Source: Health Products and Food Branch (CA) Revision Year: 2019
Patients should be instructed not to give STATEX (morphine sulfate) to anyone other than the patient for whom it was prescribed, as such inappropriate use may have severe medical consequences, including death. STATEX should be stored securely to avoid theft or misuse.
STATEX should only be prescribed by persons knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for the treatment of pain, and in the detection and management of respiratory depression, including the use of opioid antagonists.
Patients should be cautioned not to consume alcohol while taking STATEX as it may increase the chance of experiencing serious adverse events, including death.
Hyperalgesia that will not respond to a further dose increase of morphine sulfate can occur at particularly high doses. A morphine sulfate dose reduction or change in opioid may be required.
Like all opioids, STATEX is a potential drug of abuse and misuse, which can lead to overdose and death. Therefore, STATEX should be prescribed and handled with caution.
Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse and abuse.
Opioids, such as STATEX, should be used with particular care in patients with a history of alcohol and illicit/prescription drug abuse. However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.
STATEX drops, syrup and tablets are intended for oral use only. The tablets should be swallowed whole, and not chewed or crushed. Abuse of oral dosage forms can be expected to result in serious adverse events, including death.
Morphine sulfate administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquilizers, sedative/hypnotics, tricyclic antidepressants or general anesthetics. These patients should be monitored for signs of hypotension after initiating or titrating the dose of STATEX.
The use of STATEX in patients with circulatory shock should be avoided as it may cause vasodilation that can further reduce cardiac output and blood pressure.
As with other opioids, tolerance and physical dependence may develop upon repeated administration of STATEX and there is a potential for development of psychological dependence.
Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid, and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.
However, tolerance does not develop at an equal rate for all side effects. Cross-tolerance exists with all opioids. In the wake of tolerance, the patient’s dosage might be increased if needed.
Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning (see ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, <Adjustment or Reduction of Dosage>).
STATEX is an opioid with no approved use in the management of addictive disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission is for the management of pain requiring opioid analgesia. Patients with a history of addiction to drugs or alcohol may be at higher risk of becoming addicted to STATEX; extreme caution and awareness is warranted to mitigate the risk.
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.
Morphine sulfate and other morphine-like opioids have been shown to decrease bowel motility. Morphine sulfate may obscure the diagnosis or clinical course of patients with acute abdominal conditions (see CONTRAINDICATIONS).
STATEX is not recommended to be used in pregnant women unless, in the judgment of the physician, the potential benefits outweigh the risks. If STATEX was used during pregnancy, special attention to NOWS is warranted.
Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening.
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.
Interactions with Central Nervous System Depressants (including benzodiazepines and alcohol): morphine sulfate should be used with caution and in a reduced dosage during concomitant administration of other opioid analgesics, general anesthetics, phenothiazines and other tranquilizers, sedative-hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, benzodiazepines, centrally-active anti-emetics and other CNS depressants. Respiratory depression, hypotension and profound sedation, coma or death may result.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see DRUG INTERACTIONS). 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 STATEX 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 with 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 of overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see DRUG INTERACTIONS).
STATEX should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects, including death (see CONTRAINDICATIONS and ADVERSE REACTIONS, Sedation, and DRUG INTERACTIONS).
Severe pain antagonizes the subjective and respiratory depressant actions of opioid analgesics. Should pain suddenly subside, these effects may rapidly become manifest.
Head Injury: The respiratory depressant effects of morphine sulfate, and the capacity to elevate cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated intracranial pressure produced by trauma. Also, morphine sulfate may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients, morphine sulfate must be used with extreme caution and only if it is judged essential (see CONTRAINDICATIONS).
Serotonin Syndrome: STATEX could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (e.g. anti-depressants, migraine medications). Treatment with the serotonergic drug and/or STATEX should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. STATEX should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, tramadol, St. John’s Wort) due to the risk of serotonergic syndrome (see DRUG INTERACTIONS).
STATEX is not indicated for pre-emptive analgesia (administration pre-operatively for the management of post-operative pain).
In the case of planned chordotomy or other pain-relieving operations, patients should not be treated with STATEX for at least 24 hours before the operation and STATEX should not be used in the immediate post-operative period.
Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate. Thereafter, if STATEX is to be continued after the patient recovers from the postoperative period, a new dosage should be administered in accordance with the changed need for pain relief. The risk of withdrawal in opioid-tolerant patients should be addressed as clinically indicated.
The administration of analgesics in the peri-operative period should be managed by healthcare providers with adequate training and experience (e.g., by an anesthesiologist).
Morphine sulfate and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common post-operative complication, especially after intra-abdominal surgery with opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative patients receiving opioids. Standard supportive therapy should be implemented.
STATEX should not be used in the early post-operative period (12 to 24 hours post-surgery) unless the patient is ambulatory and gastrointestinal function is normal.
STATEX may impair the mental and/or physical abilities needed for certain potentially hazardous activities such as driving a car or operating machinery. Patients should be cautioned accordingly. Patients should also be cautioned about the combined effects of morphine sulfate with other CNS depressants, including other opioids, phenothiazine, sedative/hypnotics and alcohol.
Respiratory Depression: Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression from opioid use, 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. Morphine sulfate should be used with extreme caution in patients with substantially decreased respiratory reserve, preexisting respiratory depression, hypoxia or hypercapnia (see CONTRAINDICATIONS).
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of STATEX, the risk is greatest during the initiation of therapy or following a dose increase. Patients should be closely monitored for respiratory depression when initiating therapy with STATEX and following dose increases.
Life-threatening respiratory depression is more likely to occur in the elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.
To reduce the risk of respiratory depression, proper dosing and titration of STATEX are essential. Overestimating the STATEX dose when converting patients from another opioid product can result in a fatal overdose with the first dose. In these patients, the use of non-opioid analgesics should be considered, if feasible (see DOSAGE AND ADMINISTRATION).
Use in Patients with Chronic Pulmonary Disease: Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when initiating therapy and titrating with STATEX, as in these patients, even usual therapeutic doses of STATEX may decrease respiratory drive to the point of apnea. In these patients, use of alternative non-opioid analgesics should be considered, if possible. The use of STATEX is contraindicated in patients with acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus (see CONTRAINDICATIONS).
Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility (see ADVERSE REACTIONS, PostMarketing Experience).
Special Risk Groups: Morphine sulfate should be administered with caution to patients with a history of alcohol and drug abuse and in a reduced dosage to debilitated patients, and in patients with severely impaired pulmonary function, Addison’s disease, hypothyroidism, myxedema, toxic psychosis, prostatic hypertrophy or urethral stricture, hypopituitarism, reduced renal and/or hepatic function, hypotension, biliary tract disorder, anemia, reduced blood volume and severe malnutrition.
Cancer Patients: Nausea and vomiting are symptoms frequently observed in terminal cancer patients. If a phenothiazine drug is to be employed as an antiemetic agent, it should be administered 30 minutes before morphine and not in the same preparation because of its potentiating activity on morphine. The dose and choice of a phenothiazine drug will depend on the individual patient, the disease, therapy/ies, and degree of sedation required.
Pregnant Women: Morphine has been demonstrated to be teratogenic in animals at very high doses. Studies in humans have not been conducted. Morphine sulfate crosses the placental barrier and is not recommended to be administered to pregnant women unless, in the judgment of the physician, potential benefits outweigh the risks.
Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal Opioid Withdrawal Syndrome (NOWS), unlike opioid withdrawal syndrome in adults, may be life-threatening (see WARNINGS AND PRECAUTIONS, Neonatal Opioid Withdrawal Syndrome (NOWS)).
Pregnant women using opioids should not discontinue their medication abruptly as this can cause pregnancy complication such as miscarriage or still-birth. Tapering should be slow and under medical supervision to avoid serious adverse events to the fetus.
Labour, Delivery and Nursing Women: Since opioids can cross the placental barrier and are excreted in breast milk, STATEX is not recommended to be used in nursing women and during labour and delivery unless, in the judgment of the physician, the potential benefits outweigh the risks. Life-threatening respiratory depression can occur in the infant if opioids are administered to the mother. Naloxone, a drug that counters the effects of opioids, should be readily available if STATEX is used in this population.
Pediatrics (<18 years of age): The safety and efficacy of STATEX have not been studied in the pediatric population. Therefore, use of STATEX is not recommended in patients under 18 years of age.
Geriatrics (>65 years of age): In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and titrate slowly, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).
Patients with Hepatic Impairment: Morphine should be administered with caution and in a reduced dosage in patient with hepatic impairment.
Patients with Renal Impairment: Morphine should be administered with caution and in a reduced dosage in patient with renal impairment.
Adverse effects of STATEX (morphine sulfate) drops, suppositories, syrup and tablets are similar to those of other opioid analgesics, and represent an extension of pharmacological effects of the drug class. The major hazards of opioids include respiratory and central nervous system depression and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.
The most frequently observed adverse effects of STATEX are sedation, nausea and vomiting, constipation and sweating.
Sedation: Sedation is a common side effect of opioid analgesics, especially in opioid naïve individuals. Sedation may also occur partly because patients often recuperate from prolonged fatigue after the relief of persistent pain. Most patients develop tolerance to the sedative effects of opioids within three to five days and, if the sedation is not severe, will not require any treatment except reassurance. If excessive sedation persists beyond a few days, the dose of the opioid should be reduced and alternate causes investigated. Some of these are: concurrent CNS depressant medication, hepatic or renal dysfunction, brain metastases, hypercalcemia and respiratory failure. If it is necessary to reduce the dose, it can be carefully increased again after three or four days if it is obvious that the pain is not being well controlled. Dizziness and unsteadiness may be caused by postural hypotension, particularly in elderly or debilitated patients, and may be alleviated if the patient lies down.
Nausea and Vomiting: Nausea is a common side effect on initiation of therapy with opioid analgesics and is thought to occur by activation of the chemoreceptor trigger zone, stimulation of the vestibular apparatus and through delayed gastric emptying. The prevalence of nausea declines following continued treatment with opioid analgesics. When instituting therapy with an opioid for chronic pain, the routine prescription of an antiemetic should be considered. In the cancer patient, investigation of nausea should include such causes as constipation, bowel obstruction, uremia, hypercalcemia, hepatomegaly, tumor invasion of celiac plexus and concurrent use of drugs with emetogenic properties. Persistent nausea which does not respond to dosage reduction may be caused by opioid-induced gastric stasis and may be accompanied by other symptoms including anorexia, early satiety, vomiting and abdominal fullness. These symptoms respond to chronic treatment with gastrointestinal prokinetic agents.
Constipation: Practically all patients become constipated while taking opioids on a persistent basis. In some patients, particularly the elderly or bedridden, fecal impaction may result. It is essential to caution the patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged opioid therapy. Stimulant laxatives, stool softeners, and other appropriate measures should be used as required. As fecal impaction may present as overflow diarrhea, the presence of constipation should be excluded in patients on opioid therapy prior to initiating treatment for diarrhea. The following adverse effects occur less frequently with opioid analgesics.
Cardiovascular: Supra-ventricular tachycardia, postural hypotension, palpitations, faintness and syncope.
Dermatologic: Pruritus, urticaria, other skin rashes and edema.
Endocrine: A syndrome of inappropriate antidiuretic hormone secretion characterized by hyponatremia secondary to decreased free-water excretion may be prominent (monitoring of electrolytes may be necessary).
Gastrointestinal: Dry mouth, anorexia, constipation, cramps, taste alterations and biliary tract cramps.
CNS: Euphoria, dysphoria, weakness, insomnia, dizziness, confusional symptoms and occasionally hallucinations.
Genitourinary: Urinary retention or hesitance, reduced libido or potency.
Withdrawal (Abstinence) Syndrome: Physical dependence with or without psychological dependence tend to occur on chronic administration. An abstinence syndrome may be precipitated when opioid administration is discontinued or opioid antagonists administered. The following withdrawal symptoms may be observed after opioids are discontinued: body aches, diarrhea, gooseflesh, loss of appetite, nervousness or restlessness, runny nose, sneezing, tremors or shivering, stomach cramps, nausea, trouble with sleeping, unusual increase in sweating and yawning, weakness, tachycardia and unexplained fever. With appropriate medical use of opioids and gradual withdrawal from the drug, these symptoms are usually mild.
Androgen deficiency: 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. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.
Interaction with Benzodiazepines and Other Central Nervous System (CNS) Depressants: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants (e.g. other opioids, sedatives/hypnotics, antidepressants, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, phenothiazines, neuroleptics, antihistamines, antiemetics, and alcohol) and beta-blockers, increases the risk of respiratory depression, profound sedation, coma, and death. 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 (see WARNINGS AND PRECAUTIONS, Neurologic, Interactions with Central Nervous System Depressants (including benzodiazepines and alcohol) and Psychomotor Impairment). STATEX should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects.
Oral Anticoagulants: Morphine may enhance response to anticoagulants; however, short term use does not likely have a significant effect.
Skeletal Muscle Relaxants: CNS depressant effect of morphine adds to the neuromuscular blockade of muscle relaxants and atelectasis and increased respiratory depression may occur. Exert great caution if used concurrently.
Antimuscarinics: May result in increased risk of severe constipation and/or urinary retention.
Levallorphan/Naloxone: Antagonize the analgesic, CNS and respiratory depressant effects of opioid agonist analgesics and may precipitate withdrawal symptoms in physically dependent patients: dosage of levallorphan or naloxone should be carefully titrated when used to treat opioid overdosage in dependent patients.
Neuromuscular Blocking Agents: Respiratory depressant effects of neuromuscular blocking agents may be additive to central respiratory depressant effects of opioid analgesics; caution is recommended when an opioid drug is administered during surgery or in the immediate postoperative period to a patient who has received a neuromuscular blocking agent.
Serotonergic agents: Co-administration of morphine sulfate with a serotonergic agent, such as a Selective Serotonin Re-uptake Inhibitor or a Serotonin Norepinephrine Re-uptake Inhibitor, may increase the risk of serotonin syndrome, a potentially life-threatening condition (see WARNINGS AND PRECAUTIONS).
Interactions with food have not been established.
Interactions with herbal products have not been established.
Morphine interferes with the diagnostic determination of cerebrospinal fluid pressure, the concentrations of; plasma amylase, plasma lipase, serum alanine aminotransferase (SGPT), serum aspartate aminotransferase (SGOT), serum bilirubin and serum alkaline phosphatase.
The concomitant use of alcohol should be avoided (see WARNINGS AND PRECAUTIONS, General).
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