Morphine sulfate

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

Composition:

Active substance: morphine sulphate;

One tablet contains morphine sulphate pentahydrate 5 mg (0.005 g) or 10 mg (0.01 g);

Excipients: StarLac® (lactose monohydrate, maize starch), microcrystalline cellulose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, flat cylindrical tablets with beveled edges; the company trademark is printed on one side of the tablet; 10 mg tablets have a score line for division.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

Acts as an agonist on opioid receptors of the central nervous system (CNS), particularly on μ-receptors and, to a lesser extent, on κ-receptors. Stimulation of μ-receptors causes supraspinal analgesia, respiratory depression, and euphoria; stimulation of κ-receptors causes spinal analgesia, miosis, and sedation.

Central nervous system

Has pronounced analgesic and sedative effects (hypnotic and anxiolytic). Suppresses respiration through direct action on respiratory centers in the brainstem. Suppresses the cough reflex through direct action on the cough center in the medulla oblongata. Antitussive effects may occur at doses lower than those typically used for analgesia. Causes miosis even in complete darkness. Pinpoint pupils are a sign of opioid overdose, but this symptom is not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin in the brainstem may also lead to this symptom). In cases of morphine overdose, mydriasis associated with hypoxia is more commonly observed than miosis.

Gastrointestinal tract and other smooth muscles

Increases tone of smooth musculature, particularly in the antral portion of the stomach and intestines, thereby slowing movement of food contents and reducing peristalsis, which leads to constipation. Increases tone of the urinary bladder, bronchi, gastrointestinal sphincters, and biliary tract. May cause spasm of the sphincter of Oddi, resulting in increased intrabiliary pressure.

Cardiovascular system

Induces histamine release, leading to peripheral vasodilation or occurring without it, causing itching, facial flushing, eye reddening, sweating, and/or orthostatic hypotension.

Endocrine system

Opioids may affect the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal systems. Possible increases in serum prolactin, and decreases in plasma cortisol, estrogen, and testosterone levels, combined with low or normal levels of ACTH, LH, or FSH. These hormonal changes may be accompanied by clinical symptoms.

Other pharmacological effects

In vitro studies and animal studies have shown various effects of natural opioids such as morphine on components of the immune system; the clinical significance of these findings remains unclear.

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

Pharmacokinetics.

Well absorbed in the gastrointestinal tract. Subject to presystemic elimination. Metabolized not only in the liver but also in the kidneys and intestinal mucosa. The main renal metabolite is morphine-3-glucuronide; morphine-6-glucuronide is also formed. The elimination half-life from plasma is 2.5–3 hours.

Clinical characteristics.

Indications.

Severe pain.

Contraindications.

Hypersensitivity to any component of the drug; respiratory depression due to respiratory center suppression; abdominal pain of unknown etiology (acute abdomen); head trauma; predisposition to bronchospasm; paralytic ileus; gastric retention; severe hepatic insufficiency; concomitant use of monoamine oxidase inhibitors (MAOIs); intracranial hypertension; stroke; status epilepticus; cachexia; acute alcohol intoxication; delirium; fever.

Interaction with other medicinal products and other forms of interaction.

Morphine should be used with caution in patients who are concurrently receiving other central nervous system (CNS) depressants, including sedatives or hypnotics, general anesthetics, phenothiazines, other tranquilizers (benzodiazepines or drugs with benzodiazepine-like effects), muscle relaxants, antihypertensive agents, gabapentin or pregabalin, and alcohol. Combining these medicinal products with the usual dose of morphine increases the risk of respiratory depression, arterial hypotension, profound sedation, coma, or fatal outcome due to enhanced CNS depressant effects. Doses and duration of concomitant therapy should be limited (see section "Special precautions for use").

Morphine may increase the area under the concentration-time curve (AUC) of gabapentin when administered concomitantly. Patients should be closely monitored for signs of CNS depression, particularly somnolence; the dosage of gabapentin or morphine should be reduced accordingly.

Opioid receptor agonists/antagonists (e.g., buprenorphine, nalbuphine, pentazocine) should not be administered to patients who have received treatment with pure opioid agonists.

Medicinal products that block acetylcholine action (antihistamines, antiparkinsonian agents, antiemetics, etc.) may interact with morphine, enhancing anticholinergic adverse effects.

Cimetidine inhibits morphine metabolism.

It is known that MAO inhibitors interact with narcotic analgesics, causing excitation or CNS depression with hypertensive or hypotensive crises. The drug should not be administered concomitantly with MAO inhibitors or within 2 weeks after discontinuation of MAOI therapy.

Plasma morphine concentration may be reduced by rifampicin.

In patients with acute coronary syndrome receiving morphine, delayed onset of therapeutic effect and reduced magnitude of effect of oral antithrombotic agents that inhibit P2Y12 receptors have been observed. This interaction may be related to decreased gastrointestinal motility caused by morphine and other opioids. Data indicate a potential reduction in the effectiveness of P2Y12 receptor inhibitors when administered concomitantly with morphine (see section "Special precautions for use"); the clinical significance of these data is unknown. For patients with acute coronary syndrome in whom discontinuation of morphine therapy is not feasible and rapid P2Y12 receptor inhibition is essential, parenteral P2Y12 receptor inhibitors are recommended.

Although there are no pharmacokinetic studies on the concomitant use of ritonavir with morphine, it is known that ritonavir induces hepatic enzymes that catalyze morphine glucuronidation, which may reduce plasma morphine concentrations.

Special precautions for use.

The main risk associated with opioid overdose is respiratory depression. Patients should be carefully 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").

Sleep-related breathing disorders

Opioids may cause sleep-related breathing disorders, including central sleep apnea and sleep-related hypoxemia. Opioids increase the risk of central sleep apnea in a dose-dependent manner. Consideration should be given to reducing the total opioid dose in patients with central sleep apnea.

Severe skin adverse reactions

Cases of acute generalized exanthematous pustulosis (AGEP) associated with morphine use, which may be life-threatening or lead to fatal outcomes, have been reported. This reaction usually occurs within the first 10 days of treatment. Patients should be informed about the signs and symptoms of AGEP and advised to seek immediate medical attention if such symptoms occur. If signs or symptoms suggestive of severe skin reactions develop, morphine should be discontinued and alternative therapy considered.

Hepatic and biliary disorders

Morphine may cause dysfunction and spasm of the sphincter of Oddi, thereby increasing pressure in the biliary tract and increasing the risk of biliary disorders and pancreatitis.

As with all narcotic agents, the dose should be reduced in elderly patients, patients with hypothyroidism, renal impairment, and chronic liver disease. Use with caution in patients with respiratory impairment, severe bronchial asthma (see section "Contraindications"), seizure disorders (see section "Contraindications"), arterial hypotension with hypovolemia, severe cor pulmonale, opioid dependence, biliary tract diseases, pancreatitis, inflammatory bowel diseases, prostatic hypertrophy, and adrenal insufficiency. The medicinal product must not be used if there is a risk of paralytic ileus (see section "Contraindications"). If ileus is suspected or occurs during treatment, the drug should be discontinued immediately.

Morphine may lower the seizure threshold in patients with a history of epilepsy (see section "Contraindications").

Do not administer within 4 hours before additional analgesic procedures (e.g., surgery, nerve block). If continuation of therapy is necessary, the dose should be adjusted according to the patient's postoperative condition. The medicinal product should be used with caution in the preoperative period and during the first 24 hours after surgery. In patients after abdominal surgery, the drug may be administered only after normal intestinal function has been restored.

Rifampicin reduces plasma morphine levels when co-administered (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, the analgesic effect of morphine should be monitored, and morphine doses adjusted during and after rifampicin treatment.

Oral antithrombotic agents inhibiting P2Y12 receptors

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

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

Due to a possible association between the development of acute chest syndrome and morphine use in patients with sickle cell anemia during vaso-occlusive crisis, patients should be closely monitored for symptoms of ACS.

Adrenal insufficiency

Opioid analgesics may cause reversible adrenal insufficiency, requiring patient monitoring and glucocorticoid replacement therapy (see section "Pharmacological properties"). Symptoms of adrenal insufficiency may include 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 be associated with reduced sex hormone levels and increased prolactin levels (see section "Pharmacological properties"). Symptoms include decreased libido, impotence, or amenorrhea.

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

Concomitant use of morphine and sedative medicinal products such as benzodiazepines or drugs 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"). Therefore, prescribing morphine in combination with sedative drugs should only be considered when no alternative treatment options are available. If concomitant use of morphine and sedative medicinal products is necessary, the lowest effective doses should be used, and the duration of treatment should be as short as possible.

Disorders related to opioid use (abuse and dependence)

Repeated use of opioids may lead to the development of tolerance and/or physical and/or psychological dependence (see section "Adverse reactions").

Repeated use of Morphine sulfate may lead to opioid use disorders (OUD). The risk of developing OUD increases with higher opioid doses and longer duration of treatment. Misuse or intentional incorrect use of the drug 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 patients who use tobacco products, and in patients with other psychiatric disorders in their history (e.g., major depression, anxiety disorders, and personality disorders).

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

Patients should be under appropriate supervision to detect signs of addictive behavior (e.g., early patient requests for prescription renewal). This supervision includes reviewing concomitant opioid and psychoactive drug therapy (e.g., benzodiazepines). Patients showing signs and symptoms of OUD should be referred for consultation with an addiction specialist.

The potential risk can be minimized by appropriate selection of morphine dose or dosage form and by gradual discontinuation of morphine. Abrupt discontinuation of treatment may cause withdrawal syndrome (see section "Adverse reactions"). If a patient no longer requires morphine therapy, the drug dose should be gradually reduced to prevent withdrawal syndrome. With prolonged use of the drug, tolerance may develop, which may necessitate gradual dose escalation to achieve adequate analgesia.

Morphine carries the same risks of abuse as other potent opioid agonists. Individuals with latent or overt predisposition to drug addiction may abuse morphine. Morphine should be used with particular caution in patients with a history of alcohol or drug dependence.

Cases of hyperalgesia, where increasing the dose does not lead to analgesic effect, may occur, particularly with high-dose morphine. In such cases, either the morphine dose should be reduced or the drug should be replaced with another opioid medicinal product.

Parenteral administration of formulations intended for oral use may result in death.

This medicinal product should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption due to the presence of lactose monohydrate.

Use during pregnancy or breastfeeding.

Do not use during pregnancy or labor due to the risk of neonatal respiratory depression. Use in breastfeeding women is not recommended, as morphine passes into breast milk.

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

According to preclinical data, morphine may reduce fertility (see section "Pharmacological properties").

Ability to affect reaction speed when driving or operating machinery.

Treatment with this medicinal product may cause sedation; therefore, it is recommended to refrain from driving or operating machinery during treatment.

Method of Administration and Dosage

For oral use. The dosage regimen should be individually determined.

The initial dose of the medicinal product depends on the severity of pain and the patient's prior use of analgesics. The medicinal product should be administered at the dose prescribed by the physician every 4 hours. In case of increasing pain or development of tolerance to morphine, the dose should be increased using available dosage strengths of 5 mg and 10 mg.

In elderly patients, dose reduction may be appropriate compared to doses used in adults.

Patients switching from parenteral to oral administration of morphine require an increased dose to compensate for the reduced analgesic effect associated with oral administration. The dose increase is typically 100%. Individual dose adjustment is necessary for such patients.

For adults and children aged 12 years and older who have not previously used opioids, the initial morphine dose is usually 5–10 mg every 4 hours. For pain not controlled by weaker opioids, the initial morphine dose is typically 10 mg every 4 hours.

Children aged 3–5 years are prescribed 5 mg every 4 hours; children aged 6–12 years – 5–10 mg every 4 hours.

The daily morphine dose may be increased up to 200 mg, provided adverse reactions are monitored and emergency specialized care is available. If pain cannot be controlled with the titrated dose and daily doses exceeding 200 mg are required (usually in chronic oncological pain), continuous close monitoring of the patient is necessary (see sections "Adverse Reactions" and "Overdose").

In postoperative pain, patients with body weight below 70 kg are prescribed 5 mg every 4 hours; patients with body weight of 70 kg and above – 10 mg every 4 hours. Oral morphine formulations should be used cautiously during the first 24 hours after surgery due to the dynamic recovery of intestinal function.

Therapeutic Goals and Discontinuation of Treatment

Before initiating treatment with Morphine Sulfate, the treatment strategy—including duration of therapy, therapeutic 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 continuously monitor the patient to assess the need for continued treatment, adjust the dose if necessary, and make decisions regarding discontinuation. If the patient no longer requires Morphine Sulfate therapy, gradual dose reduction may be appropriate to prevent withdrawal symptoms. Abrupt discontinuation of opioid therapy may lead to abstinence syndrome. If pain is not adequately controlled, consider possible hyperalgesia, tolerance, or progression of the underlying disease (see section "Special Precautions").

Duration of Treatment

The medicinal product should not be used longer than necessary.

Children

Not recommended for children under 3 years of age.

Overdose

Symptoms: pinpoint pupils, skeletal muscle flaccidity, bradycardia, respiratory depression, arterial hypotension; in severe cases – circulatory failure, coma. Overdose may result in fatal outcome. Cases of rhabdomyolysis progressing to renal failure have been reported. Respiratory failure may lead to death. Aspiration pneumonia is possible.

Treatment: Immediate priority is ensuring free airway access and application of assisted or controlled ventilation.

In patients without respiratory depression, activated charcoal may be administered orally if given within 1 hour after overdose (50 g for adults, 1 g/kg for children).

Pure opioid antagonists are specific antidotes in opioid poisoning. Other supportive measures may be used as needed.

In severe morphine overdose, administer naloxone 0.8 mg intravenously. Repeat injections every 2–3 minutes if necessary, or administer naloxone by infusion: 2 mg in 500 mL of 0.9% sodium chloride solution or 5% glucose solution (0.004 mg/mL). The infusion rate should be adjusted according to the previously administered bolus dose and the patient's response. Naloxone has a relatively short duration of action; therefore, the patient's condition must be closely monitored until full recovery of respiratory function.

In less severe overdose, administer naloxone 0.2 mg intravenously. Repeat injections every 2 minutes as needed, increasing the dose by 0.1 mg increments.

Naloxone should not be administered in cases of morphine overdose if there is no respiratory or circulatory depression. Naloxone should be administered cautiously to patients physically dependent on morphine, as sudden and complete reversal of opioid effects may precipitate acute withdrawal syndrome.

Side effects.

When used at recommended doses, the most common adverse effects of morphine are nausea, vomiting, constipation, and drowsiness. Nausea and vomiting are not typical during prolonged use of the drug. If such reactions occur, morphine administration may be combined with appropriate symptomatic therapy.

The adverse effects listed below are categorized by frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), unknown (cannot be estimated based on available data).

Immune system disorders: unknown – allergic reactions, anaphylactic reactions, anaphylactoid reactions.

Psychiatric disorders: common – confusion, insomnia; uncommon – agitation, euphoria, hallucinations, mood alterations; unknown – drug dependence, dysphoria, thinking disorders.

Nervous system disorders: common – dizziness, headache, involuntary muscle contractions, somnolence; uncommon – seizures, paraesthesia, loss of consciousness, myoclonus; unknown – hyperalgesia, allodynia, hyperhidrosis.

Eye disorders: uncommon – visual disturbances; unknown – miosis.

Ear and labyrinth disorders: uncommon – vertigo.

Cardiac disorders: uncommon – palpitations, facial flushing, hypotension; unknown – bradycardia, tachycardia, hypertension.

Respiratory, thoracic and mediastinal disorders: uncommon – bronchospasm, pulmonary edema, respiratory depression; unknown – cough suppression, central sleep apnea syndrome.

Gastrointestinal disorders: very common – nausea; common – abdominal pain, anorexia, constipation, dry mouth, vomiting; uncommon – dyspepsia, intestinal obstruction, taste disturbances, increased liver enzymes; unknown – biliary pain, pancreatitis, exacerbation of pancreatitis, sphincter of Oddi spasm.

Skin and subcutaneous tissue disorders: common – hyperhidrosis, rash; uncommon – urticaria; unknown – acute generalized exanthematous pustulosis (AGEP).

Renal and urinary disorders: uncommon – urinary retention; unknown – ureteral spasm, amenorrhea, decreased libido, erectile dysfunction.

General disorders: common – asthenia, pruritus; uncommon – weakness, peripheral edema; unknown – development of drug tolerance, withdrawal syndrome.

Drug dependence and withdrawal syndrome

The use of opioid analgesics may lead to the development of physical and/or psychological dependence or tolerance. Repeated administration of Morphine sulfate may result in drug dependence, even when used at therapeutic doses. The risk of developing drug dependence is influenced by individual patient risk factors, dosage, and duration of opioid treatment (see section "Special precautions"). Abrupt discontinuation of treatment or administration of opioid antagonists may trigger withdrawal syndrome; sometimes, withdrawal symptoms may occur between doses.

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

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.

Keep out of reach and sight of children.

Packaging.

Tablets 0.005 g, pack size 50 (10×5) in blisters in a carton; tablets 0.01 g, pack size 10 (10×1), 50 (10×5) in blisters in a carton, 140 (10×14) in blisters in a bulk pack.

Prescription status. Prescription only.

Manufacturer.

Interkhim Limited Liability Company.

Manufacturer's address and place of business.

40-A, 21st km of Starokyivska Road, Odesa, Ukraine, 65025.