DROPERIDOL

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DROPIZOL (DROPIZOL)

Composition:

Active substance: tincture of opium, standardized;

1 ml of oral drops, solution, contains 1 ml of standardized tincture of opium corresponding to 10 mg of anhydrous morphine;

1 drop contains 50 mg of tincture of opium corresponding to 0.5 mg (10 mg/ml) of anhydrous morphine;

1 ml = 20 drops;

Excipients: ethanol, purified water.

The medicinal product contains 33% v/v ethanol (alcohol).

Pharmaceutical form. Oral drops, solution.

Main physicochemical characteristics: reddish-brown liquid.

Pharmacotherapeutic group. Antidiarrheal agents. Agents inhibiting peristalsis. ATC code A07D A02.

Pharmacological properties.

Pharmacodynamics.

Alkaloids of opium (opioids and isoquinoline derivatives) cause constipation, euphoria, and exert analgesic and sedative effects depending on the dose and derivative substance.

These effects are mediated by opioid receptors, which are widely distributed in the central nervous system. To a lesser extent, they are also present in the vas deferens, knee joints, gastrointestinal tract, heart, and organs and cells of the immune system.

Opioid peptides alter gastrointestinal tract (GI tract) function by interacting with opioid receptor pathways in the intestine that control motility and secretion. Opioid receptors are localized in the human gastrointestinal tract, but their relative distribution varies depending on the layer and region of the GI tract.

μ-Opioid receptor agonists inhibit gastric emptying, increase pyloric muscle tone, induce phase pressure activity in the pyloric and duodenal channels, disrupt the migrating motor complex, delay transit time through the small and large intestine, and increase resting tone of the anal sphincter. Additionally, opioids reduce intestinal secretion of electrolytes and water, thereby promoting net fluid absorption. Furthermore, μ-, κ-, and δ-opioid receptors contribute to opioid inhibition of intestinal motility. The result of all these effects is constipation.

The use of opium for the treatment of diarrhea has been clinically proven. Controlled clinical trials are lacking.

No clinical trials involving pediatric populations have been conducted; therefore, the medicinal product is not considered suitable for this patient group due to safety concerns regarding its use.

Pharmacokinetics.

Absorption

Maximum plasma concentration of morphine (the main alkaloid of standardized opium tincture) is reached within 2–4 hours after oral administration.

Distribution

After absorption, morphine binds to plasma proteins by approximately 30%.

Metabolism

Opium alkaloids are extensively metabolized into glucuronide conjugates (3-glucuronide (M3G) and 6-glucuronide (M6G)), which undergo enterohepatic circulation. The 6-glucuronide is a metabolite of morphine that is approximately 50 times more potent than the parent compound. Morphine is also demethylated, leading to the formation of another active metabolite—normorphine.

Codeine is metabolized to codeine-6-glucuronide, morphine (the only active metabolite), and norcodeine. Since codeine is present in opium extract in amounts tenfold lower than morphine, its hepatic transformation has minimal impact on the overall bioavailability of morphine.

Elimination

The elimination half-life of the drug is approximately 2 hours. The half-life of M3G has been reported to range from 2.4 to 6.7 hours. About 90% of the total amount of morphine is excreted within 24 hours, with trace amounts detectable in urine over 48 hours.

Elimination of glucuronide conjugates occurs primarily via the kidneys through both glomerular filtration and tubular secretion.

Fecal excretion is low (< 10%).

Non-clinical safety data

Several studies have shown that morphine causes chromosomal damage in somatic and germ cells of animals and in human somatic cells. Therefore, genotoxic effects in humans are expected. Long-term animal studies on the carcinogenic potential of morphine have not been conducted.

Adverse effects not observed in clinical trials but observed in animals exposed at higher than normal human exposure levels: fetal growth retardation and increased incidence of nervous system and skeletal defects.

Animal studies have shown toxic effects on reproductive function throughout pregnancy (CNS developmental abnormalities, fetal growth retardation, skeletal defects, testicular atrophy, changes in neurotransmitter systems and behavior, dependence).

In addition, morphine affects fertility in male offspring. Animal studies have also shown that morphine may negatively affect the function of reproductive organs or gametes and, via disruption of the endocrine system, may adversely affect male and female fertility.

The clinical relevance of these non-clinical findings has not been established.

Clinical characteristics.

Indications.

Dropyzol is indicated for symptomatic treatment of severe diarrhea caused by adverse effects of chemotherapy cytostatic agents or radiation, or by neuroendocrine tumors, in adult patients when the use of other antidiarrheal agents has not provided sufficient efficacy.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Opioid dependence.

Glaucoma.

Severe impairment of liver or kidney function.

Alcoholic delirium.

Severe head injury.

Risk of developing paralytic ileus.

Chronic obstructive pulmonary disease.

Asthmatic state.

Severe respiratory depression with hypoxia and/or hypercapnia.

Cardiac failure due to lung disease (cor pulmonale).

Interaction with other medicinal products and other forms of interactions.

It should be noted that the risk of sedation, respiratory depression, coma, or death increases due to the additive CNS depressant effects of ethanol, hypnotics (e.g., zolpidem), general anesthetics (e.g., barbiturates), MAO inhibitors (e.g., safinamide), tricyclic antidepressants, and psychotropic agents with sedative properties (such as phenothiazines), gabapentin, antiemetics (particularly bromopride, meclizine, metoclopramide), antihistamines (e.g., carbinoxamine, doxylamine), and other opioid medicinal products (e.g., alfentanil, butorphanol, fentanyl, hydrocodone, hydromorphone, levorphanol, remifentanil, sufentanil, tapentadol, tramadol). When co-administering the above-mentioned drugs with opium tincture, the dose and duration of treatment with Dropyzol should be limited (see section "Special precautions for use").

Dropyzol should not be used concomitantly with other morphine agonists/antagonists (buprenorphine, nalbuphine, nalmafene, naltrexone, pentazocine) due to their competitive binding to receptors, which may intensify withdrawal symptoms and reduce therapeutic efficacy.

Due to its ethanol content, Dropyzol should not be used concomitantly with disulfiram or metronidazole. Both of these drugs may cause disulfiram-like reactions (flushing, tachypnea, tachycardia).

Rifampicin induces CYP3A4 in the liver, thereby increasing the metabolism of morphine, codeine, and methadone. As a result, the effects of these opioids are reduced or neutralized.

Concomitant use of morphine and antihypertensive drugs may enhance the hypotensive effect of antihypertensive agents or other drugs with hypotensive properties.

Morphine inhibits glucuronidation of zidovudine in vitro.

The duration of action of morphine may be reduced after administration of fluoxetine.

Cimetidine and ranitidine do not affect the bioavailability of opium in the form of oral drops.

It is known that monoamine oxidase inhibitors (MAOIs) interact with narcotic analgesics, causing either CNS stimulation or depression, accompanied by hypertensive or hypotensive crises. The product should not be taken concomitantly with MAOIs and should not be used within 2 weeks after discontinuation of MAOI therapy.

Interactions with other medicinal products

Amphetamines and their analogs may reduce the sedative effect of opioids. Loxapine and periciazine may enhance the sedative effect of opioids. Concomitant use of flibanserin and opioids may increase the risk of CNS depression. Opioids may increase plasma concentrations of desmopressin and sertraline.

Special precautions for use.

Dropzil should only be used after studying the etiology of the disease associated with symptoms and exclusively in cases where the use of other antidiarrheal agents has been ineffective.

Dropzil drops should be used with caution in patients with the following conditions:

• advanced age;
• chronic kidney disease and/or liver disease;
• history of alcoholism;
• diagnosed biliary colic, cholelithiasis, or biliary tract disorders;
• head injury or increased intracranial pressure;
• decreased consciousness;
• cardiopulmonary shock;
• use of monoamine oxidase inhibitors (including moclobemide) and within two weeks after their discontinuation;
• adrenocortical insufficiency;
• hypothyroidism;
• low blood pressure with hypovolemia;
• pancreatitis;
• benign prostatic hyperplasia and other conditions that may impair urination;
• concomitant use of other antidiarrheal or antiperistaltic agents, anticholinergics, antihypertensive agents (see section "Interaction with other medicinal products and other forms of interaction");
• seizure disorders;
• gastrointestinal bleeding.

If difficulty with urination occurs, the patient should consult a physician.

Dosage adjustment may be required in elderly patients, patients with hypothyroidism, and patients with mild to moderate renal or hepatic impairment.

The use of Dropzil should be avoided in elderly patients with a history of falls or fractures. The use of opium tincture may lead to ataxia, psychomotor impairment, and loss of consciousness, which may result in falls and fractures. If treatment with Dropzil is necessary, consider reducing the use of other central nervous system-acting medicinal products that may increase the risk of falls. All other appropriate measures should be taken to minimize the risk of falls in elderly patients.

Antiperistaltic antidiarrheal agents should be used with caution in patients with intestinal infections or inflammatory bowel diseases due to the increased risk of toxin absorption, as well as the risk of developing toxic megacolon and intestinal perforation. Due to the risk of paralytic ileus, Dropzil is not recommended for use before surgical procedures and for 24 hours following them. If paralytic ileus is suspected during Dropzil treatment, therapy should be discontinued immediately.

Repeated use of Dropzil may lead to dependence and tolerance, and the use of opium may result in dependence on this substance. Particular caution should be exercised in patients prone to drug or alcohol dependence.

Risks associated with concomitant use of sedative medicinal products such as benzodiazepines or medicinal products of the same class

Concomitant use of Dropzil and sedative medicinal products such as benzodiazepines or medicinal products of the same class may result in sedation, respiratory depression, coma, and death. Due to these risks, concomitant use of such sedative medicinal products should be prescribed only to patients for whom alternative treatment options are not feasible. If a decision is made to prescribe Dropzil 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 sedative effects. Prescribers of Dropzil are strongly advised to inform patients and caregivers about the need to monitor breathing, as the drug may cause respiratory depression, coma, and death (see section "Interaction with other medicinal products and other forms of interaction").

The drug should be used in reduced doses and with maximum caution in patients who are also receiving other opioids, sedatives, tricyclic antidepressants, and monoamine oxidase inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

Dropzil should be used with caution in high-risk patient groups, such as patients with epilepsy and liver disease.

Opioids may suppress the hypothalamic-pituitary-adrenal (HPA) axis or gonadal axis at multiple levels, and this effect is most pronounced after prolonged use. This may lead to symptoms of adrenal insufficiency (see also section "Adverse reactions").

The medicinal product Dropzil contains 33% ethanol (alcohol), i.e., up to 260 mg per dose, equivalent to 6.6 mL of beer or 2.8 mL of wine, relative to the total volume.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of opium-containing drugs in pregnant women are limited. Animal studies have shown reproductive toxicity (see section "Preclinical safety data").

Dropzil is not recommended during pregnancy, except when the benefit clearly outweighs the risks associated with its use for both mother and child.

Neonatal withdrawal syndrome may occur if morphine is used during pregnancy up to delivery.

Breastfeeding

Opium is excreted in breast milk, where its concentration is higher than in maternal plasma. Breastfeeding should be discontinued or therapy with Dropzil should be stopped, taking into account the benefits of breastfeeding for the infant and the therapeutic effect of Dropzil for the mother. If Dropzil is used during breastfeeding, infants should be carefully monitored for symptoms of respiratory depression and sedative effects.

Fertility

There are insufficient data to assess the risk to human fertility. Animal studies have shown chromosomal damage to reproductive cells (see section "Preclinical safety data"). Men and women of reproductive potential should use reliable contraception during treatment with Dropzil.

Ability to influence reaction speed when driving or operating machinery.

Due to its adverse reactions, Dropzil may significantly affect the patient's general condition, attention, and reaction speed, and thus the ability to drive vehicles or operate machinery. Patients receiving treatment with Dropzil are strictly prohibited from driving vehicles or operating machinery.

Method of administration and dosage.

Special caution should be exercised when using this medicinal product due to the presence of morphine. The duration of treatment should be as short as possible.

Dosage

The usual initial dose for adult patients is 5–10 drops 2–3 times daily.

Single doses should not exceed 1 mL, and the total daily dose should not exceed 6 mL.

Dosage must be determined by a physician, taking into account individual patient characteristics (age, body weight, medical history, etc.), in order to use the lowest effective dose for the shortest possible duration.

Administration

Dropezil is administered orally only.

Dropezil may be taken undiluted (as drops) or mixed with a glass of water. If diluted with water, the medicinal product should be used immediately. If used undiluted, the prescribed dose may be administered using a regular spoon.

Special patient groups

Elderly patients

Caution should be exercised when administering Dropezil to elderly patients. Reduced doses should be used at the beginning of treatment.

Patients with renal impairment

In renal insufficiency, elimination of the active substance and its metabolites is slowed and prolonged. Therefore, Dropezil should be avoided in such patients or administered at a reduced dose (see sections "Contraindications" and "Special precautions for use").

Patients with hepatic impairment

In patients with impaired liver function, morphine contained in the medicinal product may cause coma. Dropezil should be avoided in such patients or administered at a reduced dose (see sections "Contraindications" and "Special precautions for use").

Children

The safety and efficacy of Dropezil in children (under 18 years of age) have not been established. There are currently insufficient data to provide dosage recommendations for children. Dropezil should not be used in children (under 18 years of age) for safety reasons (see section "Pharmacological properties. Pharmacodynamics").

Overdose

In case of exceeding the recommended doses, the risks for the patient are primarily determined by the toxicity of morphine. Lethal doses are defined by the morphine content.

Symptoms of overdose: miosis, respiratory depression, drowsiness, decreased skeletal muscle tone, and a sharp drop in arterial pressure. In severe cases, circulatory disturbances, stupor, coma, bradycardia, non-cardiogenic pulmonary edema, hypotension, and death may occur; abuse of high doses of potent opioids such as oxycodone may lead to fatal outcome.

Management in case of overdose

Primary attention should be given to ensuring airway patency and providing assisted or controlled lung ventilation.

In case of overdose, intravenous administration of an opioid antagonist may be indicated.

In addition, gastric lavage may be effective.

When treating concomitant circulatory shock, supportive therapy should be applied as needed (artificial respiration, oxygen supply, administration of vasopressors, and infusion therapy).

Adverse reactions.

Adverse reactions reported during the use of Dropezil oral drops, and information obtained from publications and post-marketing experience with other medicinal products based on morphine.

Adverse reactions are classified by organ systems and frequency of occurrence: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

Reporting of suspected adverse reactions

Reporting adverse reactions following the registration of a medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua/.

Shelf life. 3 years.

Storage conditions.

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

Do not store in the refrigerator and do not freeze!

After opening, the drops should be stored in the original packaging for no more than 4 weeks.

Keep out of reach and sight of children.

Packaging.

10 ml of oral drops in a bottle closed with a white cap equipped with a dropper and child-resistant closure. 1 or 3 bottles per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Lomapharm GmbH.

Manufacturer's address and place of business.

Langes Feld 5, Emmerthal, Niedersachsen, 31860, Germany