Morphine hydrochloride

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

Composition:

Active substance: morphine;

1 ml of solution contains 20 mg of morphine hydrochloride;

Excipients: sodium chloride, diluted hydrochloric acid, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: transparent colorless or slightly yellowish or yellowish-brown liquid.

Pharmacotherapeutic group. Analgesics. Opioids. Natural opium alkaloids. Morphine.

ATC code N02A A01.

Pharmacological properties.

Pharmacodynamics.

Morphine binds to stereospecific receptors in the central nervous system (CNS), altering both the perception of pain and the emotional response to pain.

Different subtypes of opioid receptors are believed to mediate various therapeutic and adverse effects observed with morphine administration. Morphine is a pure opioid agonist. Morphine has a very high affinity for μ (mu) receptors, and lower affinity for σ (sigma) and κ (kappa) receptors. The effects on the CNS are mediated by binding to receptors responsible for the following effects:

μ (mu) receptors: supraspinal analgesia, respiratory depression, euphoria, and psychological dependence;

κ (kappa) receptors: spinal analgesia, miosis (pupillary constriction), and sedation;

σ (sigma) receptors: dysphoria and hallucinations.

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

Pharmacokinetics.

Distribution.

Morphine is distributed predominantly to the kidneys, liver, lungs, and spleen, with lower concentrations in the brain and muscles. Morphine crosses the blood-brain barrier. Approximately 35% of the dose is protein-bound in the blood. Morphine crosses the placenta and is excreted into breast milk.

Biotransformation.

Morphine is primarily conjugated with glucuronic acid in the liver and intestine, forming morphine-3-glucuronide and morphine-6-glucuronide. The latter metabolite is pharmacologically active and is believed to contribute to the analgesic effect of morphine, particularly after repeated oral administration. In contrast, morphine-3-glucuronide is considered to have antagonistic properties, and it is hypothesized that this metabolite may underlie the paradoxical pain experienced by some patients following morphine administration. Other active metabolites include normorphine, codeine, and morphine ether sulfate. Enterohepatic recirculation is likely to occur.

Elimination.

Morphine is excreted mainly as metabolites, primarily via the kidneys. However, approximately 10% of the dose is excreted in bile via feces. About 90% of the administered morphine dose is eliminated within 24 hours, although traces may be detected in urine for 48 hours or longer. The mean elimination half-life is approximately 2 hours for morphine and 2.4–6.7 hours for morphine-3-glucuronide. In patients with hepatic impairment, the elimination half-life may be prolonged (see section "Dosage and administration").

Clinical characteristics.

Indications.

Severe pain that can be adequately controlled only with opioid analgesics.

Premedication.

Myocardial infarction.

Acute pulmonary edema.

Contraindications.

Hypersensitivity to morphine, other opioids, or to any of the excipients.

Concomitant treatment with opioid agonist/antagonist (see section "Interaction with other medicinal products and other forms of interaction").

Paralytic ileus or gastrointestinal obstruction.

Respiratory depression, severe bronchial asthma, or obstructive lung disease.

Severe hepatic insufficiency.

Acute abdomen.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of opioid agonists/antagonists, including naltrexone.

Mechanism: competitive binding to opioid receptors.

Effect: accelerated onset of withdrawal symptoms.

Monoamine oxidase inhibitors (MAOIs).

Mechanism: unknown.

Effect: possible hypotension, enhanced central nervous system (CNS) depression, and respiratory depression. Morphine and MAOIs should not be used concurrently or within 14 days after discontinuation of MAOIs (see section "Special precautions for use").

CNS depressants (other opioid analgesics, barbiturates, centrally acting muscle relaxants, chloral hydrate, phenothiazines, gabapentin, or pregabalin).

Mechanism: additive CNS depression.

Effect: possible respiratory depression, hypotension, pronounced sedation, or coma. Morphine should be used with caution in patients receiving CNS depressants (see section "Special precautions for use").

Sedative medicines such as benzodiazepines or similarly acting agents.

The use of opioids together with sedative medicines such as benzodiazepines or similarly acting agents increases the risk of sedation, respiratory depression, coma, and fatal outcome due to additive effects of CNS depressants. The dose and duration of concomitant use should be limited (see section "Special precautions for use").

Tricyclic antidepressants.

Amitriptyline and clomipramine may enhance the analgesic effect of morphine. This may be related to the fact that these agents increase the bioavailability of morphine.

Rifampicin and rifapentine.

Mechanism: enhanced metabolism of morphine due to induction of cytochrome P450 3A4.

Effect: plasma levels of morphine may be reduced. Decreased analgesic effect.

Oral antiplatelet therapy with P2Y12 inhibitors.

In patients with acute coronary syndrome who received morphine, delayed and reduced effect of oral antiplatelet therapy with P2Y12 inhibitors has been observed. This interaction may be related to decreased gastrointestinal motility and may 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 who received them concomitantly with morphine (see section "Special precautions for use"). For patients with acute coronary syndrome in whom morphine cannot be discontinued and for whom rapid P2Y12 inhibition is considered critical, administration of a parenteral P2Y12 inhibitor may be appropriate.

Alcohol.

Mechanism: additive CNS depression.

Effect: enhanced sedation. Concomitant use should be avoided.

Antacids.

Concomitant use of morphine with antacids may lead to faster release of morphine than expected; therefore, these medicinal products should not be used simultaneously, and an interval of approximately 2 hours should be maintained.

Due to morphine-induced reduction in gastrointestinal motility, the absorption rate of other medicinal products may be decreased.

Special precautions for use.

Patients who have been treated with or have received MAO inhibitors within 14 days are at particular risk of severe interaction effects (see section "Interaction with other medicinal products and other forms of interaction").

Reduced efficacy of P2Y12 inhibitors has been observed during the first 24 hours of concomitant treatment with morphine (see section "Interaction with other medicinal products and other forms of interaction").

The medicinal product should be used with caution before surgery and during the first 24 hours after surgery.

Morphine may lead to dependence. Cases of drug abuse and misuse have been reported.

Opioid use disorders (OUD) (misuse, 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 developing OUD. Misuse or intentional inappropriate use of morphine may lead to overdose and/or death. The risk of developing 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 existing psychiatric disorders (e.g., major depression, anxiety, and personality disorders).

Morphine has a potential for abuse similar to that of other potent opioid agonists and should be used with particular caution in patients with a history of alcohol or drug abuse. It should also be used with caution in opioid-dependent patients.

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

Symptoms can be minimized by dose or dosage form adjustment and gradual tapering of morphine. Abrupt discontinuation of treatment may cause withdrawal syndrome (see section "Undesirable effects").

Morphine treatment should be limited to short-term use and under strict medical supervision in patients with a history of drug abuse or opioid dependence. Patients should be monitored for signs of drug-seeking behavior (e.g., early requests for additional doses). This includes monitoring concomitant use of opioids and psychoactive medicinal products (e.g., benzodiazepines). Patients showing signs and symptoms of OUD should be considered for consultation with an addiction specialist.

Reports of psychological dependence on opioids in patients appropriately treated for pain are rare, but data on the true prevalence of psychological dependence in chronic patients are lacking.

Intracranial hypertension and head injury.

Morphine should be used with caution in cases of increased intracranial pressure, as it may cause further elevation of pressure. In patients with head injury, morphine may complicate diagnosis or clinical course. Morphine should be administered to these patients only when the benefit clearly outweighs the risk.

Respiratory depression.

Respiratory rate should be closely monitored. Drowsiness may be a sign of decompensation. It is important to reduce the morphine dose if concomitant treatment with other analgesics is prescribed, as such combinations increase the risk of sudden onset of respiratory depression.

Chronic constipation or other gastrointestinal disorders.

Opioids inhibit smooth muscle peristalsis. Therefore, it is important to ensure before initiating treatment that the patient does not have an obstructive syndrome, particularly intestinal obstruction. Constipation is a common adverse effect of opioids. Constipation prophylaxis should be initiated concurrently with morphine administration.

Sleep-related breathing disorders.

Opioids may cause sleep-related breathing disorders, including central sleep apnea (CSA) and nocturnal hypoxemia. Opioid use increases the risk of CSA in a dose-dependent manner. For patients with CSA, consideration should be given to reducing the total opioid dose.

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

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

Adrenal insufficiency.

Opioid analgesics may cause reversible adrenal insufficiency, which requires monitoring and glucocorticoid replacement therapy. Adrenal insufficiency may present with symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.

Reduced sex hormone levels and increased prolactin levels.

Long-term use of opioid analgesics may lead to decreased sex hormone levels and increased prolactin levels. Symptoms include decreased libido, impotence, or amenorrhea.

Cases of hyperalgesia, where dose escalation does not result in 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.

Severe skin reactions.

Acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, has been reported in association 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 attention if such symptoms occur.

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

Hepatobiliary disorders.

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

Risk associated with concomitant use of sedatives such as benzodiazepines or similar-acting agents.

Concomitant use of morphine and sedatives such as benzodiazepines or similar-acting agents may result in sedation, respiratory depression, coma, or death. Because of these risks, concomitant treatment with such sedatives should be reserved for patients for whom no alternative treatment options are available. If concomitant use of morphine with sedative agents is decided upon, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be closely monitored for signs and symptoms of respiratory depression and sedation. Therefore, patients and caregivers should be informed about such symptoms (see section "Interaction with other medicinal products and other forms of interaction").

Rifampicin may reduce morphine blood concentrations. The analgesic effect of morphine should be monitored and the morphine dose adjusted during and after rifampicin treatment.

Morphine may lower the seizure threshold in patients with epilepsy.

Morphine should be used with caution in patients:

• with impaired consciousness;
• with seizures;
• with biliary tract disorders;
• with pancreatitis;
• with hypotension associated with hypovolemia;
• with atrial fibrillation and other supraventricular tachycardias;
• with acute abdominal pain;
• receiving treatment with opioid agonist-antagonist analgesics;
• receiving treatment with other CNS depressants (see section "Interaction with other medicinal products and other forms of interaction");
• who abuse alcohol (see section "Interaction with other medicinal products and other forms of interaction").

Morphine should be used with maximum caution and in reduced doses in patients with:

• Addison's disease;
• prostate hypertrophy;
• hypothyroidism;
• reduced lung capacity;
• renal and/or hepatic impairment; and in elderly patients (see section "Posology and method of administration").

Elderly patients.

Due to the particular sensitivity of elderly individuals to adverse effects affecting the CNS (confusion) or gastrointestinal disorders, and physiological decline in renal function, caution should be exercised. Concomitant use of other medications, especially tricyclic antidepressants, further increases the likelihood of adverse effects such as confusion and constipation. Prostate and urinary tract disorders, common in this population, increase the risk of urinary retention. However, these considerations should not restrict the use of morphine in elderly patients if appropriate precautions are taken.

Concomitant use of alcohol and morphine may enhance the sedative effect of morphine; concurrent use should be avoided.

The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

Due to the mutagenic properties of morphine, both men and women of reproductive potential should use reliable contraception during morphine treatment. Morphine should not be used during pregnancy, particularly during the third trimester. If no alternative pain treatment is available, the benefits to the mother and potential risks to the fetus should be carefully considered. Morphine crosses the placenta and may cause respiratory depression and psychophysiological depression in the newborn if administered during labor. Resuscitation may be required. If necessary, administration of an opioid antagonist should be considered. Newborns whose mothers received opioid analgesics during pregnancy should be monitored for signs of neonatal abstinence syndrome. Treatment may include opioid medications and supportive measures.

Lactation.

Morphine should not be used during breastfeeding. Morphine passes into breast milk. The ratio of morphine concentrations in milk to plasma is approximately 3:1.

Fertility.

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

Ability to influence the speed of reactions while driving or operating machinery.

Morphine may significantly impair the ability to drive or operate machinery, especially at the beginning of treatment, during dose escalation, and when used concomitantly with alcohol or sedative drugs.

Method of Administration and Dosage.

Administer intramuscularly, subcutaneously, intravenously, or epidurally.

The dose depends on the severity of pain, patient's age, and prior analgesic requirements. There is considerable individual variation in dose requirements and response, even among patients with normal liver and kidney function.

Intravenous administration.

For continuous intravenous infusion, the drug should be administered slowly as an infusion at a rate of 2 mg/min until pain relief is achieved. Higher doses may be required in opioid-tolerant patients.

Epidural administration.

The usual initial dose is 2–4 mg, typically diluted with 0.9% sodium chloride solution. After the analgesic effect subsides, usually within 6–24 hours, a repeat dose of 1–2 mg may be administered if needed. For prolonged cancer pain, patients often require higher doses and continuous epidural infusion. The daily dose in adults generally does not exceed 100 mg/day, but higher doses may be necessary in some cases to control pain, especially in advanced stages of disease.

Recommended doses.

Adults.

Myocardial infarction, pulmonary edema: initially 2–8 mg may be administered very slowly by intravenous injection, with additional 2–6 mg doses given as needed at intervals of 5–15 minutes.

Severe pain: 10–20 mg intramuscularly or subcutaneously.

Premedication: doses are individualized.

Elderly patients.

In elderly patients, the initial dose should be lower, and dosage should be individually titrated to achieve the desired therapeutic response. Morphine is eliminated more slowly in elderly patients; therefore, a reduced daily dose may be required.

Hepatic impairment.

In patients with impaired liver function, the elimination half-life is prolonged. Morphine should be used with caution in such patients (see section "Special precautions"). The initial dose should be reduced, and the dosing intervals may be extended.

Renal impairment.

Morphine is primarily metabolized in the liver to inactive metabolites, which are excreted by the kidneys. Since one of the metabolites, morphine-6-glucuronide, is pharmacologically active, dose reduction is recommended in patients with acute or chronic renal failure. Patients with moderate to severe renal insufficiency (GFR 15–60 mL/min) should receive 50% of the normal dose at usual intervals, while patients with end-stage renal failure (GFR < 15 mL/min) should receive 25% of the normal dose at usual intervals.

Reduced gastrointestinal motility.

Dosage should be carefully adjusted in patients with reduced gastrointestinal motility.

Treatment goals and discontinuation.

Before initiating morphine therapy, the treatment strategy—including duration and goals of therapy, as well as 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 morphine therapy is no longer required, it may be appropriate to gradually taper the dose 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 precautions").

Duration of treatment.

Morphine should not be used for longer than necessary.

Children.

0.1–0.2 mg/kg body weight intramuscularly or subcutaneously every 2–4 hours (maximum dose is 15 mg/day).

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

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

Overdose.

Toxicity.

Sensitivity to morphine varies widely among individuals. Therefore, symptoms of intoxication may occur in adults after single doses corresponding to a subcutaneous or intravenous dose of approximately 30 mg. In cancer patients, these doses are often exceeded without causing serious adverse effects.

Symptoms.

Severe morphine overdose is characterized by respiratory depression, profound miosis (markedly constricted pupils), extreme drowsiness, which may progress to stupor or coma. Cold and clammy skin, rhabdomyolysis progressing to renal failure, muscle weakness, sometimes bradycardia and hypotension. In cases of serious overdose, especially after intravenous administration, apnea, circulatory collapse, cardiac arrest, and death may occur. Respiratory failure may lead to a fatal outcome. Aspiration pneumonia.

Treatment.

The primary step is to ensure a patent airway and initiate assisted or controlled ventilation. The opioid antagonist naloxone is a specific antidote for respiratory depression caused by opioid overdose or unusual sensitivity to opioids. Therefore, naloxone should be administered in doses according to patient needs, preferably intravenously, simultaneously with the initiation of respiratory resuscitation. Naloxone: 0.4 mg for adults (children: 0.01 mg/kg) administered slowly intravenously. Injections should be repeated if necessary. The effect begins within 30–60 seconds and usually lasts 45–60 minutes. After intramuscular injection, the effect begins within 10 minutes and lasts 2–3 hours. Patients should be monitored for respiratory depression for up to 24 hours. Transfusion therapy, oxygen therapy, vasopressors, and other supportive treatments should be administered as needed. Gastric lavage may be required to remove unabsorbed drug.

Adverse reactions.

The main risks associated with morphine use are respiratory depression and, to a lesser extent, circulatory depression. Most adverse reactions are dose-dependent. The most common adverse reactions are constipation, nausea, and sedation. Constipation occurs in all patients. Nausea and vomiting occur in approximately 30% of patients and decrease with prolonged use. If nausea and vomiting occur during administration of the drug, it may be combined with an antiemetic agent if necessary. The sedative effect usually diminishes after several days of treatment. In susceptible patients, spasms of the biliary ducts and urinary tract may occur.

System Organ Classes	Frequency
	Very common (≥1/10)	Common (≥1/100, <1/10)	Uncommon (≥1/1000, <1/100)	Rare (≥1/10000, <1/1000)	Very rare (<1/10000)	Frequency not known (cannot be estimated from available data)
Investigations		Increased ADH secretion.
Blood and lymphatic system disorders	Anemia.
Cardiac disorders			Tachycardia, bradycardia, palpitations.	From asthenia to syncope and cardiac failure.
Nervous system disorders	Sedation, headache, dizziness.	Confusion.	Increased intracranial pressure, lethargy, tremor, paraesthesia, hyperhidrosis.		High doses may cause CNS excitation (hyperalgesia (see section "Special warnings and precautions for use"), allodynia, which will not respond to dose escalation), myoclonus.
Eye disorders		Miosis.	Visual disturbances, including blurred vision, diplopia, nystagmus.
Respiratory, thoracic and mediastinal disorders		Dyspnoea, hypoxia.	Respiratory depression, bronchospasm, hypercapnia.	Asthmatic attacks in hypersensitive patients.	Lung oedema.	Central sleep apnoea syndrome.
Gastrointestinal disorders	Constipation, nausea, vomiting.	Flatulence.	Colic, paralytic ileus, dry mouth, bloating, dyspepsia.			Pancreatitis.
Renal and urinary disorders		Urinary retention after oral or parenteral administration.	Urinary tract spasms, oliguria.
Skin and subcutaneous tissue disorders		Rash, pruritus (due to histamine release).		Urticaria (due to histamine release), formication.		Acute generalised exanthematous pustulosis.
Musculoskeletal and connective tissue disorders			Cramps, muscle stiffness, back pain.
Metabolism and nutrition disorders		Decreased appetite.
Infections and infestations		Urinary tract infections.
Vascular disorders	Orthostatic hypotension.		Hypertension, facial flushing.	Hypotension.	Phlebitis at injection site.
General disorders and administration site conditions	Fever.		Withdrawal symptoms (restlessness, vomiting, increased appetite, irritability, tremor, hyperactivity, nasal congestion, convulsions and crying) were observed in neonates of mothers who used morphine during pregnancy (see section "Special warnings and precautions for use"). Inadequacy, tolerance.	Peripheral oedema, blisters and swelling at injection site.		Abstinence syndrome.
Immune system disorders				Anaphylactic/anaphylactoid reactions.
Hepatobiliary disorders			Spasm of bile ducts.			Sphincter of Oddi spasm.
Psychiatric disorders Psychiatric side effects may occur after morphine administration and may vary depending on intensity and character (depending on personality and duration of treatment).	Mood swings (usually excitement, sometimes dysphoria).	Changes in activity (usually depression, occasionally excitement) and changes in cognitive and sensory function (e.g., decision-making, perceptual disturbances, hallucinations (transient), nightmares, especially in elderly patients). Confusion, insomnia.	Psychological and physical dependence, disorientation, anxiety, excitement.

Drug dependence and withdrawal syndrome (abstinence syndrome).

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

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

Psychological symptoms include dysphoria, anxiety, and irritability.

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

Shelf life. 30 months.

Storage conditions.

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

Keep out of reach of children.

Incompatibility. Do not mix with other medicinal products. Use only the solvent specified in the section "Dosage and administration".

Packaging. 1 ml or 5 ml in an ampoule, 5 ampoules per blister, 1 or 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu"".

Manufacturer's address and location of business activity.

41, Kulikivska Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine.