Morphine-zn

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MOPHIN-ZN (MORPHIN-ZN)

Composition:

Active substance: morphine;

One tablet contains morphine hydrochloride trihydrate equivalent to 5 mg or 10 mg of 100% anhydrous substance;

Excipients: Celactose 80 (a mixture of monohydrate lactose and powdered cellulose (75:25)), microcrystalline cellulose, corn starch, colloidal anhydrous silicon dioxide, magnesium stearate, crospovidone.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white or almost white, round cylindrical tablets with a flat surface and beveled edges.

Pharmacotherapeutic group.

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

Pharmacological Properties.

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

Central Nervous System

Has pronounced analgesic and sedative effects (hypnotic and anxiolytic). Suppresses respiration via direct action on respiratory centers in the brainstem. Suppresses the cough reflex via 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 cause 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 the 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 independently of 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 increase in serum prolactin levels, decreased plasma levels of cortisol, estrogen, and testosterone, in combination with low or normal levels of adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), or follicle-stimulating hormone (FSH). These hormonal changes may be accompanied by clinical symptoms.

Other Pharmacological Effects

Various effects of natural opioids such as morphine on components of the immune system have been demonstrated in in vitro studies and in animal models; the clinical significance of these findings remains unclear.

Pharmacokinetics.

Well absorbed in the gastrointestinal tract. Undergoes presystemic elimination. Metabolized not only in the liver but also in the kidneys and intestinal mucosa. The main urinary 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 syndrome, including pain associated with malignant tumors, severe trauma, myocardial infarction, and in the postoperative period.

Contraindications.

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

Interaction with other medicinal products and other forms of interactions.

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 medicinal products with benzodiazepine-like effects), muscle relaxants, antihypertensive agents, gabapentin or pregabalin, and alcohol. Combining these agents with the usual dose of morphine may result in respiratory depression, arterial hypotension, profound sedation, coma, or fatal outcomes 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 plasma concentration–time curve (AUC) of gabapentin when administered concomitantly. Patients should be closely monitored for signs of CNS depression (e.g., somnolence); the dosage of gabapentin or morphine should be reduced accordingly.

Opioid receptor agonist/antagonists (e.g., buprenorphine, nalbuphine, pentazocine) should not be administered to patients who have been treated 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 either CNS stimulation or depression, accompanied by hypertensive or hypotensive crises. The medicinal product should not be administered concomitantly with MAO inhibitors or within 2 weeks after discontinuation of MAOI therapy.

Rifampicin may reduce the plasma concentration of morphine.

In patients with acute coronary syndrome who received morphine, delayed and reduced effects of oral antiplatelet therapy with P2Y12 inhibitors (e.g., prasugrel, clopidogrel, ticagrelor) have been observed. This interaction may be related to reduced gastrointestinal motility and may also apply to other opioids. The clinical significance of this interaction is not fully known, 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"). In patients with acute coronary syndrome for whom morphine cannot be discontinued and for whom rapid P2Y12 inhibition is considered critical, administration of a parenteral P2Y12 inhibitor may be appropriate.

Although pharmacokinetic data on the concomitant use of ritonavir and morphine are lacking, it is known that ritonavir induces hepatic enzymes that catalyze the glucuronidation of morphine, which may reduce plasma morphine concentrations.

Special precautions for use.

The main risk associated with opioid overdose is respiratory depression. 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").

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

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

Rifampicin may reduce blood concentrations of morphine (see section "Interaction with other medicinal products and other forms of interaction"). The analgesic effect of morphine should be monitored, and the morphine dose adjusted during and after rifampicin treatment.

Do not administer within 4 hours before additional analgesic procedures (e.g., surgery, nerve block). If continued treatment is necessary, dosage 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. After abdominal surgery, the drug may be administered only after normal intestinal function has been restored.

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 nocturnal 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 and morphine use in patients with sickle cell anemia during vaso-occlusive crisis, monitoring for symptoms of ACS is required.

Adrenal insufficiency

Opioid analgesics may cause reversible adrenal insufficiency, requiring monitoring and glucocorticoid replacement therapy (see section "Pharmacological properties"). Adrenal insufficiency may present with symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.

Reduction in sex hormone levels and increased prolactin levels

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

Severe skin adverse reactions

Acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, has been reported in association with morphine use. Most cases of AGEP 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 or 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, leading to increased intra-abdominal pressure and an increased risk of biliary tract symptoms and pancreatitis.

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

Concomitant administration of morphine hydrochloride and sedative agents such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma, or death (see section "Interaction with other medicinal products and other forms of interaction"); therefore, such patients require close medical supervision. Their caregivers should also be informed about the potential for these symptoms. When co-prescribing these sedative drugs, the risks for patients for whom alternative treatment options are not feasible must be considered. If a decision is made to co-prescribe morphine with sedative drugs, the lowest effective dose should be used, and the duration of treatment 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-ZN. Repeated use of Morphine-ZN may lead to OUD. Higher doses and longer duration of opioid treatment may increase the risk of OUD. Misuse of morphine or intentional inappropriate use 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-related disorders), in current tobacco users, or in patients with other psychiatric disorders (e.g., major depression, anxiety, and personality disorders).

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

Before initiating and during morphine treatment, 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 appear.

Symptoms can be minimized by dose or dosage form adjustment and gradual morphine discontinuation. Abrupt cessation of treatment may cause withdrawal syndrome (see section "Adverse reactions"). If morphine therapy is no longer required, the dose should be gradually reduced to prevent withdrawal syndrome.

Patients should be monitored for signs of addictive 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.

Cases of hyperalgesia, where dose escalation does not result in analgesia, may occur very rarely, particularly with high-dose administration. In such cases, either the dose should be reduced or the drug replaced with another opioid medicinal product.

Parenteral administration of dosage forms intended for oral use may result in fatal outcomes.

The drug 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.

The drug is not used 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.

Neonatal withdrawal syndrome may occur in newborns if the mother received prolonged morphine treatment during pregnancy. Newborns whose mothers received opioid analgesics during pregnancy should be monitored for signs of neonatal withdrawal syndrome.

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Administered orally. The dosage regimen should be individually determined.

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

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

For patients switching from parenteral to oral morphine administration, the dose should be increased to compensate for the reduced analgesic effect associated with oral administration. Typically, a dose increase of 100% is required; individual dose adjustment is necessary for such patients.

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

Children aged 3–5 years should be given 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 a daily dose exceeding 200 mg is required (usually in chronic oncological pain), continuous close monitoring of the patient is essential (see "Adverse Reactions" and "Overdose").

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

Treatment Goals and Discontinuation.

Before initiating treatment with Morphine-ZN, the treatment strategy—including duration, goals, and a plan for discontinuation according to the pain management protocol—should be discussed and agreed upon with the patient. During therapy, the physician should maintain regular contact with the patient to assess the need for continued treatment, consider discontinuation, and adjust doses if necessary. When a patient no longer requires morphine therapy, gradual dose reduction may be appropriate 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-ZN should not be used longer than necessary.

Children.

The medicinal product is not recommended for children under 3 years of age.

Overdose.

Symptoms: pinpoint pupils, skeletal muscle flaccidity, bradycardia, respiratory depression, arterial hypotension, and in severe cases—circulatory failure, coma, and aspiration pneumonia. Overdose may result in fatal outcome, including due to respiratory failure. Cases of rhabdomyolysis progressing to renal failure have been reported.

Treatment. Immediate measures should ensure unobstructed airway and provide assisted or controlled ventilation.

If respiratory depression is not present, administration of activated charcoal may be considered, provided the required dose (50 g for adults, 1 g/kg for children) is administered within 1 hour after overdose.

Pure opioid antagonists are specific antidotes in opioid poisoning. Other supportive measures may be implemented 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). Infusion rate should be based on the previously administered bolus dose and adjusted according to the patient's response. Naloxone has a relatively short duration of action; therefore, the patient's condition must be closely monitored until complete recovery of respiratory function.

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

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.

Adverse Reactions

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 according to frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from available data).

Immune system disorders: not known – allergic reactions, anaphylactic reactions, anaphylactoid reactions.

Psychiatric disorders: common – confusion, insomnia; uncommon – agitation, euphoria, hallucinations, mood alterations; not known – drug dependence, dysphoria, thought disorders.

Nervous system disorders: common – dizziness, headache, involuntary muscle contractions, somnolence; uncommon – seizures, paraesthesia, loss of consciousness, allodynia, myoclonus; not known – hyperalgesia.

Eye disorders: uncommon – visual disturbances; not known – miosis.

Ear and labyrinth disorders: uncommon – vertigo.

Cardiovascular disorders: uncommon – palpitations, facial flushing, arterial hypotension; not known – bradycardia, tachycardia, arterial hypertension.

Respiratory, thoracic and mediastinal disorders: uncommon – bronchospasm, pulmonary edema, respiratory depression; not known – 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; not known – biliary pain, pancreatitis, exacerbation of pancreatitis**, spasm of the sphincter of Oddi**.

Skin and subcutaneous tissue disorders: common – hyperhidrosis, rash; uncommon – urticaria; not known – acute generalized exanthematous pustulosis.

Renal and urinary disorders: uncommon – urinary retention; not known – ureteric spasm, amenorrhea, decreased libido, erectile dysfunction.

General disorders and administration site conditions: common – asthenia, pruritus; uncommon – weakness, peripheral edema; not known – development of drug tolerance, withdrawal syndrome.

Drug dependence and withdrawal syndrome.

Repeated use of opioid analgesics, including Morphine-ZN, 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 (see section "Special precautions"). Abrupt discontinuation of treatment or administration of opioid antagonists may precipitate withdrawal syndrome; sometimes withdrawal symptoms may occur between doses.

Physical withdrawal symptoms: body aches, tremor, restless legs syndrome, diarrhea, abdominal cramps, rhinorrhea, and flu-like symptoms, nausea, tachycardia, mydriasis, anxiety, irritability, dysphoric mood.

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

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister pack, 1 or 5 blister packs per carton.

Prescription status.

Prescription only.

Manufacturer.

Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorovya Narodu"".

Manufacturer's address and location of business activity.

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