accidental ingestion of even one dose of Morphine Sulfate Oral Solution, 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 (2.6)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose:

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Morphine Sulfate Oral Solution. 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). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].



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. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Warnings and Precautions (5.2, 5.6), Patient Counseling Information (17)].

NDC 75826-131-15

15mL

Morphine Sulfate

Oral Solution ^†

CII

100 mg / 5 mL

(20 mg/mL) ^†Color Added

ONLY FOR USE IN PATEINTS

WHO ARE OPIOID TOLERANT

PHARMACIST: Dispense the

Enclosed Medication Guide to

each patient.

Rx Only

PRINCIPAL DISPLAY PANEL - 30 ml Bottle Label

NDC 75826-131-01

30ml



Morphine Sulfate Oral Solution ^†

CII

100 mg / 5 ml

(20 mg/ml) ^†Color Added



ONLY FOR USE IN PATEINTS WHO ARE OPIOD TOLERANT



PHARMACIST: Dispense the Enclosed Medication Guide to each patient



Rx Only

Morphine Sulfate Oral Solution 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 Oral Solution and know how they will react to the medication.

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

NDC 75826-129-05

100 mL

Morphine Sulfate

Oral Solution

CII

10 mg / 5 mL

PHARMACIST: Dispense the

Enclosed Medication Guide to

each patient.

Rx Only

NDC 75826-130-05

100 mL

Morphine Sulfate

Oral Solution

CII

20 mg / 5 mL

PHARMACIST: Dispense the

Enclosed Medication Guide to

each patient.

Rx Only

Morphine Sulfate Oral Solution is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The morphine in Morphine Sulfate Oral Solution may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with morphine solutions of different concentrations, when prescribing, dispensing, and administering Morphine Sulfate Oral Solution. Ensure that the dose is communicated clearly and dispensed accurately. Always use the enclosed calibrated oral syringe or dosing cup when administering Morphine Sulfate Oral Solution to ensure the dose is measured and administered accurately. A household teaspoon or tablespoon is not an adequate measuring device. Given the inexactitude of the household spoon measure and the possibility of using a tablespoon instead of a teaspoon, which could lead to overdosage, it is strongly recommended that caregivers obtain and use a calibrated measuring device. Health care providers should recommend a calibrated device that can measure and deliver the prescribed dose accurately, and instruct caregivers to use extreme caution in measuring the dosage.

The morphine in Morphine Sulfate Oral Solution may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Morphine Sulfate Oral Solution therapy.

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

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

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

Do not abruptly discontinue Morphine Sulfate Oral Solution 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 Oral Solution, there are a variety of factors that should be considered, including the dose of Morphine Sulfate Oral Solution 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 Oral Solution who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.



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



When managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.4), Drug Abuse and Dependence ( 9.3)].

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Morphine Sulfate Oral Solution with benzodiazepines or other CNS depressants (e.g., non- benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [ see Drug Interactions ( 7) ]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.



If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when Morphine Sulfate Oral Solution is 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) ].

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 Oral Solution [see Warnings and Precautions ( 5.4), 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 ( 5.2, 5.4, 5.6)].



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

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

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Morphine Sulfate Oral Solution in patients with impaired consciousness or coma.

The use of Morphine Sulfate Oral Solution in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

See full prescribing information for complete boxed warning.

• Ensure accuracy when prescribing, dispensing, and administering Morphine Sulfate Oral Solution. Dosing errors due to confusion between mg and mL, and other morphine solutions of different concentrations can result in accidental overdose and death. ( 2.1, 5.1)
• Morphine Sulfate Oral Solution exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and monitor regularly for these behaviors and conditions. ( 5.2)
• 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. ( 5.3)
• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. ( 5.4)
• Accidental ingestion of Morphine Sulfate Oral Solution, especially by children, can result in a fatal overdose of morphine. ( 5.4)
• Prolonged use of Morphine Sulfate Oral Solution 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. ( 5.5)
• 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. ( 5.6, 7)