Morphine Oral Solution

Morphine sulfate oral solution is contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.3)] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [seeWarnings and Precautions (5.6)] • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.7), Drug Interactions (7)]. • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.11)] • Hypersensitivity to morphine (e.g., anaphylaxis) [see Adverse Reactions (6)]

Risk of Accidental Overdose and Death due to Medication Errors

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 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.

Addiction, Abuse, and Misuse

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.

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 [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of morphine sulfate 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 [seeDosage 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 100 mg per 5 mL (20 mg/mL) is for use in opioid-tolerant patients only. 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.

Neonatal Opioid Withdrawal Syndrome

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), Patient Counseling Information (17)].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of morphine sulfate 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 [seeDrug Interactions (7)]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when morphine sulfate 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) and Patient Counseling Information (17)].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

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.

Patients with Chronic Pulmonary Disease

Morphine sulfate oral solution-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of morphine sulfate oral solution [see Warnings and Precautions (5.3)].

Elderly, Cachectic, or Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.3)].

Monitor such patients closely, particularly when initiating and titrating morphine sulfate oral solution and when morphine sulfate oral solution is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Interaction with Monoamine Oxidase Inhibitors

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.

Adrenal Insufficiency

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

Severe Hypotension

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.

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

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), morphine sulfate oral solution may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with morphine sulfate 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.

Risks of Use in Patients with Gastrointestinal Conditions

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.

Increased Risk of Seizures in Patients with Seizure Disorders

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.

Withdrawal

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)].

When discontinuing morphine sulfate oral solution, gradually taper the dosage [see Dosage and Administration (2.4)].

Do not abruptly discontinue morphine sulfate oral solution [see Drug Abuse and Dependence (9.3)].

Risks of Driving and Operating Machinery

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 [see Patient Counseling Information (17)].

Morphine Sulfate Oral Solution is an opioid agonist, available in 100 mg per 5 mL (20 mg/mL) strength for oral administration. 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. Its molecular formula is C17H21NO7S, 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 pKa is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4).

For the 100 mg per 5 mL (20 mg/mL) strength: Each 5 mL of oral solution contains 100 mg of morphine sulfate, USP and the following inactive ingredients: citric acid anhydrous, edetate disodium, glycerin, sodium benzoate, sorbitol solution, and purified water.

Mechanism of Action

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

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

Pharmacodynamics

Effects on the Central Nervous System

Morphine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

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

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6)].

Effects on the Immune System

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

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.3)].

Concentration–Adverse Reaction Relationships

There is a relationship between increasing morphine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.2, 2.3)].

Pharmacokinetics

Absorption

Morphine, when administered as morphine sulfate is about two-thirds absorbed from the gastrointestinal tract with the maximum analgesic effect occurring 60 minutes post-administration. The oral bioavailability of morphine sulfate is less than 40% and shows large inter-individual variability due to extensive pre-systemic metabolism.

Administration of 30 mg of morphine sulfate oral solution every six hours for 5 days resulted in a comparable 24-hour exposure (AUC). The steady-state levels were achieved within 48 hours for both tablets and solution. The mean steady state Cmax values were about 78 and 58 ng/mL for tablet and solution, respectively.

Food Effects: Although the presence of a food effect was not assessed with morphine sulfate oral solution, significant food effect is not expected with a solution formulation.

Distribution

Once absorbed, morphine sulfate is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. Although the primary site of action is the CNS, only small quantities cross the blood-brain barrier. Morphine sulfate also crosses the placental membranes and has been found in breast milk. The volume of distribution of morphine sulfate is approximately 1 to 6 L/kg, and morphine sulfate is 20 to 35% reversibly bound to plasma proteins.

Elimination

Metabolism: The major pathway of morphine sulfate detoxification is conjugation, either with D-glucuronic acid to produce glucuronides or with sulfuric acid to produce morphine-3-etheral sulfate. While a small fraction (less than 5%) of morphine sulfate is demethylated, virtually all morphine sulfate is converted by hepatic metabolism to the 3- and 6- glucuronide metabolites (M3G and M6G; about 50% and 15%, respectively). M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.

Excretion: Most of a dose of morphine sulfate is excreted in urine as M3G and M6G, with elimination of morphine sulfate occurring primarily as renal excretion of M3G. Approximately 10% of the dose is excreted unchanged in urine. A small amount of glucuronide conjugates are excreted in bile, with minor enterohepatic recycling. Seven to 10% of administered morphine sulfate is excreted in the feces.

The mean adult plasma clearance is approximately 20 to 30 mL/min/kg. The effective terminal half-life of morphine sulfate after IV administration is reported to be approximately 2 hours. In some studies involving longer periods of plasma sampling, a longer terminal half-life of morphine sulfate of about 15 hours was reported.

Specific Populations

Race/Ethnicity: There may be some pharmacokinetic differences associated with race. In one published study, Chinese subjects given intravenous morphine sulfate had a higher clearance when compared to Caucasian subjects (1852 +/- 116 mL/min compared to 1495 +/- 80 mL/min).

Sex: While evidence of greater post-operative morphine sulfate consumption in men compared to women is present in the literature, clinically significant differences in analgesic outcomes and pharmacokinetic parameters have not been consistently demonstrated. Some studies have shown an increased sensitivity to the adverse effects of morphine sulfate, including respiratory depression, in women compared to men.

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

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

Morphine Sulfate Oral Solution

Morphine Sulfate Oral Solution 100 mg per 5 mL is a clear/colorless solution available in one strength as follows:

100 mg per 5 mL (20 mg/mL) Oral Solution

Bottle of 30 mL with an oral syringe - NDC 50383-965-30

Bottle of 120 mL with an oral syringe - NDC 50383-965-04

Storage

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

PROTECT FROM MOISTURE.

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

Medication Errors

Advise patients that morphine sulfate oral solution is available in a concentration of 100 mg per 5 mL (20 mg/mL). Inform patients about the concentration they have been prescribed and provide detailed instruction on how to measure and take the correct dose of morphine sulfate oral solution, and to always use the enclosed measuring device when administering morphine sulfate oral solution to ensure that the dose is measured and administered accurately [see Warnings and Precautions (5.1)].

If the prescribed concentration is changed, instruct patients on how to correctly measure the new dose to avoid errors which could result in accidental overdose and death.

Addiction, Abuse, and Misuse

Inform patients that the use of morphine sulfate oral solution, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.2)]. Instruct patients not to share morphine sulfate oral solution with others and to take steps to protect morphine sulfate oral solution from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting morphine sulfate oral solution or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.3)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3)]. Instruct patients to take steps to store morphine sulfate oral solution securely and to dispose of unused morphine sulfate oral solution by flushing the unused oral solution down the toilet.

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if morphine sulfate oral solution is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.5), Drug Interactions (7)].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see Drug Interactions (7)].

MAOI Interaction

Inform patients not to take morphine sulfate oral solution while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking morphine sulfate oral solution [see Warnings and Precautions (5.7), Drug Interactions (7)].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.8)].

Important Administration Instructions

Instruct patients how to properly take morphine sulfate oral solution.

• Advise patients to always use the enclosed calibrated oral syringe when administering morphine sulfate oral solution 100 mg per 5 mL (20 mg/mL) to ensure the dose is measured and administered accurately [see Warnings and Precautions (5.1)]. • Advise patients never to use household teaspoons or tablespoons to measure morphine sulfate oral solution. • Inform patients that the 100 mg per 5 mL (20 mg/mL) formulation is only for patients who are already receiving opioid-therapy and have demonstrated opioid-tolerance. Use of this formulation may cause fatal respiratory depression when administered to patients who have not had previous exposure to opioids [see Indications and Usage (1), Dosage and Administration (2.1)] • Advise patients not to adjust the dose of morphine sulfate oral solution without consulting with a physician or other healthcare professional. • If patients have been receiving treatment with morphine sulfate oral solution for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose as abrupt discontinuation of the medication could precipitate withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the medication [see Dosage and Administration (2.4)].

Hypotension

Inform patients that morphine sulfate oral solution may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.9)].

Anaphylaxis

Inform patients that anaphylaxis have been reported with ingredients contained in morphine sulfate oral solution. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome: Inform female patients of reproductive potential that prolonged use of morphine sulfate oral solution during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

Embryo-Fetal Toxicity: Inform female patients of reproductive potential that morphine sulfate oral solution can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

Driving or Operating Heavy Machinery

Inform patients that morphine sulfate oral solution may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.14)].

Constipation

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

Disposal of Unused Morphine Sulfate Oral Solution

Advise patients to dispose of unused Morphine Oral Solution by flushing down the toilet.

Manufactured by:

Hi-Tech Pharmacal Co., Inc.

Amityville, NY 11701

Rev.965:00 04/17

INSTRUCTIONS FOR USE

Morphine Sulfate Oral Solution 100 mg per 5 mL (20 mg/mL)

Oral Syringe

Important information about measuring Morphine Sulfate Oral Solution

• Always use the oral syringe provided with your Morphine Sulfate Oral Solution to make sure you measure the right amount. • Measure the dose of medicine from the widest part of the plunger. Do not measure from the narrow tip. See figure 1

1. Insert the tip of the oral syringe into the medicine bottle.

2. Pull back the plunger to the line that matches the dose prescribed by your healthcare provider.

3. Remove the oral syringe from the medicine bottle.

4. Take your medicine by slowly pushing the plunger until the oral syringe is empty.

Figure 1

Morphine Sulfate Oral Solution, CII

(mor-pheen)

Rx Only

Morphine Sulfate Oral Solution is: • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage short term (acute) and long term (chronic) pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. • An opioid pain medicine that can put you at risk for overdose and death. Even if you takeyour dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.

Important information about morphine sulfate: • Get emergency help right away if you take too much Morphine Sulfate Oral Solution (overdose). When you first start taking Morphine Sulfate Oral Solution, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. • Taking Morphine Sulfate Oral Solution with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. • Never give anyone else your Morphine Sulfate Oral Solution. They could die from taking it. Store Morphine Sulfate Oral Solution away from children and in a safe place to prevent stealing or abuse. Selling or giving away Morphine Sulfate Oral Solution is against the law.

Do not take Morphine Sulfate Oral Solution if you have: • severe asthma, trouble breathing, or other lung problems. • a bowel blockage or have narrowing of the stomach or intestines. • an allergy to morphine

Before taking Morphine Sulfate Oral Solution, tell your healthcare provider if you have a history of: • head injury, seizures • liver, kidney, thyroid problems • problems urinating • pancreas or gallbladder problems • abuse of street or prescription drugs, alcohol addiction, or mental health problems. Tell your healthcare provider if you are: • pregnant or planning to become pregnant. Prolonged use of Morphine Sulfate Oral Solution during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. • breastfeeding. Morphine Sulfate Oral Solution passes into breast milk and may harm your baby. • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Morphine Sulfate Oral Solution with certain other medicines can cause serious side effects that could lead to death.

When taking Morphine Sulfate Oral Solution: • Do not change your dose. Take Morphine Sulfate Oral Solution exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. • See the detailed Instructions for Use for information about how to take Morphine Sulfate Oral Solution 100 mg/5mL (20 mg per mL). • Always use the enclosed calibrated oral syringe that comes with Morphine Sulfate Oral Solution to correctly measure your dose. Never use a household teaspoon or tablespoon to measure Morphine Sulfate Oral Solution. • Take your prescribed dose every 4 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. • Call your healthcare provider if the dose you are taking does not control your pain. • If you have been taking Morphine Sulfate Oral Solution regularly, do not stop taking Morphine Sulfate Oral Solution without talking to your healthcare provider. • After you stop taking Morphine Sulfate Oral Solution, flush unused Morphine Sulfate Oral Solution down the toilet.

While taking Morphine Sulfate Oral Solution DO NOT: • Drive or operate heavy machinery, until you know how Morphine Sulfate Oral Solution affects you. Morphine Sulfate Oral Solution can make you sleepy, dizzy, or lightheaded. • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Morphine Sulfate Oral Solution may cause you to overdose and die.

The possible side effects of Morphine Sulfate Oral Solution: • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help if you have: • trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. These are not all the possible side effects of Morphine Sulfate Oral Solution. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to Hi-Tech Pharmacal Co., Inc. at 1-800-262-9010 or FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov.

Manufactured by: Hi-Tech Pharmacal Co., Inc. Amityville, NY 11701

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

Issued: 04/2017

This medicine may interact with the following medications:

• alcohol
• antihistamines for allergy, cough and cold
• atropine
• certain medicines for anxiety or sleep
• certain medicines for bladder problems like oxybutynin, tolterodine
• certain medicines for depression like amitriptyline, fluoxetine, sertraline
• certain medicines for Parkinson's disease like benztropine, trihexyphenidyl
• certain medicines for seizures like phenobarbital, primidone
• certain medicines for stomach problems like dicyclomine, hyoscyamine
• certain medicines for travel sickness like scopolamine
• cimetidine
• general anesthetics like halothane, isoflurane, methoxyflurane, propofol
• ipratropium
• local anesthetics like lidocaine, pramoxine, tetracaine
• MAOIs like Carbex, Eldepryl, Marplan, Nardil, and Parnate
• medicines that relax muscles for surgery
• other narcotic medicines for pain or cough
• phenothiazines like chlorpromazine, mesoridazine, prochlorperazine, thioridazine

Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs interact differently in each person, we cannot guarantee that this information includes all possible interactions. This information is not a substitute for medical advice. Always speak with your healthcare provider about possible interactions with all prescription drugs, vitamins, herbs and supplements, and over-the-counter drugs that you are taking.