Omnonon-zn

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

Composition:

Active substances: 1 ml of solution contains morphine hydrochloride, recalculated to 100 % substance – 11.5 mg; noscapine, recalculated to 100 % substance – 5.4 mg; papaverine hydrochloride, recalculated to 100 % substance – 0.72 mg; codeine, recalculated to 100 % substance – 1.44 mg; thebaine, recalculated to 100 % substance – 0.1 mg;

Excipients: disodium edetate, glycerin, hydrochloric acid solution 1 M, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: transparent colorless or slightly yellowish liquid.

Pharmacotherapeutic group.

Analgesics. Opioids. Natural opium alkaloids. Morphine, combinations. ATC code N02A A51.

Pharmacological Properties.

Pharmacodynamics.

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

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

Omnonpon-ZH in some cases is better tolerated than morphine and less frequently causes spasm of smooth muscles (due to the spasmolytic effects of papaverine, thebaine, and noscapine).

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

Pharmacokinetics.

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

Clinical characteristics.

Indications.

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

Contraindications.

Respiratory impairment due to depression of the respiratory center, severe hepatic insufficiency, head injury, intracranial hypertension, stroke, cachexia, epileptic status, severe general exhaustion, abdominal pain of unknown etiology, acute alcohol intoxication, delirium, concomitant treatment with monoamine oxidase inhibitors (MAOIs), fever, arterial hypotension, atrioventricular conduction disturbances, comatose state, glaucoma, bronchoobstructive syndrome, age over 75 years, bronchospasm or predisposition to bronchospasm, individual hypersensitivity to the components of the drug.

The drug is contraindicated in children (under 18 years of age) for pain relief following tonsillectomy/adenoidectomy performed for the treatment of obstructive sleep apnea, as these patients are more susceptible to respiratory complications. The drug is contraindicated in children under 12 years of age.

Interaction with other medicinal products and other types of interactions.

With concomitant use:

• With other agents that have a depressant effect on the central nervous system (benzodiazepines or drugs with benzodiazepine-like effects, gabapentin or pregabalin), enhanced central nervous system depression may occur, increasing the risk of sedation, respiratory depression, coma, and fatal outcome; therefore, doses and duration of concomitant therapy should be limited (see section "Special precautions").
• With beta-blockers – enhanced depressant effect on the central nervous system;
• With butadione – possible accumulation of morphine; with dopamine – reduced analgesic effect of Omnopon-ZH;
• With cimetidine – enhanced respiratory depression;
• With phenothiazine derivatives and barbiturates – enhanced hypotensive effect and respiratory depression. Long-term use of barbiturates (especially phenobarbital) or narcotic analgesics leads to development of cross-tolerance. Chlorpromazine enhances the analgesic, as well as the miotic and sedative effects of Omnopon-ZH.

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

The spasmolytic effect of papaverine is enhanced by diphenhydramine, metamizole, and diclofenac. The hypotensive effect is enhanced when used concomitantly with antihypertensive agents, tricyclic antidepressants, procainamide, reserpine, and quinidine.

When used concomitantly with cardiac glycosides, a pronounced enhancement of myocardial contractile function is observed.

Papaverine may reduce the anti-Parkinson effect of levodopa and the hypotensive effect of methyldopa.

When used concomitantly with alprostadil for intracavernosal injection, there is a risk of priapism.

Phentolamine potentiates the effect of papaverine on the corpora cavernosa of the penis when administered together.

Papaverine may potentiate the effects of alcohol when used concomitantly.

In patients who smoke, metabolism of papaverine is accelerated, and its plasma concentration and pharmacokinetic effects are reduced.

The tonic effect of anticholinergic agents on smooth muscle may be reduced under the influence of papaverine.

Spasmolytic activity of papaverine may be reduced under the influence of morphine. However, papaverine is used together with morphine to reduce the spasmogenic effect of the latter.

There are reports of hepatitis development with concomitant use of papaverine and furadantin.

When reserpine and papaverine are used concomitantly, antihypertensive action is enhanced.

When used concomitantly with antidepressants, hypotensive effect may be enhanced.

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

Special precautions for use.

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

Use with caution in patients with impaired liver or kidney function, hypothyroidism, adrenal insufficiency, prostatic hyperplasia, shock, myasthenia gravis, inflammatory gastrointestinal disorders, and in patients aged 60 years and older.

Morphine causes pronounced euphoria. With repeated use, drug dependence may develop. Withdrawal syndrome may occur several hours after discontinuation of prolonged treatment and peak within 36–72 hours.

Alcohol consumption must be avoided during treatment.

In cases of overdose, if consciousness is preserved, activated charcoal may be administered orally.

Patients must be closely monitored for signs and symptoms of respiratory depression and sedation. Therefore, patients and caregivers should be informed about these symptoms (see section "Interaction with other medicinal products and other forms of interaction").

Respiratory failure requires respiratory support and administration of a stimulatory antagonist—naloxone. Administration of the opioid antagonist naloxone in opioid-dependent individuals may precipitate withdrawal symptoms. Supportive therapy is aimed at respiratory support and reversing shock through naloxone administration. The dose administered depends on the degree of respiratory failure and level of coma.

High doses of the drug, especially in elderly patients, may lead to respiratory depression and hypotension, resulting in circulatory failure and coma. The occurrence of adverse reactions depends on individual sensitivity to opioid receptors. Hyperthermia may occur in elderly patients. Exercise caution when prescribing the drug to patients with supraventricular tachycardia, severe heart failure with signs of decompensation, or stenosing coronary atherosclerosis.

Convulsions are more frequently observed in children. Drug toxicity depends on individual sensitivity to morphine and the amount administered.

Coma is characterized by pinpoint pupils and respiratory depression, which may indicate overdose. Pupil dilation indicates the development of hypoxia.

The drug is not recommended for use in children with impaired respiratory function, including neuromuscular disorders, severe cardiac and/or respiratory insufficiency, multiple injuries, or major surgical interventions, as these factors may exacerbate symptoms of codeine/morphine toxicity. The drug may be used in children aged 12 years and older only if non-opioid analgesics (e.g., ibuprofen, paracetamol) are ineffective, due to the risk of respiratory depression.

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

Cases of hyperalgesia, where dose escalation fails to produce analgesic effect, may occur very rarely, particularly with high-dose administration. In such cases, it is necessary either to reduce the dose or switch to another opioid medicinal product.

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

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 developing CSA, and this risk is dose-dependent. 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 the development of ACS and morphine use in patients with sickle cell anemia who received morphine during vaso-occlusive crisis, careful monitoring for signs and symptoms of ACS is required.

Adrenal insufficiency

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

Reduction in sex hormone levels and increased prolactin levels

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

Severe skin adverse reactions (SSAR)

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

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

Hepatobiliary disorders

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

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

Concomitant use of morphine and sedative drugs, such as benzodiazepines or drugs with benzodiazepine-like effects, may result in sedation, respiratory depression, coma, and fatal outcomes (see section "Interaction with other medicinal products and other forms of interaction"). When co-prescribing these sedative drugs for patients with no alternative treatment options, these risks should be considered. If concomitant use of morphine with sedative drugs is decided upon, the lowest effective doses should be used, and treatment duration should be as short as possible.

Disorders related to opioid use (DRO) (abuse, dependence, and withdrawal syndrome)

Repeated use of opioids may lead to tolerance and physical and/or psychological dependence. Repeated use of the medicinal product Omnopon-ZN may lead to DRO. Higher doses and longer duration of opioid treatment may increase the risk of DRO. Misuse or intentional inappropriate use of morphine may lead to overdose and/or death. The risk of DRO 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, and in patients with pre-existing psychiatric disorders (e.g., major depression, anxiety, personality disorders).

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

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

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

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

Data from preclinical studies indicate reduced fertility and risk of chromosomal damage in rats following morphine administration.

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 efficacy of P2Y12 inhibitors has been observed (see section "Interaction with other medicinal products and other forms of interaction").

Excipients

This medicinal product contains less than 1 mmol/dose of sodium, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy or breastfeeding.

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

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

Ability to affect reaction speed when driving or operating machinery.

During treatment with Omnopon-ZN, patients should not drive or engage in other potentially hazardous activities requiring rapid psychomotor responses.

Method of Administration and Dosage

The drug should be administered subcutaneously. The dosage regimen is individual. Generally, 1 ml should be administered to adults.

The dose should be reduced for elderly patients, individuals with mental disorders, and patients with hepatic or renal insufficiency.

Omnonpon-ZN is a drug of choice in oncological diseases. The appropriate dose should be administered every 12–24 hours depending on the severity of pain.

Maximum doses for adults: single dose – 1.5 ml; daily dose – 5 ml.

Treatment Goals and Discontinuation

Before initiating treatment, the treatment strategy—including duration, treatment goals, and a plan for discontinuation—should be discussed and agreed upon with the patient, in accordance with the pain management protocol. During therapy, the physician should maintain regular contact with the patient to assess the need for continuing treatment, consider the possibility of discontinuation, and, if necessary, adjust the dosage. When the patient no longer requires therapy, it may be appropriate to gradually reduce 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 Warnings and Precautions for Use").

Treatment Duration

The medicinal product should not be used longer than necessary.

Children.

The drug is contraindicated in children under 12 years of age.

Use in children (under 18 years of age) for post-tonsil-/adenoidectomy pain relief to treat obstructive sleep apnea is contraindicated, as these patients are more susceptible to respiratory complications.

Overdose.

The earliest and most dangerous sign of overdose is depression of the respiratory center. Respiratory failure may lead to fatal outcome. Aspiration pneumonia is possible.
Management: general resuscitation measures, administration of opioid receptor antagonists and agonist-antagonists (naloxone, nalorphine). The specific antidote for morphine poisoning is naloxone (0.01 mg/kg intravenously, repeated every 20–30 minutes if necessary, followed by intramuscular administration every 2 hours until respiration is restored). Perform transfusion therapy, oxygen therapy, and peritoneal dialysis. Analgetics are contraindicated.

Adverse Reactions

Cardiovascular system: bradycardia or tachycardia, cardiac arrhythmias, orthostatic hypotension, arterial hypotension may occur with prolonged use.

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

Central and peripheral nervous system: sedative or excitatory effects (especially in elderly patients), delirium, hallucinations, increased intracranial pressure with potential subsequent impairment of cerebral circulation, headache, hypothermia, drowsiness, weakness, dizziness, mood disturbances, anxiety, hyperhidrosis, dysphoria, allodynia, hyperalgesia (see section "Special precautions for use"). When high doses are used, euphoria and muscle rigidity may develop, as well as drug dependence.

Eye disorders: miosis, visual disturbances, diplopia.

Gastrointestinal system: dry mouth, nausea, vomiting, constipation, anorexia, diarrhea, pancreatitis.

Hepatobiliary system and bile ducts: spasm of the biliary tract leading to increased levels of biliary enzymes, jaundice, hepatic dysfunction, elevated liver transaminase activity, spasm of the sphincter of Oddi.

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

Blood and lymphatic system: eosinophilia.

Skin, subcutaneous tissue, and immune system: allergic reactions including pruritus, urticaria, anaphylactic shock, skin rash, skin hyperemia, anaphylactoid reactions, acute generalized exanthematous pustulosis (AGEP).

General disorders: decreased libido, sweating.

Other: injection site reactions, including thrombosis at the injection site, asthenic conditions.

Drug dependence and withdrawal syndrome

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

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

Psychological withdrawal symptoms: anxiety, irritability, dysphoric mood.

One of the factors contributing to opioid 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 of children.

Packaging.

1 mL in an ampoule; 5 ampoules in a blister; 1, 2, or 20 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

Manufacturer's address and place of business.

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