Morphine hydrochloride

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MORPHINE HYDROCHLORIDE (MORPHINE HYDROCHLORIDE)

Composition:

Active substance: morphine;

1 ml of solution contains morphine hydrochloride, calculated as 100% substance – 8.6 mg;

Excipients: diluted hydrochloric acid, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical characteristics: clear, colorless or slightly yellowish or brownish liquid.

Pharmacotherapeutic group.

Analgesics. Opioids. Natural opium alkaloids. Morphine. ATC code N02A A01.

Pharmacological properties.

Pharmacodynamics.

An opioid analgesic. Has a pronounced analgesic effect. The mechanism of action is due to stimulation of various subtypes of opioid receptors in the central nervous system (delta, mu, and kappa). Activation of delta-receptors causes analgesia; mu-receptors – supraspinal analgesia, euphoria, physical dependence, respiratory depression, stimulation of vagal centers; kappa-receptors – spinal analgesia, sedative effect, miosis.

It suppresses interneuronal transmission of pain impulses in the central part of the afferent pathway, reduces the emotional assessment of pain, and causes euphoria, which promotes the development of dependence (physical and psychological). By reducing excitability of pain centers, it exerts an anti-shock effect. In high doses, it exhibits sedative activity and induces sleep. It inhibits conditioned reflexes, reduces summation capacity of the central nervous system, and potentiates the action of depressant agents. It reduces excitability of the thermoregulatory center and stimulates vasopressin secretion. It has practically no effect on vascular tone. It suppresses the respiratory center, reduces excitability of the cough center, and stimulates vagal centers, causing bradycardia. It stimulates neurons of the oculomotor nerves, resulting in pupil constriction (miosis). It may stimulate chemoreceptors of trigger zones in the medulla oblongata and induce nausea and vomiting. However, it suppresses the vomiting center; therefore, repeated administration of morphine hydrochloride and emetic agents given after morphine hydrochloride does not induce vomiting. It increases smooth muscle tone in internal organs: sphincters of Oddi, urinary bladder, gastric antrum, intestines, biliary tract, and bronchi. It reduces peristalsis, slows movement of food masses, and promotes constipation development.

Analgesic effect develops within 5–15 minutes after subcutaneous and intramuscular administration and lasts for 4–5 hours.

There are reports that in male rats, morphine may reduce fertility and cause chromosomal damage in germ cells.

Pharmacokinetics.

After subcutaneous and intramuscular administration, it is rapidly absorbed into systemic circulation. The majority of the dose is metabolized to form glucuronides and sulfates. It penetrates histohematogenous barriers, including the blood-brain barrier and placental barrier (may cause fetal respiratory center depression), and passes into breast milk. The elimination half-life is 2–3 hours. It is excreted primarily as metabolites by the kidneys (90%), the remainder via bile; small amounts are secreted by all exocrine glands. In patients with impaired liver or kidney function, as well as in elderly patients, the elimination half-life may be prolonged.

Clinical characteristics.

Indications.

Severe pain syndrome, including pain associated with malignant neoplasms, myocardial infarction, severe injuries, preoperative preparation, and the postoperative period.

Contraindications.

• Individual hypersensitivity to morphine hydrochloride;
• Respiratory depression due to suppression of the respiratory center;
• Predisposition to bronchospasm;
• Severe hepatic and/or renal insufficiency;
• Head trauma, intracranial hypertension;
• Stroke;
• Cachexia;
• Epileptic status;
• Severe general exhaustion;
• Abdominal pain of unknown etiology;
• Acute alcohol intoxication;
• Pheochromocytoma;
• Delirium;
• Fever.

Morphine must not be administered during therapy with monoamine oxidase inhibitors (MAOIs), or within 2 weeks after discontinuation of such therapy.

Interaction with other medicinal products and other forms of interactions.

When used concomitantly:

• With other agents that depress the central nervous system (CNS) (benzodiazepines or benzodiazepine-like drugs, gabapentin or pregabalin), an enhanced CNS depressant effect may occur, increasing the risk of sedation, respiratory depression, coma, and fatal outcome; therefore, doses and duration of concomitant treatment should be limited (see section "Special precautions");
• With beta-adrenergic blockers – enhanced central nervous system depressant effect of morphine hydrochloride;
• With phenylbutazone – possible accumulation of morphine hydrochloride;
• With dopamine – reduced analgesic effect of morphine hydrochloride;
• With cimetidine – enhanced respiratory depression by morphine hydrochloride;
• With phenothiazine derivatives and barbiturates – enhanced hypotensive effect and respiratory depression by morphine hydrochloride;

Morphine hydrochloride may be administered no earlier than 2 weeks after discontinuation of MAO inhibitors (see section "Contraindications").

Long-term use of barbiturates (especially phenobarbital) or narcotic analgesics may lead to development of cross-tolerance.

Chlorpromazine enhances the analgesic, miotic, and sedative effects of morphine hydrochloride.

Naloxone reverses respiratory depression and analgesia caused by narcotic analgesics. Nalorphine reverses respiratory depression caused by narcotic analgesics while preserving their analgesic effect.

In patients with acute coronary syndrome who received morphine, delayed onset and reduced effect of oral antiplatelet therapy with P2Y12 inhibitors (e.g., prasugrel, clopidogrel, ticagrelor) have been observed. This interaction may be related to decreased gastrointestinal motility and may also apply to other opioids. The clinical significance of this interaction is unknown, but data suggest a potential reduction in the efficacy of P2Y12 inhibitors in patients receiving them concomitantly with morphine (see section "Special precautions"). In patients with acute coronary syndrome in whom morphine cannot be discontinued and rapid P2Y12 inhibition is considered critical, parenteral administration of a P2Y12 inhibitor may be considered.

Special precautions for use.

Do not use for labor analgesia, as morphine hydrochloride crosses the placental barrier and may cause respiratory depression in the newborn.

Use with caution in patients with mild to moderate hepatic and renal impairment, hypothyroidism, adrenal insufficiency, prostatic hyperplasia, shock, myasthenia gravis, inflammatory gastrointestinal disorders, and in patients aged 60 years and older.

Morphine hydrochloride causes pronounced euphoria. With repeated administration, rapid development of psychological and physical dependence occurs (within 2–14 days from the start of treatment). Withdrawal syndrome may appear several hours after discontinuation of prolonged therapy and peak at 36–72 hours.

Alcohol consumption must be avoided during treatment.

In cases of overdose, if consciousness is preserved, activated charcoal may be administered orally. Patients must be closely monitored for signs and symptoms of respiratory depression and sedation. Therefore, patients and caregivers should be informed about these symptoms (see section "Interaction with other medicinal products and other forms of interaction").

Respiratory depression requires respiratory support and administration of an opioid antagonist – naloxone. However, its use in opioid-dependent individuals may precipitate withdrawal syndrome. Supportive therapy includes respiratory support and reversal of shock by naloxone administration. The dose of naloxone administered depends on the severity of respiratory depression and the degree of coma.

High-dose administration, especially in elderly patients, may lead to respiratory depression and hypotension, resulting in circulatory insufficiency and coma. The occurrence of adverse reactions depends on individual sensitivity to opioid receptors. Seizures may occur in children; high-dose administration may also lead to progression of renal failure. Convulsions are more commonly observed in children. The toxicity of the drug depends on individual sensitivity to morphine and the amount administered.

Comatose state is characterized by constricted pupils and respiratory depression, which may indicate overdose. Dilated pupils suggest the development of hypoxia. Pulmonary edema after overdose is a common cause of fatal outcome.

Cases of hyperalgesia, where dose escalation fails to provide analgesic effect, may occur very rarely, particularly with high-dose administration. In such cases, the dose should be reduced or the drug replaced with another opioid medicinal product.

Rifampicin, when co-administered, reduces plasma morphine levels. The analgesic effect of morphine should be monitored, and the morphine dose adjusted during and after rifampicin therapy.

Oral antiplatelet therapy with P2Y12 inhibitors (e.g., prasugrel, clopidogrel, ticagrelor)

During the first 24 hours of concomitant treatment with P2Y12 inhibitors and morphine, reduced effectiveness of P2Y12 inhibitor therapy has been observed (see section "Interaction with other medicinal products and other forms of interaction").

Sleep-related breathing disorders

Opioids may 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 manner. For patients with CSA, consider reducing the total opioid dose.

Acute chest syndrome (ACS) in patients with sickle cell anemia

Due to a possible association between ACS development and morphine use in patients with sickle cell anemia during vaso-occlusive crisis, careful monitoring for signs and symptoms of ACS is required.

Adrenal insufficiency

Opioid analgesics may cause reversible adrenal insufficiency, requiring patient monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency may include nausea, vomiting, loss of appetite, increased fatigue, weakness, dizziness, or low blood pressure.

Reduction in sex hormone levels and increased prolactin levels

Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin levels. Symptoms include reduced libido, impotence, or amenorrhea.

Severe skin adverse reactions

Cases of acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or lead to fatal outcomes, have been reported with morphine use. Most of these reactions occurred within the first 10 days of treatment. Patients should be informed about the signs and symptoms of AGEP and advised to seek medical help if such symptoms occur.

If signs or symptoms suggestive of these skin reactions appear, morphine should be discontinued and alternative treatment considered.

Hepatobiliary disorders

Morphine may cause dysfunction and spasm of the sphincter of Oddi, thereby increasing intra-abdominal pressure and increasing the risk of symptoms related to biliary tract and pancreatitis.

Risk associated with concomitant use of sedatives such as benzodiazepines or medicinal products with benzodiazepine-like effects

Concomitant use of morphine and sedative medicinal products such as benzodiazepines or medicinal products with benzodiazepine-like effects may result in sedation, respiratory depression, coma, and death (see section "Interaction with other medicinal products and other forms of interaction"). When concomitant use of these sedatives is unavoidable, the risks should be carefully considered. If concomitant use of morphine with sedatives is decided upon, the lowest effective doses should be used, and treatment duration should be as short as possible.

Opioid use disorders (OUD) (abuse, dependence, and withdrawal syndrome)

Tolerance and physical and/or psychological dependence may develop after repeated use of opioids such as morphine; repeated use of morphine may lead to OUD. Higher doses and longer duration of opioid treatment may increase the risk of OUD. Misuse or intentional inappropriate use of morphine may lead to overdose and/or death. The risk of OUD is increased in patients with a personal or family history (parents or siblings) of substance use disorders (including alcohol use disorders), in current tobacco users, or in patients with other psychiatric disorders (e.g., major depression, anxiety, and personality disorders).

Morphine carries the same abuse potential as other potent opioid agonists and should be used with particular caution in patients with a history of alcohol or drug dependence.

Before initiating and during treatment with morphine, the goals of therapy and a plan for discontinuation should be discussed with the patient (see section "Method of administration and dosage"). Patients should also be informed about the risks and signs of OUD before and during treatment. Patients should be advised to contact their physician if such signs occur.

The potential risk can be minimized by appropriate dose selection or dosage form and by gradual discontinuation of morphine. Abrupt discontinuation or prolonged intervals between doses may precipitate withdrawal syndrome.

Patients should be monitored for signs of opioid-seeking behavior (e.g., early requests for additional doses). This includes checking for concomitant use of opioids and psychoactive medicinal products (e.g., benzodiazepines). Patients showing signs and symptoms of OUD should be referred for consultation with an addiction specialist.

Data are available on reduced fertility and increased risk of chromosomal damage in rats following morphine administration.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy and breastfeeding.

Newborns whose mothers received opioid analgesics during pregnancy should be monitored for neonatal abstinence syndrome. Treatment may include opioid and supportive therapy.

Fertility. Preclinical data indicate that morphine may reduce fertility (see section "Pharmacological properties").

Ability to affect reaction speed when driving or operating machinery.

During treatment with morphine hydrochloride, patients should not drive or engage in other potentially hazardous activities requiring rapid psychomotor reactions.

Administration and Dosage

The dosage regimen is individual. Generally, adults should be administered subcutaneously or intramuscularly 1 mL (10 mg of morphine hydrochloride), or slowly intravenously 0.5–1 mL (5–10 mg of morphine hydrochloride).

Dosage should be reduced in elderly patients and those with psychiatric disorders, as well as in patients with mild to moderate hepatic or renal impairment.

Morphine is the opioid of choice in oncological conditions. The appropriate dose should be administered every 12–24 hours depending on the intensity of pain.

Maximum doses for adults by subcutaneous administration: single dose – 2 mL (20 mg of morphine hydrochloride), daily dose – 5 mL (50 mg of morphine hydrochloride).

Treatment Goals and Discontinuation

Before initiating morphine therapy, the treatment strategy—including duration, treatment goals, and a plan for discontinuation—should be discussed and agreed upon with the patient, in accordance with pain management protocols. During therapy, the physician should maintain regular contact with the patient to assess the need for continued treatment, consider the possibility of discontinuation, and, if necessary, adjust the dosage. When a patient no longer requires morphine therapy, gradual dose reduction may be advisable to prevent the development of withdrawal syndrome**. In the absence of adequate pain control, consider the possibility of hyperalgesia, tolerance, or progression of the underlying disease (see section "Special Warnings and Precautions for Use").**

Duration of Treatment

Morphine should not be used longer than necessary.

Children.

Initial doses for children with acute pain:

• under 1 month of age: 0.15 mg/kg body weight administered intramuscularly or subcutaneously;
• from 1 month to 12 years of age: up to 0.2 mg/kg body weight administered intramuscularly or subcutaneously.

Subsequent doses should be adjusted according to the patient's response.

For management of postoperative pain in children:

• under 1 month of age: 0.15 mg/kg body weight administered intramuscularly or subcutaneously;
• from 1 month to 12 years of age: up to 0.2 mg/kg body weight administered intramuscularly or subcutaneously.

Doses should be adjusted based on patient response.

For premedication: 0.15 mg/kg body weight administered intramuscularly.

The maximum daily dose for intramuscular or subcutaneous administration is 15 mg.

In special cases, intravenous administration may be used: 0.05–0.1 mg/kg body weight.

Morphine should be used with caution in neonates and young children, as they are more sensitive to opioids due to lower body weight.

Overdose.

An early and dangerous manifestation is respiratory center depression. Respiratory depression leads to cyanosis, followed by tissue hypoxia, capillary damage, and shock. Respiratory failure may result in death. Aspiration pneumonia is possible.

Treatment: general resuscitation measures, administration of opioid receptor antagonists and agonist-antagonists (naloxone, nalorphine). The specific antidote for morphine hydrochloride poisoning is naloxone (0.01 mg/kg administered intravenously, repeated every 20–30 minutes if necessary, then intramuscularly every 2 hours until respiration is restored). Perform transfusion therapy, oxygen therapy, peritoneal dialysis. Analgetics are contraindicated.

Adverse Reactions

Cardiovascular system: with prolonged use – bradycardia or tachycardia, cardiac arrhythmias, orthostatic hypotension, hypertension, facial flushing; phlebitis (after parenteral administration).

Respiratory system: respiratory depression, bronchospasm, central sleep apnea syndrome.

Nervous system: sedative or excitatory effects (especially in elderly patients), delirium, hallucinations, increased intracranial pressure with potential subsequent impairment of cerebral circulation, hypothermia, headache, mood changes, restlessness, fatigue, drowsiness, hyperhidrosis, dysphoria, allodynia, hyperalgesia (see section "Special Precautions"). When high doses are used, euphoria and drug dependence may develop.

Eye disorders: pupillary constriction.

Musculoskeletal and connective tissue disorders: muscle rigidity.

Gastrointestinal system: nausea, vomiting, constipation, dry mouth, biliary spasm with subsequent increase in biliary enzyme levels, pancreatitis, spasm of the sphincter of Oddi.

Urinary system: urinary retention or worsening of this condition in patients with benign prostatic hyperplasia and urethral stenosis.

Other: allergic reactions including rash, pruritus, urticaria, anaphylactoid reactions, anaphylactic shock, and angioneurotic edema, acute generalized exanthematous pustulosis, asthenic states; erythema and thickening at the injection site after intravenous administration.

Drug dependence and withdrawal syndrome (abstinence syndrome)

Repeated administration of opioid analgesics, even at therapeutic doses, may lead to the development of physical and/or psychological dependence and tolerance. The risk of developing opioid dependence may vary depending on individual patient risk factors, dosage, and duration of opioid treatment. Abrupt discontinuation of treatment or administration of opioid antagonists may precipitate withdrawal syndrome; sometimes withdrawal symptoms may occur between doses (see section "Special Precautions").

Physical withdrawal symptoms: body aches, tremor, restless legs syndrome, diarrhea, abdominal cramps, flu-like symptoms, nausea, tachycardia, mydriasis.

Psychological withdrawal symptoms: anxiety, irritability, dysphoric mood.

One of the factors contributing to drug dependence is drug craving.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Packaging.

1 ml in an ampoule; 5 ampoules per blister; 1, 2, or 20 blisters per cardboard box.

1 ml in an ampoule; 10 ampoules per blister; 1 or 10 blisters per cardboard box.

Prescription status.

By prescription only.

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorovya Narodu".

Manufacturer's address and location of business activity.

41 Kuilikivska Street, Kharkiv, Kharkiv Region, 61002, Ukraine.