Morphine Sulfate

1 INDICATIONS AND USAGE Morphine Sulfate Oral Solution 2 mg/mL is indicated for the management of: adults with pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. pediatric patients 2 years of age and older with 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 use in opioid-tolerant adult patients who require higher doses of opioids for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. Limitations of Use: Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions ( 5.2) ], reserve opioid analgesics, including Morphine Sulfate Oral Solution, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain . Morphine Sulfate Oral Solution is an opioid agonist. Morphine Sulfate 2 mg/mL is indicated for the management of: adults with pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) pediatric patients 2 years of age and older with 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: use in opioid-tolerant adult patients who require higher doses of opioids for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate . ( 1 ) Limitations of Use : Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including Morphine Sulfate Oral Solution for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 , 5.2 )

2 DOSAGE AND ADMINISTRATION Morphine Sulfate Oral Solution 20 mg/mL is only for opioid-tolerant adult patients . ( 2.1 ) Morphine Sulfate Oral Solution should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.2 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of Morphine Sulfate Oral Solution for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.2 , 5 ) Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.2 ) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.2 , 5.2 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Morphine Sulfate Oral Solution. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.3 ) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with Morphine Sulfate Oral Solution, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.3 , 5.2 , 5.3 , 5.4 ). Adults: Initiate treatment with Morphine Sulfate Oral Solution 10 to 20 mg every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Morphine Sulfate Oral Solution. ( 2.4 , 2.5 ) Pediatric Patients 2 Years of Age and Older: Initiate treatment with Morphine Oral Solution 2 mg/mL at a dose of 0.15 mg/kg to 0.3 mg/kg every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Do not exceed 20 mg as an initial dose in pediatrics. See Full Prescribing Information for complete information on pediatric dosing. ( 2.3 ) Periodically reassess patients receiving Morphine Sulfate Oral Solution to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.5 ) Do not rapidly reduce or abruptly discontinue Morphine Sulfate Oral Solution in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.6 , 5.15 ) 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 and pediatric patients 2 years of age and older. Strongly advise patients and caregivers to always use a 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 in opioid-tolerant adult patients who have already been receiving opioid therapy. This concentration is to be used only in adult patients who have already been titrated to a stable analgesic regimen using lower concentrations of morphine sulfate and who can benefit from use of a higher concentration (smaller volume) of oral solution. Adult patients considered to be opioid tolerant are those who are receiving…

5 WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.7 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate closely, particularly during initiation and titration. ( 5.8 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.10 ) Severe Hypotension: Regularly evaluate during dosage initiation and titration. Avoid use of Morphine Sulfate Oral Solution in patients with circulatory shock. ( 5.11 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of Morphine Sulfate Oral Solution in patients with impaired consciousness or coma. ( 5.12 ) 5.1 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 sulfate oral solutions of different concentrations, when prescribing, dispensing, and administering Morphine Sulfate Oral Solution. Ensure that the dose is communicated clearly and dispensed accurately. Instruct patients and caregivers on how to measure and take or administer the correct dose of Morphine Sulfate Oral Solution and to use extreme caution when measuring the dose. Instruct patients and caregivers to always use the enclosed calibrated oral syringe or dosing cup when administering Morphine Sulfate Oral Solution to ensure the dose is measured and administered accurately. Instruct them to never use a household teaspoon or tablespoon to measure a dose because household teaspoons or tablespoons are not adequate measuring devices. 5.2 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. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [ see Adverse Reactions (6) ]. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Morphine Sulfate Oral Solution, and reassess 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 frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [ see Dosage and Administration (2.2) and Warnings and Precautions (5.3) ]. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when…

4 CONTRAINDICATIONS 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 [ see Warnings and Precautions ( 5.8 ) ]. Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [ see Warnings and Precautions ( 5.9 ) and Drug Interactions ( 7 ) ]. Known or suspected gastrointestinal obstruction, including paralytic ileus [ see Warnings and Precautions ( 5.13 ) ]. Hypersensitivity to morphine (e.g., anaphylaxis) [ see Adverse Reactions ( 6 ) ]. Significant respiratory depression. ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ). Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days. ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) Hypersensitivity to morphine. ( 4 )

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 Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [ see Warnings and Precautions (5.4) ]. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [ see Dosage and Administration (2.3) and Warnings and Precautions (5.2 , 5.3 , 5.4 ) ]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Oral Solution if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [ see Warnings and Precautions (5.3 , 5.9) ]. Intervention: Do not use Morphine Sulfate Oral Solution in patients taking MAOIs or within 14 days of stopping such treatment. Examples: Phenelzine, tranylcypromine, linezolid. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Morphine Sulfate Oral Solution and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine. Muscle Relaxants Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected decrease the dosage of Morphine Sulfate Oral Solution and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.3) and Warnings and Precautions (5.3 , 5.4) ] . Examples: Cyclobenzaprine, metaxalone. Cimetidine Clinical Impact: The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report. Intervention: Evaluate patients for increased respiratory and CNS depression when Morphine Sulfate Oral Solution is used concomitantly with cimetidine. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs…

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy can cause neonatal opioid withdrawal syndrome [ see Warnings and Precautions ( 5.5 ) ]. 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 background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [ see Warnings and Precautions ( 5.5 ) ]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, 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 methodol…

8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [ see Adverse Reactions ( 6 ) 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 ) ].

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [ see Warnings and Precautions ( 5.2 ) ] Life-Threatening Respiratory Depression [ see Warnings and Precautions ( 5.3 ) ] Interactions with Benzodiazepine or Other CNS Depressants [ see Warnings and Precautions ( 5.4 ) ] Neonatal Opioid Withdrawal Syndrome [ see Warnings and Precautions ( 5.5 ) ] Opioid-Induced Hyperalgesia and Allodynia [ see Warnings and Precautions (5.7) ] Adrenal Insufficiency [ see Warnings and Precautions ( 5.10 ) ] Severe Hypotension [ see Warnings and Precautions ( 5.11 ) ] Gastrointestinal Adverse Reactions [ see Warnings and Precautions ( 5.13 ) ] Seizures [ see Warnings and Precautions ( 5.14 ) ] Withdrawal [ see Warnings and Precautions ( 5.15 ) ] The following adverse reactions associated with the use of morphine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serious adverse reactions associated with morphine use included: respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest. The common adverse reactions seen on initiation of therapy with morphine in adults were dose-dependent and were typical opioid-related adverse reactions. The most frequent of these included constipation, nausea, and somnolence. Other commonly observed adverse reactions included: lightheadedness, dizziness, sedation, vomiting, and sweating. The frequency of these events depended upon several factors including clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual. Other less frequently observed adverse reactions from opioid analgesics, including morphine sulfate included: Body as a Whole: malaise, withdrawal syndrome Cardiovascular System: bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia Digestive System: anorexia, biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst Endocrine: hypogonadism Hemic and Lymphatic System: anemia, thrombocytopenia Metabolic and Nutritional Disorders: edema, weight loss Musculoskeletal: skeletal muscle rigidity, decreased bone mineral density Nervous System: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, depression, dry mouth, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo, headache Respiratory System: hiccup, hypoventilation, voice alteration Skin and Appendages: dry skin, urticaria, pruritus Special Senses: amblyopia, eye pain, taste perversion Urogenital System: abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention or hesitancy, anti-diuretic effect, amenorrhea Serotonin Syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Morphine Sulfate Oral Solution. Androgen Deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time. [ see Clinical Pharmacology (12.2) ]. Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [ see Warnings and Precautions (5.7) ]. Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Clinical Trial Experience in Pediatr…