Oramorph

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ORAMORPH (ORAMORPH)

Composition:

Active substance: morphine sulfate;

1 ml of oral solution contains 2 mg of morphine sulfate;

Excipients: sucrose, glucose solution, methylparaben (E 218), propylparaben (E 216), ethanol 96%, purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear, almost colorless solution, free from particulate matter.

Pharmacotherapeutic group.

Analgesics. Opioids. Opium alkaloids. ATC code N02A A01.

Pharmacological properties.

Pharmacodynamics.

Morphine binds to specific receptors located at various levels of the central nervous system, as well as in various peripheral organs.

It reduces pain sensation and response to pain due to interaction with central nervous system receptors.

Pharmacokinetics.

Absorption.

Morphine is moderately absorbed from the gastrointestinal tract following oral administration. After oral administration of radiolabeled morphine in humans, peak plasma levels are reached approximately within 15 minutes. Morphine undergoes significant first-pass metabolism in the liver, resulting in systemic bioavailability of approximately 25%.

Distribution.

After administration of a therapeutic dose, approximately one third of morphine in plasma is protein-bound.

Metabolism.

Morphine metabolism primarily involves conjugation of morphine with 3- and 6-glucuronides. Small amounts are also metabolized via N-demethylation and N-dealkylation. Morphine-6-glucuronide has pharmacological effects similar to those of morphine. The half-life of morphine is about 2 hours. The half-life (T1/2) of morphine-6-glucuronide is slightly longer.

Excretion.

A small amount of morphine is excreted in feces. The remainder is excreted in urine, primarily as conjugates. Approximately 90% of a single dose of morphine is eliminated from the body within the first 24 hours. Enterohepatic recirculation of morphine and its metabolites is possible; therefore, a small amount of morphine may be detected in urine or feces for several days after the last dose.

Clinical characteristics.

Indications.

Severe-intensity pain or pain not controlled by analgesics with lower potency, including pain associated with malignant tumors.

Contraindications.

• Hypersensitivity to the active substance or to other substances closely related from a chemical standpoint, and/or to any component of the medicinal product. Hypersensitivity to morphine is characterized by facial flushing, itching, and bronchospasm (anaphylactic reactions may also occur during administration);
• Acute respiratory depression, obstructive respiratory tract diseases, bronchial asthma attacks (see section "Special precautions" for information on use in controlled asthma);
• Cardiac intoxication due to chronic lung disease;
• Acute alcohol intoxication;
• Delirium;
• All forms of acute abdomen and paralytic ileus (see section "Special precautions");
• Increased intracranial pressure (see section "Special precautions");
• Head injuries (see section "Special precautions");
• History of biliary tract surgery;
• Convulsive disorders;
• Uncontrolled epilepsy;
• Central nervous system depression, particularly caused by other medicinal products such as hypnotics, sedatives, tranquilizers, etc.;
• Coma (see section "Special precautions");
• Pheochromocytoma. Morphine and certain other opioids may induce release of endogenous histamine and thereby stimulate catecholamine release;
• Acute/severe liver disease;
• Concomitant use with monoamine oxidase inhibitors (MAOIs), as well as within 2–3 weeks after discontinuation of such treatment (see section "Interaction with other medicinal products and other forms of interaction");
• Concomitant use of naltrexone;
• Use in children under 1 year of age (see section "Dosage and administration").

Oromorph is generally also contraindicated during pregnancy and breastfeeding (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Monoamine oxidase inhibitors.

It is known that monoamine oxidase inhibitors interact with narcotic analgesics, leading to excitation or depression of the central nervous system with hypertensive or hypotensive crisis; therefore, their use with Oromorph is contraindicated.

Gabapentin.

Cases of interaction have been reported with concomitant use of morphine and gabapentin, likely due to increased opioid-related adverse reactions. The mechanism of this interaction is unknown. Therefore, these medicinal products should be used in combination with caution, and patients should be closely monitored for signs of central nervous system depression such as somnolence; the dose of gabapentin or morphine should be reduced accordingly.

Ritonavir.

Currently, there are insufficient pharmacokinetic data on the concomitant use of ritonavir with morphine; however, it is known that ritonavir may increase glucuronosyltransferase activity. Therefore, concomitant use of ritonavir and morphine may lead to decreased serum morphine concentrations with possible loss of analgesic efficacy.

Rifampicin.

Rifampicin may reduce morphine serum concentration and diminish its analgesic effect.

Cimetidine.

Cimetidine inhibits morphine metabolism.

CNS depressants.

It should be noted that morphine potentiates the effects of central nervous system depressants such as tranquilizers, anesthetics, sedatives, hypnotics, neuroleptics, tricyclic antidepressants, and alcohol.

Esmolol.

Morphine may increase the plasma concentration of esmolol.

Domperidone/metoclopramide.

Opioid analgesics, including morphine, may reduce the gastrointestinal effects of domperidone and metoclopramide.

Mexiletine.

Concomitant use of morphine may delay absorption of mexiletine.

Phenothiazine antiemetics.

Phenothiazine antiemetics may be used concomitantly with morphine; however, their hypotensive effect should be taken into account.

Sedatives such as benzodiazepines or similar agents.

Concomitant use of opioids with sedative agents such as benzodiazepines or similar agents increases the risk of sedation, respiratory depression, coma, and death due to additional CNS depressant effects. The dose and duration of concomitant use should be limited (see section "Special precautions").

Combined use of morphine and other central nervous system depressants, such as other morphine-like medicinal products (analgesics, antitussives, and substitution agents), tricyclic antidepressants, neuroleptics (including phenothiazines), barbiturates, benzodiazepines, non-benzodiazepine anxiolytics (e.g., meprobamate), hypnotics, sedatives (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedative H1-antihistamines, centrally acting antihypertensives, baclofen, thalidomide, gabapentin or pregabalin, and alcohol, may enhance morphine's adverse effects, particularly respiratory depression. Medicinal products that inhibit the cytochrome P450 system, such as cimetidine, may slow morphine metabolism, leading to increased plasma concentrations.

Morphine may potentiate the effects of neuromuscular blockers, muscle relaxants, dicoumarol, and other oral anticoagulants.

The effect of diuretic agents may be reduced.

Contraindicated combinations.

• Monoamine oxidase inhibitors.

Due to central nervous system depression, concomitant use may cause hypotension and respiratory depression (see section "Contraindications").

• Naltrexone.

Concomitant use may result in patient insensitivity to the analgesic effect of morphine.

Not recommended combinations.

• Alcohol.

Alcohol enhances the sedative effect of morphine. Concomitant use may increase the risk of impaired alertness, making driving and operating machinery hazardous. Consumption of alcohol and medicinal products containing alcohol is not recommended.

Combinations requiring special precautions.

• Rifampicin.

Concomitant use reduces the concentration and activity of morphine and its active metabolite. Close monitoring of the patient is required during and after rifampicin therapy, and morphine dosage should be adjusted if necessary.

• Cimetidine and other cytochrome P450 inhibitors.

These agents slow morphine metabolism, resulting in increased plasma morphine concentrations.

• P2Y12 inhibitor.

In patients with acute coronary syndrome receiving morphine, delayed and reduced effects of oral antiplatelet therapy with P2Y12 inhibitors have been observed. This interaction may be related to decreased gastrointestinal motility and may apply to other opioids. Clinical significance is unknown, but data suggest a potential reduction in P2Y12 inhibitor efficacy in patients concomitantly receiving morphine and a P2Y12 inhibitor (see section "Special precautions"). For patients with acute coronary syndrome who cannot be denied morphine and in whom rapid P2Y12 inhibition is considered critical, parenteral P2Y12 inhibitor administration may be considered.

Combinations to be considered.

• Other morphine agonist analgesics (alfentanil, codeine, dextromoramide, dextropropoxyphene, dihydrocodeine, fentanyl, oxycodone, pethidine, phenoperidine, remifentanil, sufentanil, tramadol).
• Morphine-like antitussives (dextromethorphan, noscapine, pholcodine).
• Morphine-based antitussive agents (codeine, ethylmorphine).
• Barbiturates.
• Other sedative medicinal products (neuroleptics, sedative antidepressants, muscle relaxants, sedative H1-antihistamines). Concomitant use may enhance central depression and increase the risk of impaired alertness, making driving and operating machinery hazardous.
• Oral anticoagulants (including dicoumarol). Morphine may potentiate the effect of these agents.
• Diuretics. Morphine may suppress diuretic action.

Special precautions for use.

Oromorph, due to its analgesic effect and influence on the level of consciousness, pupil diameter, and respiratory dynamics, may complicate the clinical assessment of a patient's condition and interfere with the diagnosis of severe abdominal conditions.

Morphine sulfate should be used with caution:

• during the first 24 hours after surgery,
• in patients with hypothyroidism (see "Dosage and administration"),
• in cases where respiratory function is impaired (e.g., kyphoscoliosis, emphysema, cor pulmonale, severe obesity).

Asthma.

Opioid drugs may be used cautiously in controlled bronchial asthma. However, such drugs are contraindicated during asthma exacerbations.

Head injuries and increased intracranial pressure.

Oromorph is contraindicated in patients with increased intracranial pressure, traumatic brain injury, or coma. Morphine's ability to increase cerebrospinal fluid pressure may be significantly enhanced if the patient already has elevated intracranial pressure due to trauma. Additionally, morphine may cause confusion, miosis, vomiting, and other adverse reactions that can mask the clinical course in patients with traumatic brain injury.

Abdominal organ diseases.

Morphine sulfate should not be used when there is a risk of developing paralytic ileus or if the patient has intestinal or biliary tract obstruction. The drug should be discontinued immediately if there is suspicion of the presence or development of paralytic ileus during treatment.

Use with caution is advised in patients with obstructive gastrointestinal disorders, biliary colic, biliary tract surgery, acute pancreatitis, or benign prostatic hyperplasia. Laxatives should be used if constipation occurs.

Use with caution in patients with inflammatory bowel disease. Morphine administration may mask the diagnosis or clinical course in patients with acute abdominal conditions or postoperative complications of abdominal surgery.

Hypotensive effect.

Morphine administration may cause severe hypotension in patients unable to maintain hemostatic blood pressure due to reduced blood volume or when used concomitantly with drugs such as phenothiazines or certain anesthetics.

Dependence, withdrawal syndrome (abstinence), and abuse.

The use of opioid analgesics may be associated with the development of physical and/or psychological dependence or tolerance. Tolerance is a state in which higher doses of morphine at shorter intervals are required to achieve the same analgesic effect. Tolerance to most effects of morphine usually develops within 2–3 weeks of therapy with moderate doses, more rapidly with higher doses. After discontinuation of treatment, tolerance decreases and disappears within 2 weeks. Morphine dependence may be both physical and psychological. This condition arises after repeated administration of the drug and is characterized by a strong craving for the drug or another substance with similar properties, which may develop within 1–2 weeks of treatment at therapeutic doses. The risk increases with longer duration of use and higher doses. Symptoms can be minimized by dose adjustment or formulation modification and gradual morphine withdrawal. For specific symptoms, see section "Adverse reactions." Withdrawal symptoms may occur upon abrupt discontinuation of treatment or administration of a morphine antagonist such as naloxone. Sudden cessation of morphine in a physically dependent patient leads to a withdrawal syndrome, the severity of which depends on the patient type, dose administered, frequency of administration, and duration of treatment. Withdrawal symptoms typically appear within several hours, peak at 36–72 hours, and then gradually subside. Symptoms include yawning, mydriasis, lacrimation, rhinorrhea, sneezing, fear, tremor, headache, weakness, sweating, anxiety, irritability, sleep disturbances or insomnia, restlessness, agitation, anorexia, nausea, vomiting, diarrhea with dehydration, bone pain, abdominal and muscular cramps, tachycardia, tachypnea, arterial hypertension, elevated body temperature, and vasomotor disturbances.

In the absence of treatment, the most pronounced withdrawal symptoms disappear within 5–14 days. For this reason, Oromorph should not be prescribed for pain that can be managed with weaker analgesics or for patients not under strict medical supervision. Morphine sulfate is an opioid agonist and a controlled narcotic substance. As with other opioid agonists, cases of morphine sulfate abuse are possible. This should be considered when prescribing morphine in situations where the physician or pharmacist is concerned about the risk of abuse or illegal use of the drug by the patient. Morphine has a potential for abuse similar to that of other potent agonistic opioids and should be used with particular caution in patients with a history of alcohol or drug abuse. Morphine sulfate abuse is also possible via inhalation or parenteral administration. Such routes of administration significantly increase the risk of overdose and death in individuals with substance dependence.

Hypersensitivity reactions.

Hypersensitivity and anaphylactic reactions have occurred during administration of the drug. Extreme caution should be exercised in patients with a history of allergic reactions to opiates. Oromorph is contraindicated in patients with known hypersensitivity to morphine sulfate.

Special patient groups.

Morphine is metabolized in the liver; therefore, due to the risk of increased oral bioavailability, the drug should be used with caution in patients with liver disease. Dose reduction is recommended in patients with chronic hepatic or renal insufficiency, severe hypothyroidism, adrenal insufficiency, benign prostatic hyperplasia, or shock. The active metabolite morphine-6-glucuronide may accumulate in patients with renal insufficiency, leading to respiratory depression and central nervous system depression.

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.

Severe skin adverse reactions

Cases of acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have 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 system 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.

Disorders related to opioid use (abuse and dependence)

Tolerance and physical and/or psychological dependence may develop after repeated use of opioids such as Oromorph.

Repeated use of Oromorph may lead to opioid use disorders (OUD). Higher opioid doses and longer duration of use may increase the risk of developing OUD. Abuse or intentional misuse of Oromorph 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-related disorders), current tobacco users, or patients with other psychiatric disorders (e.g., major depression, anxiety, or personality disorders).

Before initiating and during therapy with Oromorph, discuss treatment goals and discontinuation plans with the patient (see "Dosage and administration"). 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.

Patients should be monitored for signs of addictive behavior (e.g., early requests for additional doses). This includes monitoring concomitant use of opioids and psychoactive drugs (particularly benzodiazepines). Patients exhibiting signs and symptoms of OUD should be considered for consultation with an addiction specialist.

Excipients.

This medicinal product is contraindicated in patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

The product contains the excipients methylparaben (E 218) and propylparaben (E 216), which may cause allergic reactions (possibly delayed).

This medicinal product contains 10 vol.% ethanol (alcohol), i.e., up to 0.81 g, equivalent to 20 ml of beer or 8.3 ml of wine per dose. It is harmful for patients with alcoholism. Caution is advised when used in pregnant women, breastfeeding women, children, patients with liver disease, and patients with epilepsy.

Acute chest syndrome (ACS) in patients with sickle cell anemia (SCA). ACS symptoms are well-documented. Due to the possible association between ACS and morphine use in SCA patients receiving morphine during vaso-occlusive crisis, monitoring for ACS symptoms is justified.

Risks of concomitant use of sedatives such as benzodiazepines or similar drugs.

Concomitant use of Oromorph oral solution and sedative drugs such as benzodiazepines or similar agents may cause sedation, respiratory depression, coma, and fatal outcomes (see "Interaction with other medicinal products and other forms of interaction"). Due to these risks, concomitant prescription of these sedative drugs should only be considered if no alternative treatment options are available. If a decision is made to prescribe Oromorph oral solution together with sedative medicinal products, 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, it is strongly recommended to inform patients and caregivers about these signs and symptoms (see "Interaction with other medicinal products and other forms of interaction").

Oral antiplatelet therapy with P2Y12 inhibitors.

During the first day of concomitant use of a P2Y12 inhibitor and morphine, reduced effectiveness of P2Y12 inhibitor treatment has been observed.

Adrenal insufficiency.

Opioid analgesics may cause reversible adrenal insufficiency, requiring monitoring and glucocorticoid replacement therapy.

Symptoms of adrenal insufficiency may include, for example, nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.

Reduction of sex hormones and increased prolactin.

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

Hyperalgesia.

Hyperalgesia, which does not respond to further increases in morphine dose, may occur, particularly with high-dose use of the drug. Dose reduction or opioid substitution may be required.

Rifampicin.

Plasma concentrations of morphine may be reduced by rifampicin. Analgesic efficacy of morphine should be monitored and morphine doses adjusted during and after rifampicin treatment.

Precautions for use.

Morphine should be prescribed with caution to elderly, very elderly, or debilitated patients (see "Dosage and administration") and to patients suffering from:

• organic brain disorders;
• respiratory insufficiency and chronic lung diseases (especially if associated with bronchial hypersecretion), as well as in all conditions causing airway obstruction and in cases of reduced respiratory reserve (e.g., kyphoscoliosis and obesity);
• biliary or renal colic;
• benign prostatic hyperplasia;
• myxedema and hyperthyroidism;
• acute hepatitis and hepatopathies;
• chronic renal and hepatic dysfunction (see "Dosage and administration");
• adrenal insufficiency;
• shock and severe hypotensive states;
• slow gastrointestinal transit and inflammatory or obstructive intestinal disorders;
• opioid dependence;
• cardiovascular disorders and cardiac arrhythmias;

and also to patients after surgical procedures on the urinary tract.

Use during pregnancy or breastfeeding.

Pregnancy.

There are insufficient data on the safety of its use during pregnancy.

Morphine crosses the placental barrier; therefore, the drug should not be used during pregnancy, especially in the first trimester. Use during pregnancy is only possible if the expected benefit outweighs any potential risks to the fetus.

When using the drug during pregnancy, it should be noted that infants born to mothers who chronically take morphine may exhibit withdrawal syndrome. Newborns whose mothers received opioid analgesics during pregnancy should be monitored for signs of withdrawal syndrome (neonatal abstinence syndrome). Treatment may include opioid and supportive therapy.

During labor, the risk of gastric stasis and aspiration pneumonia in women increases. Since morphine rapidly crosses the placental barrier, it should not be used during the second stage of labor or preterm labor due to the risk of secondary respiratory depression in the newborn/infant.

The product contains ethanol, which should be taken into account when used in pregnant women.

Breastfeeding.

There are insufficient data on the safety of its use during breastfeeding. The drug should not be used during breastfeeding. Morphine is excreted in breast milk and may therefore cause respiratory depression in the newborn/infant.

Fertility.

Long-term use of opioid analgesics may cause hypogonadism and adrenal insufficiency in both men and women. These effects are considered dose-dependent and may lead to amenorrhea, reduced libido, infertility, and erectile dysfunction. Animal studies have shown that morphine may reduce fertility. Preclinical animal studies have reported reduced fertility and chromosomal damage in germ cells.

Ability to affect reaction speed when driving or operating machinery.

Morphine sulfate may adversely affect attention and motor coordination; therefore, driving vehicles or operating machinery requiring skill and rapid reaction should be avoided during treatment.

This effect is further enhanced when the drug is used in combination with alcohol or CNS depressants.

Method of administration and dosage.

For oral use.

Dosage.

The dosage may be increased under medical supervision depending on the intensity of pain and the patient's history regarding analgesic requirements.

Dose titration may be appropriate when switching patients from other morphine products to Oramorph therapy.

Morphine sulfate is readily absorbed from the gastrointestinal tract following oral administration. However, when oral morphine preparations are used instead of parenteral morphine, the dose usually needs to be increased by 50–100% to achieve the same level of analgesia.

Treatment goals and discontinuation

Before initiating therapy with Oramorph, the treatment strategy, including duration and treatment goals, 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 the possibility of discontinuation, and adjust doses if necessary. When a patient no longer requires therapy with Oramorph, gradual dose reduction may be advisable to prevent withdrawal symptoms (see section "Special precautions").

Duration of treatment

Oramorph should not be used for longer than necessary.

Special patient groups.

Dose reduction may be advisable for elderly patients and patients with chronic liver disease, renal impairment, severe hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy, shock, or when sedative effects are undesirable.

Discontinuation of therapy.

Abstinence syndrome may occur if opioid therapy is abruptly discontinued. Therefore, the dose should be gradually reduced until therapy is stopped.

Children.

Administered to children aged 1 year and older.

Overdose.

Symptoms.

Signs of morphine intoxication and overdose may include miosis, respiratory depression, and hypotension. In more severe cases, aspiration pneumonia, circulatory failure, and deepening coma may develop. Convulsions may occur in infants and children. Death may result from respiratory failure.

Treatment.

For adults, administer 0.4–2 mg naloxone intravenously. Repeat every 2–3 minutes if necessary, up to a maximum dose of 10 mg; alternatively, administer 2 mg in 500 mL of isotonic sodium chloride solution or 5% glucose solution (4 mcg/mL).

For children, administer naloxone at a dose of 5–10 mcg per 1 kg body weight. If this does not result in the desired clinical improvement, administer the next dose at 100 mcg/kg body weight. The most important measure is ensuring airway patency and adequate ventilation. Measures to maintain fluid and electrolyte balance should be taken. Oxygen, intravenous fluids, and other supportive measures may be used as needed. Peak plasma morphine concentration occurs within 15 minutes after administration; therefore, gastric lavage and activated charcoal are of limited effectiveness. Caution. The duration of action of naloxone (2–3 hours) may be shorter than the duration of action of morphine overdose. It is recommended to observe the patient who has regained consciousness after naloxone treatment for at least 6 hours after the last dose of naloxone.

Adverse Reactions

The most common adverse reactions to morphine sulfate when the drug is used at recommended doses are nausea, vomiting, constipation, drowsiness, and confusion. These effects are usually transient; therefore, persistent symptoms may indicate an underlying condition or overdose. Constipation does not diminish with continued therapy. All these adverse effects are expected and require appropriate management. Laxatives may be used when constipation occurs.

Even at therapeutic doses, the drug causes respiratory depression and, to a lesser extent, circulatory depression. Respiratory depression is usually mild or moderate and does not lead to significant consequences in patients without pre-existing respiratory impairment; however, it may cause serious complications in patients with bronchopulmonary disorders, such as atelectasis.

Severe respiratory and circulatory depression, leading to respiratory arrest and circulatory collapse, has been observed after oral or parenteral administration of opioid analgesics. Abrupt discontinuation of therapy may result in withdrawal syndrome (see section "Special Warnings and Precautions for Use").

Morphine use has been associated with drug abuse and misuse. Prolonged or inappropriate use of the drug may lead to dependence and addiction. The list of known adverse reactions, for which frequency has not been established, is presented below.

Immune system disorders: hypersensitivity, anaphylactic reactions

Cardiovascular system disorders: bradycardia, tachycardia, atrial flutter, loss of consciousness, syncope, circulatory depression (even less pronounced than respiratory depression), hypotension (more pronounced in hypovolemia), facial flushing

Nervous system disorders: drowsiness, headache, increased intracranial pressure (which may worsen pre-existing cerebral disorders), allodynia, hyperalgesia, circulatory depression, respiratory arrest, collapse, visual disturbances, dizziness, emotional excitement, insomnia, irritability, anxiety, euphoria and dysphoria, asthenia, myoclonus (especially in elderly patients and patients with renal impairment, in cases of overdose or too rapid dose escalation), hyperhidrosis

Gastrointestinal disorders: dry mouth sensation, nausea, vomiting, constipation, unknown – pancreatitis

Renal and urinary disorders: dysuria, urinary tract spasm, oliguria, and urinary retention (more pronounced in patients with concomitant urethroprostatic pathology)

Skin and subcutaneous tissue disorders: urticaria, pruritus and other skin rashes, facial, neck, and upper chest flushing, hyperhidrosis, unknown – acute generalized exanthematous pustulosis (AGEP)

Endocrine system disorders: increased vasopressin endocrine secretion and decreased adrenocorticotropic hormone, thyroid-stimulating hormone, 17-hydroxy- and 17-ketocorticosteroids

Hepatobiliary disorders: biliary tract spasm with transient increase in plasma amylase and lipase levels, unknown – sphincter of Oddi spasm

Psychiatric disorders: confusion, mental clouding, anxiety, mood changes, dysphoric mood, apathy, development of dependence, and, particularly in elderly patients, nightmares and hallucinations

Eye disorders: miosis

Ear and labyrinth disorders: vertigo

Respiratory, thoracic and mediastinal disorders: respiratory depression, bronchoconstriction. High doses may cause pronounced respiratory depression. In patients with asthma, morphine sulfate may provoke bronchospasm. Unknown – central sleep apnea syndrome

Musculoskeletal and connective tissue disorders: muscle rigidity

General disorders and administration site conditions: hypothermia, drug dependence, withdrawal syndrome

Reproductive system and breast disorders: decreased libido, erectile dysfunction

Description of selected adverse reactions

Repeated use of Oramorph may lead to drug dependence, even at therapeutic doses. The risk of developing drug dependence may vary depending on individual patient risk factors, dosage, and duration of opioid treatment (see section "Special Warnings and Precautions for Use").

Dependence, withdrawal syndrome (abstinence), and abuse

The use of opioid analgesics may be associated with the development of physical and/or psychological dependence or tolerance. Withdrawal syndrome may be triggered by abrupt discontinuation of opioid therapy or administration of opioid antagonists, and may sometimes occur between doses of the drug.

Physiological symptoms of withdrawal include body aches, tremor, restless legs syndrome, diarrhea, abdominal cramps, nausea, flu-like symptoms, tachycardia, and mydriasis. Psychological symptoms include dysphoric mood, anxiety, and irritability. One of the factors contributing to drug addiction is drug craving.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Shelf life after first opening of the bottle – 3 months.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

100 ml of the drug in a bottle, with 1 adapter, child-resistant cap, and measuring pipette, in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

L. Molteni & C. dei F.lli Alitti Società di Esercizio S.p.A.

Manufacturer's address and place of business.

S.S. 67 (Tosco Romagnola), Località Granatico - 50018 Scandicci, Italy