Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS

5.1 Risks with Neuraxial Administration
Control of pain by neuraxial opioid delivery is always accompanied by considerable risk to the patient and requires a high level of skill to be successfully accomplished. The task of treating these patients must be undertaken by experienced clinical teams, well-versed in patient selection, evolving technology and emerging standards of care.
In the case of epidural or intrathecal administration, Morphine Injections 1 mg/ml should be administered by or underthe direction of a physician experienced in the techniques and familiar with the patient management problems associated with epidural or intrathecal drug administration. The physician should be familiar with patient conditions (such as infection at the injection site, bleeding diathesis, anticoagulant therapy, etc.) which call for special evaluation of the benefit versus risk potential.
Because epidural administration has been associated with less potential for immediate or late adverse effects than intrathecal administration, the epidural route should be used whenever possible.
For safety reasons, it is recommended that administration of Morphine Injections 1 mg/ml by the epidural or intrathecal routes be limited to the lumbar area. Thoracic epidural administration has been shown to dramatically increase the incidence of early and late respiratory depression even with doses of 1 to 2 mg.
Because of the risk of severe adverse effects when the epidural or intrathecal route of administration is employed, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial dose.
The facility must be equipped to resuscitate patients with severe opiate overdosage, and the personnel must be familiar with the use and limitations of specific narcotic antagonists (naloxone, naltrexone) in such cases.
Parenteral administration of narcotics in patients receiving epidural or intrathecal morphine may result in overdosage.

5.2 Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.
Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Morphine Injections 1 mg/ml, the risk is greatest during the initiation of therapy or following a dosage increase.
This respiratory depression and/or respiratory arrest may be severe and could require intervention.
Because of delay in maximum CNS effect with intravenously administered drug (30 min), rapid administration may result in overdosing.
Single-dose neuraxial administration may result in acute or delayed respiratory depression for periods at least as long as 24 hours.
Severe respiratory depression up to 24 hours following epidural or intrathecal administration has been reported.
Intrathecal use has been associated with a higher incidence of respiratory depression than epidural use.
Thoracic administration has been shown to dramatically increase the incidence of early and late respiratory depression even at doses of 1 to 2 mg.

Because of the risk of severe adverse effects when the epidural or intrathecal route of administration is employed, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial dose. The facility must be equipped to resuscitate patients with severe opiate overdosage, and the personnel must be familiar with the use and limitations of specific narcotic antagonists (naloxone, naltrexone) in such cases.
To reduce the risk of respiratory depression, proper dosing and titration of Morphine Injections 1 mg/ml are essential [see Dosage and Administration (2)]. Overestimating the Morphine Injections 1 mg/ml dosage can result in afatal overdose with the first dose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep- related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (Discontinuation of Morphine Injections 1 mg/ml)]

5.3 Addiction, Abuse, and Misuse
Morphine Injections 1 mg/ml contains morphine, a Schedule II controlled (FDA, USA) substance. As an opioid, Morphine Injections 1 mg/ml 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 Injections 1 mg/ml. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Morphine Injections 1 mg/ml, and monitor all patients receiving Morphine Injections 1 mg/ml 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 Injections 1 mg/ml, but use in such patients necessitates intensive counseling about the risks and proper use of Morphine Injections 1 mg/ml along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought by drug users and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Morphine Injections 1 mg/ml. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity.
5.4 Neonatal Opioid Withdrawal Syndrome
Prolonged use of Morphine Injections 1 mg/ml during pregnancy can result in withdrawal in the neonate.
Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life- threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that management by neonatology experts will be available at delivery [see Use in Specific Populations (8.1)].

5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from concomitant use of Morphine Injections 1 mg/ml with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non- benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for usein patients for whom alternative treatment options are inadequate.
Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression.
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 (7)].
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response.
If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when Morphine Injections 1 mg/ml is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7)].

5.6 Risk of Tolerance and Myoclonic Activity

Patients sometimes manifest unusual acceleration of neuraxial morphine requirements, which may cause concern regarding systemic absorption and the hazards of large doses; these patients may benefit from hospitalization and detoxification. Two cases of myoclonic-like spasm of the lower extremities have been reported in patients receiving more than 20 mg/day of intrathecal morphine. After detoxification, it might be possible to resume treatment at lower doses, and some patients have been successfully changed from continuous epidural morphine to continuous intrathecal morphine. Repeat detoxification may be indicated at a later date. The upper daily dosage limit for each patient during continuing treatment must be individualized.

5.7 Chest Wall Rigidity
Rapid intravenous administration may result in chest wall rigidity.

5.8 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. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily nonpainful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2), Warnings and Precautions (5.16)].

5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of Morphine Injections 1 mg/ml in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
Patients with Chronic Pulmonary Disease: Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended doses of Morphine Injections 1 mg/ml [see Warnings and Precautions (5.2)].
Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2)].
Monitor such patients closely, particularly when initiating and titrating Morphine Injections 1 mg/ml and when Morphine Injections 1 mg/ml is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2) ,Drug interactions (7)]. Alternatively, consider the use of non- opioid analgesics in these patients.


5.10 Interaction with Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Morphine Injections 1 mg/ml should not be used in patients taking MAOIs or within 14 days of stopping such treatment [see Drug Interactions (7)].

5.11 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.

5.12 Severe Hypotension
Morphine Injections 1 mg/ml 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 Injections 1 mg/ml.
In patients with circulatory shock, Morphine Injections 1 mg/ml may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Morphine Injections 1 mg/ml in patients with circulatory shock.

5.13 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 Injections 1 mg/ml 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 Injections 1 mg/ml. Morphine Injections 1 mg/ml should be used with extreme caution in patients with head injury or increased intracranial pressure. Pupillary changes (miosis) from morphine may obscure the existence, extent and course of intracranial pathology. High doses of neuraxial morphine may produce myoclonic events [see Warnings and Precautions (5.6)]. Clinicians should maintain a high index of suspicion for adverse drug reactions when evaluating altered mental status or movement abnormalities in patients receiving this modality of treatment.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Morphine Injections 1 mg/ml in patients with impaired consciousness or coma.

5.14 Risks of Use in Patients with Gastrointestinal Conditions
Morphine Injections 1 mg/ml is contraindicated in patients with known or suspected gastrointestinal obstruction,including paralytic ileus.
The morphine in Morphine Injections 1 mg/ml 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. As significant morphine is released into the systemic circulation from neuraxial administration, the ensuing smooth muscle hypertonicity may result in biliary colic.

5.15 Risk of Seizures
Morphine Injections 1 mg/ml may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical setting associated with seizures.
Monitor patients with a history of seizure disorders for worsened seizure control during Morphine Injections 1 mg/ml therapy.
Excitation of the central nervous system, resulting in convulsions, may accompany high doses of morphine given intravenously.

5.16 Withdrawal
Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Morphine Injections 1 mg/ml. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].
When discontinuing Morphine Injections 1 mg/ml, gradually taper the dosage [see Dosage and Administration (Discontinuation of Morphine Injections 1 mg/ml)].Do not abruptly discontinue Morphine Injections 1 mg/ml [see Drug Abuse and Dependence (9.3)].

5.17 Risks of Driving and Operating Machinery
Morphine Injections 1 mg/ml 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 Injections 1 mg/ml and know how they will react to the medication.

5.18 Risks of Use in Patients with Urinary System Disorders
Urinary retention, which may persist 10 to 20 hours following single epidural or intrathecal administration, is frequently associated with neuraxial opioid administration and must be anticipated, more frequently in male patients than female patients. Urinary retention may also occur during the first several days of hospitalization for the initiation of continuous intrathecal or epidural morphine therapy.
Early recognition of difficulty in urination and prompt intervention in cases of urinary retention is indicated. Patients who develop urinary retention have responded to cholinomimetic treatment and/or judicious use of catheters.

5.19 Risks of Use in Ambulatory Patients
Patients with reduced circulating blood volume, impaired myocardial function or on sympatholytic drugs should be monitored for the possible occurrence of orthostatic hypotension, a frequent complication in single-dose neuraxial morphine analgesia.


6 ADVERSE REACTIONS
The following serious adverse reactions are described, or described in greater detail, in other sections:

•   Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)] •   Addiction, Abuse, and Misuse [see Warnings and Precautions (5.3)] •   Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)] •   Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.5)] •   Myoclonic Activity [see Warnings and Precautions (5.6)]
•   Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.8)] •   Adrenal Insufficiency [see Warnings and Precautions (5.11)]
•   Severe Hypotension [see Warnings and Precautions (5.12)]
•   Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.14)] •   Seizures [see Warnings and Precautions (5.15)]
•    Withdrawal [see Warnings and Precautions (5.16)]
•   Urinary Retention [see Warnings and Precautions (5.18)]
•   Orthostatic Hypotension [see Warnings and Precautions (5.19)]

The following adverse reactions associated with the use of morphine were identified in clinical studies or post marketing 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.
The most serious adverse reactions encountered during administration of Morphine Injections 1 mg/ml were respiratory depression and/or respiratory arrest.
Cardiovascular System: While low doses of intravenously administered morphine have little effect on cardiovascular stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in circulating catecholamines.
Central Nervous System: myoclonus, seizures, dysphoric reactions, toxic psychosis, dizziness, euphoria, anxiety, confusion, headache. Lumbar puncture-type headache is encountered in a significant minority of cases for several days following intrathecal catheter implantation and generally responds to bed rest and/or other conventional therapy.
Gastrointestinal System: Nausea, vomiting, constipation
Skin: Generalized pruritus, urticaria, wheals, and/or local tissue irritation. Single-dose epidural or intrathecal administration is accompanied by a high incidence of dose-related generalized pruritus.
Urinary System: Urinary retention, oliguria.
Peripheral edema: There are several reports of peripheral edema.
Other: Other adverse reactions reported following morphine therapy include depression of cough reflex, interference with thermal regulation.
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 Injections.
Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [seeClinical Pharmacology (12.2)].
Hyperalgesia and Allodynia:
Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.8)].
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).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il/

Effects on Driving