CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

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

12.2 Pharmacodynamics

Effects on the Central Nervous System

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

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

Effects on the Gastrointestinal Tract and Other Smooth Muscle

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

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 (2.2, 2.5)].

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 (2.2,2.4, 2.5)].

12.3 Pharmacokinetics

Absorption

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

Administration of 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.

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.

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INDICATIONS & USAGE SECTION

Highlight: Morphine Sulfate Oral Solution is an opioid agonist:

Morphine Sulfate Oral Solution 2 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. (1)

Morphine Sulfate Oral Solution 20 mg/mL is indicated for:

• the relief of acute and chronic pain inopioid-tolerant adult patients. (1)

Limitations of Use (1):

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Morphine Sulfate Oral Solution for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

• Have not been tolerated, or are not expected to be tolerated,

• Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

1 INDICATIONS AND USAGE

Morphine Sulfate Oral Solution 2 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 painin opioid-tolerant adult patients.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions (5.2)], reserve Morphine Sulfate Oral Solution for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

• Have not been tolerated, or are not expected to be tolerated,

• Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

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.

DOSAGE & ADMINISTRATION SECTION

Highlight: * 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)

2 DOSAGE AND ADMINISTRATION

2.1 Dosage and Administration Overview

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

• Morphine Sulfate Oral Solution 2 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 to correctly measure the prescribed amount of medication.
• Morphine Sulfate Oral Solution 20 mg/mL is only indicated for use inopioid-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.

2.2 Important Dosage and Administration Instructions

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

• Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.2)].

• Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with Morphine Sulfate Oral Solution and adjust the dosage accordingly [see Warnings and Precautions (5.4)].

**2.3 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 [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.

2.4 Initial Dosage

Initiating Treatment with Morphine Sulfate Oral Solution

Adults: The recommended dosage to initiate treatment with Morphine Sulfate Oral Solution 2 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 or in pediatric patients. 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.

Adults: The recommended dosage to initiate treatment with Morphine Sulfate Oral Solution 2 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 or in pediatric patients. 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.

2.5 Titration and Maintenance of Therapy

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.

**2.6 Safe Reduction or Discontinuation of Morphine Sulfate Oral Solution

**

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)].

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DRUG INTERACTIONS SECTION

Highlight: * Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue Morphine Sulfate Oral Solution if serotonin syndrome is suspected. (7)

• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Morphine Sulfate Oral Solution because they may reduce analgesic effect of Morphine Sulfate Oral Solution or precipitate withdrawal symptoms. (7)

7 DRUG INTERACTIONS

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

Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Oral Solution

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USE IN SPECIFIC POPULATIONS SECTION

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.5)]. There are no available data with Morphine Sulfate Oral Solution in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects (see Human Data). In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse. Administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3 to 4 times the HDD; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD (see Animal Data). Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.5)].

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho- physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Morphine Sulfate Oral Solution is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Morphine Sulfate Oral Solution, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data

The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design.

Animal Data

Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (HDD).

Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35 to 322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100 to 500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear.

Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity.

An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10 to 50 mg/kg/day) during the pre- mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated.

In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater.

Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD).

Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre- gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).

8.2 Lactation

Risk Summary

Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with Morphine Sulfate Oral Solution and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Morphine Sulfate Oral Solution and any potential adverse effects on the breastfed infant from Morphine Sulfate Oral Solution or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to Morphine Sulfate Oral Solution through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped.

8.3 Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6) and Clinical Pharmacology (12.2)]. In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see Nonclinical Toxicology (13)].

8.4 Pediatric Use

The safety and effectiveness of Morphine Sulfate Oral Solution (2 mg/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) 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.

8.5 Geriatric Use

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.

8.6 Hepatic Impairment

Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than usual dosage of Morphine Sulfate Oral Solution and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

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

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OVERDOSAGE SECTION

10 OVERDOSAGE

Clinical Presentation

Acute overdose with Morphine Sulfate Oral Solution can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].

Treatment of Overdose

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist.

Because the duration of opioid reversal is expected to be less than the duration of action of morphine in Morphine Sulfate Oral Solution, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of morphine have not been conducted.

Mutagenesis

No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, morphine was found to be mutagenic in vitro increasing DNA fragmentation in human T-cells. Morphine was reported to be mutagenic in the in vivo mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the in vivo clastogenic effects reported with morphine in mice may be related to increases in glucocorticoid levels produced by morphine in this species. In contrast to the above positive findings, in vitro studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in Drosophila.

Impairment of Fertility

No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted.

Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. One study in which male rats were administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects including reduction in total pregnancies and higher incidence of pseudopregnanciesat 20 mg/kg/day (3.2 times the HDD) were reported.

Studies from the literature have also reported changes in hormonal levels in male rats (i.e. testosterone, luteinizing hormone) following treatment with morphine at 10 mg/kg/day or greater (1.6 times the HDD).

Female rats that were administered morphine sulfate intraperitoneally prior to mating exhibited prolonged estrous cycles at 10 mg/kg/day (1.6 times the HDD).

Exposure of adolescent male rats to morphine has been associated with delayed sexual maturation and following mating to untreated females, smaller litters, increased pup mortality, and/or changes in reproductive endocrine status in adult male offspring have been reported (estimated 5 times the plasma levels at the HDD).

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INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

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.

Medication Errors

• Advise patients that Morphine Sulfate Oral Solution is available in two concentrations: 2 mg/mL and 20 mg/mL. Inform patients about which concentration they have been prescribed and provide detailed instruction on how to measure and take the correct dose of Morphine Sulfate Oral Solution.
• 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.
• Instruct patients to never use household teaspoons or tablespoons to measure Morphine Sulfate Oral Solution [see Warnings and Precautions (5.1)].

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.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.4)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Morphine Sulfate 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) [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)].

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

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

If naloxone is prescribed, also advise patients and caregivers:

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

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.4)].

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 (5.6)and 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 (5.8) and 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 (5.9)].

Important Administration Instructions

• Instruct patients how to properly take Morphine Sulfate Oral Solution.
• Advise patients not to adjust the dose of Morphine Sulfate Oral Solution without consulting with a physician or other healthcare professional.
• Advise patients never to use household teaspoons or tablespoons to measure Morphine Sulfate Oral Solution.

Morphine Sulfate Oral Solution 20 mg/mL

• Inform patients that the 20 mg/mL formulation is only for adult 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)].

• Instruct patients how to measure and take the correct dose of Morphine Oral Solution 20 mg/mL using the enclosed calibrated oral syringe when measuring the prescribed amount of medication [see Dosage and Administration (2.1, 2.4), Warnings and Precautions (5.1)].

Morphine Sulfate Oral Solution 2 mg/mL

• Strongly advise patients to always use a graduated oral syringe with metric units of measurements (i.e., mL) to correctly measure the prescribed amount of medication. Inform patients that oral syringes may be obtained from their pharmacy [see Warnings and Precautions (5.1)].

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Morphine Sulfate Oral Solution without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.6)].

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 (5.10)].

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) andAdverse 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 (5.5) andUse 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 (5.15)].

Constipation

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

Manufactured by:
Tris Pharma, Inc.
Monmouth Junction, NJ 08852
www.trispharma.com

LB8245
Rev. 07
10/2021

SPL MEDGUIDE SECTION

MEDICATION GUIDE

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

Morphine Sulfate Oral Solution:

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

NDC 63629-2302-1: Bottle of 120 mL with an oral syringe

Storage

Dispense in a tight, light-resistant container with a child-resistant closure as defined in the USP.
Light Sensitive: Protect from light. Store in carton, away from direct sunlight.

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

Protect from moisture.

Store Morphine Sulfate Oral Solution securely and dispose of properly [see PATIENT COUNSELING INFORMATION (17)].

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INSTRUCTIONS FOR USE SECTION

INSTRUCTIONS FOR USE

MORPHINE SULFATE ORAL SOLUTION, CII

20 mg/mL

ORAL SYRINGE

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

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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. Protect from light. Store in carton, away from direct sunlight.

• Keep Morphine Sulfate Oral Solution and all medicines out of the reach of children.

Manufactured by:

Tris Pharma, Inc.

Monmouth Junction, NJ 08852

www.trispharma.com

For more information, please call (732) 940-0358.

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised October 2021

LB8245

Rev. 07

10/2021

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