Morphine Sulfate Tablets 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 Tablets. In patients with circulatory shock, Morphine Sulfate Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Morphine Sulfate Tablets in patients with circulatory shock.
5.10 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 Tablets 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 Tablets.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Morphine Sulfate Tablets in patients with impaired consciousness or coma.
Morphine Sulfate Tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.
The morphine in Morphine Sulfate Tablets 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.
The morphine in Morphine Sulfate Tablets 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 Tablets therapy.
Do not abruptly discontinue Morphine Sulfate Tablets in a patient physically dependent on opioids. When discontinuing Morphine Sulfate Tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of morphine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5) and Drug Abuse and Dependence (9.3)].
Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Morphine Sulfate Tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)].
Morphine Sulfate Tablets 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 Tablets and know how they will react to the medication.
The following serious adverse reactions are described, or described in greater detail, in other sections:
- Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
- Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3)]
- Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
- Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.5)]
- Adrenal Insufficiency [see Warnings and Precautions (5.8)]
- Severe Hypotension [see Warnings and Precautions (5.9)]
- Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11)]
- Seizures [see Warnings and Precautions (5.12)]
- Withdrawal [see Warnings and Precautions (5.13)]
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: biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst
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 Tablets.
Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [ see Clinical Pharmacology (12.2)].
Pediatric use information is approved for Hikma Pharmaceuticals USA Inc’s. morphine sulfate tablets. However, due to Hikma Pharmaceuticals USA Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
Table 1 includes clinically significant drug interactions with Morphine Sulfate Tablets.
|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.|
|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. Follow patients closely for signs of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3, 5.5)].|
|Examples:||Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.|
|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, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Tablets 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 effect 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 (5.7)].|
|Intervention:||Do not use Morphine Sulfate Tablets 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 Tablets and/or precipitate withdrawal symptoms.|
|Intervention:||Avoid concomitant use.|
|Examples:||Butorphanol, nalbuphine, pentazocine, buprenorphine.|
|Clinical Impact:||Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.|
|Intervention:||Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3, 5.5)].|
|Clinical Impact:||The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report.|
|Intervention:||Monitor patients for increased respiratory and CNS depression when Morphine Sulfate Tablets are used concomitantly with cimetidine.|
|Clinical Impact:||Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.|
|Intervention:||Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.|
|Clinical Impact:||The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.|
|Intervention:||Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Tablets are used concomitantly with anticholinergic drugs.|
|P-Glycoprotein (P-gp) Inhibitors|
|Clinical Impact:||The concomitant use of P-gp inhibitors can increase the exposure to morphine by two-fold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.|
|Intervention:||Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Tablets and/or the P-gp inhibitor as necessary.|
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