Sigan-dbs

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SIGAN-DBS (SIGAN-DBS)

Composition:

Active substances: 1 tablet contains paracetamol 650 mg, di cyclomenine hydrochloride 20 mg;

Excipients: microcrystalline cellulose, anhydrous lactose (10 mg), maize starch, povidone, sodium methylparahydroxybenzoate (E 219), sodium propylparahydroxybenzoate (E 217), magnesium stearate, sodium starch glycolate;

Film coating: hypromellose, polyethylene glycols 400, titanium dioxide (E 171), talc, quinoline yellow colour (E 104), sunset yellow colour (E 110).

Pharmaceutical form.

Film-coated tablets.

Main physicochemical properties: film-coated tablets of orange colour, round, biconvex, smooth on both sides.

Pharmacotherapeutic group.

Analgesics and antipyretics. Paracetamol, combinations without psychotropic agents.

ATC code N02B E51.

Pharmacological properties.

Pharmacodynamics.

A combination drug with analgesic and spasmolytic effects.

Paracetamol acts as an analgesic and antipyretic agent. The analgesic and antipyretic effects of paracetamol (a non-opioid, non-salicylate analgesic) are associated with the drug's action on the thermoregulatory center in the hypothalamus and its ability to inhibit prostaglandin synthesis.

Hydrochloride dicycloverine – a tertiary amine. Possesses anticholinergic activity, reduces smooth muscle tone, relieves pain, and blocks antagonistic activity. Hydrochloride dicycloverine selectively paralyzes M-cholinoreactive structures, blocking the transmission of impulses from postganglionic cholinergic nerves to the effector organs they innervate. It causes relaxation of smooth muscles, producing a spasmolytic effect in spasms of the smooth muscles of the stomach, intestines, biliary tract, genitourinary and vascular systems.

Pharmacokinetics.

Paracetamol is rapidly and almost completely absorbed in the gastrointestinal tract; it quickly distributes into biological fluids of the body and binds weakly to plasma proteins. Maximum plasma concentration is reached within 20–30 minutes.

Paracetamol crosses the placental barrier. A small amount passes into breast milk. Approximately 85% of paracetamol is metabolized in the liver via sulfation and glucuronidation pathways, while 15% undergoes oxidation via cytochrome P450.

The elimination half-life is approximately 3 hours. It is excreted in urine as metabolites. In cases of hepatic insufficiency, paracetamol metabolism remains unchanged.

After oral administration, dicycloverine is rapidly absorbed, with peak plasma concentration reached approximately 1.5 hours after intake. The elimination half-life is 4–6 hours. It is excreted in urine (79.5%) and feces (8.4%).

Clinical characteristics.

Indications.

Pain syndromes with a spastic component of various origins:

• headache;
• toothache;
• muscular pain, neuralgia;
• rheumatic pain, radiculitis;
• renal colic;
• menstrual pain.

Contraindications.

Hypersensitivity to the components of the medicinal product. Obstructive diseases of the gastrointestinal tract, urinary and biliary tracts with impaired patency. Peptic ulcer of the stomach or duodenum, reflux esophagitis, acute bleeding. Glaucoma, myasthenia gravis, thyrotoxicosis, heart failure. Prostate adenoma. Dynamic intestinal obstruction, paralytic ileus, pyloric stenosis of the gastrointestinal tract with obstruction, severe ulcerative colitis. Hepatic and renal insufficiency, congenital hyperbilirubinemias (Gilbert’s syndrome, Dubin–Johnson syndrome, and Rotor’s syndrome), glucose-6-phosphate dehydrogenase deficiency, severe anemia, including hemolytic anemia, and leukopenia. Alcoholism.

Interaction with other medicinal products and other types of interactions.

Features of drug interactions are determined by the properties of its components.

Paracetamol should be used with caution concomitantly with flucloxacillin, as such combined use is associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions").

Paracetamol, which is part of the medicinal product Sigan-DBS, reduces the effectiveness of diuretics.

Concomitant use of paracetamol with barbiturates, phenytoin, carbamazepine, rifampicin, and other inducers of microsomal liver enzymes, as well as anticonvulsants, increases the risk of hepatotoxic reactions, and the use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome.

Barbiturates reduce the antipyretic effect. The absorption rate of paracetamol may increase when used concomitantly with metoclopramide and domperidone, and decrease when used concomitantly with cholestyramine.

The analgesic effect of paracetamol is enhanced when combined with codeine, ascorbic acid, scopolamine, chlorphenamine, propyphenazone, and caffeine.

Concomitant use of paracetamol with azidothymidine may lead to the development of neutropenia. The anticoagulant effect of warfarin and other coumarins is enhanced with prolonged regular use of paracetamol, increasing the risk of bleeding. Occasional use does not show such an effect.

Concomitant use of paracetamol with nonsteroidal anti-inflammatory drugs increases the risk of renal complications.

When paracetamol is used concomitantly with hepatotoxic drugs, the toxic effects of the drugs on the liver are increased. Do not use simultaneously with alcohol.

The effect of dicycloverine hydrochloride is enhanced by amantadine, antipsychotic agents, benzodiazepines, monoamine oxidase inhibitors (MAO), narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetics, tricyclic antidepressants, anticholinergics, corticosteroids.

Dicycloverine hydrochloride enhances the action of digoxin and other anticholinergic agents (e.g., atropine sulfate); therefore, their concomitant administration with the medicinal product Sigan-DBS is not advisable. Concomitant use of dicycloverine with other anticholinergic agents is not recommended. The drug enhances the effect of salicylic acid, pyrazolone, codeine, caffeine. It potentiates the action of spasmolytics.

Anticholinergic drugs may neutralize the effect of anti-glaucoma agents; therefore, the medicinal product should be prescribed with caution in cases of elevated intraocular pressure and concomitant use of corticosteroids.

Since antacid agents may reduce the absorption of anticholinergic drugs, their concomitant use should be avoided.

The inhibitory effect of anticholinergic agents on gastric hydrochloric acid secretion may be neutralized by agents used for the treatment of achlorhydria and for the study of gastric secretion.

Do not use simultaneously with alcohol (ethanol).

Special precautions for use.

Since the medicinal product contains paracetamol, monitoring of peripheral blood picture and liver function is required during treatment.

Cases of metabolic acidosis with a high anion gap (high anion gap metabolic acidosis (HAGMA)) resulting from pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal insufficiency and sepsis, or in patients with poor nutrition or other sources of glutathione deficiency (e.g., chronic alcoholism) who were treated with therapeutic doses of paracetamol over a prolonged period or in combination with flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring of the patient's condition. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

Do not use simultaneously with other medications containing paracetamol due to the risk of paracetamol overdose symptoms.

Do not exceed the recommended doses.

If symptoms of illness do not resolve, consult a physician.

Patients who are regularly taking analgesics for mild forms of arthritis should consult a physician before using this medication.

Use of the drug for more than 3 days requires mandatory medical supervision.

In case of persistent headache, consult a physician.

The risk of hepatotoxic effects of paracetamol is increased in patients with alcoholic liver disease and in individuals who abuse alcohol.

Use with caution in patients with urinary retention, benign prostatic hyperplasia without urinary retention, heart failure, ulcerative colitis, and impaired kidney or liver function. May exacerbate gastroesophageal reflux.

Use with caution in patients with autonomic neuropathy, arterial hypertension, ischemic heart disease with tachyarrhythmias, tachycardia, predisposition to bronchospasm, and in individuals with increased sensitivity to nonsteroidal anti-inflammatory drugs.

It should be noted that in patients taking anticholinergic agents, including dicycloverine hydrochloride, psychosis, confusion, disorientation, ataxia, increased fatigue, or, conversely, euphoria, excitement, insomnia, and affective disturbances may occur. These symptoms usually resolve within 12–24 hours after discontinuation of the drug.

The drug may affect laboratory test results for blood glucose and uric acid levels.

In hot environmental conditions, dicycloverine hydrochloride, by reducing sweating, may cause an increase in body temperature with a risk of heat stroke. If such symptoms occur, discontinue the drug and consult a physician.

Dosage adjustment is not required when prescribing Sigan-DBS to elderly patients.

Sigan-DBS contains lactose; therefore, patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not use this medication.

Consult a physician before using the drug if the patient is taking warfarin or similar anticoagulant agents.

Use during pregnancy or breastfeeding.

The medicinal product is not recommended for women during pregnancy or breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Dicycloverine hydrochloride may cause adverse reactions affecting the nervous system and vision; therefore, patients should refrain from driving or operating machinery while taking this medication.

Administration and Dosage

Sigan-DBS should be taken orally, swallowing with a small amount of liquid (200 ml).

Adults: 1–2 tablets depending on pain severity, 1–4 times daily. For adult therapy, it is advisable to start with 4 tablets per day. The maximum daily dose may be increased to 8 tablets, provided good tolerability and absence of adverse effects.

The treatment duration should be determined individually, depending on the patient's condition and response. If therapeutic efficacy is not achieved within 2 weeks, or if signs of adverse effects occur at a dose of less than 4 tablets per day, the drug should be discontinued.

Children aged 13 to 15 years: 1 tablet 1–3 times daily; aged 15 years and older: 1–2 tablets depending on pain severity, 1–4 times daily.

The duration of treatment is determined by the physician individually, depending on the nature and course of the disease.

Children

The drug is contraindicated in children under 13 years of age.

Overdose

Caused by paracetamol

The risk of paracetamol overdose is higher in patients with non-cirrhotic alcoholic liver disease. Symptoms within the first 24 hours: pallor, anorexia, nausea, vomiting, abdominal pain. In significant overdose – hepatonecrosis.

Signs of liver damage typically appear 12–48 hours after overdose.

Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, liver failure may progress and lead to toxic encephalopathy. Acute renal failure with acute tubular necrosis may develop even in the absence of severe kidney damage. Cardiac arrhythmias have also been reported.

In patients with risk factors [long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs inducing liver enzymes; regular excessive ethanol consumption; glutathione depletion (digestive disorders, cystic fibrosis, HIV infection, fasting, cachexia)], ingestion of 5 g or more of paracetamol may lead to liver damage.

Liver injury is possible in adults who have ingested 10 g or more of paracetamol, and in children who have ingested more than 150 mg/kg body weight.

In severe poisoning, liver failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and death. Acute renal failure with acute tubular necrosis may present as severe lumbar pain, hematuria, proteinuria, and may develop even without severe liver damage. Pancreatitis has also been reported.

With prolonged use of the drug in high doses, hematological side effects may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. High-dose intake may cause central nervous system (CNS) effects such as dizziness, psychomotor agitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis).

In case of overdose, prompt medical assistance is required. The patient should be immediately hospitalized, even if early symptoms of overdose are absent. Symptoms may be limited to nausea and vomiting and may not reflect the severity of overdose or risk of organ damage. Activated charcoal should be considered if the excessive paracetamol dose was taken within the last hour. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be administered within 24 hours after paracetamol ingestion, but the maximum protective effect is achieved when administered within 8 hours. The efficacy of the antidote decreases sharply after this time. If necessary, N-acetylcysteine should be administered intravenously according to current guidelines. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

Caused by dicycloverine hydrochloride

Overdose is characterized by a biphasic pattern: initially, central nervous system (CNS) excitation occurs, manifested by restlessness, illusions, hallucinations, persistent mydriasis, tachycardia, and arterial hypertension. This is followed by CNS depression progressing to coma.

Within the first 24 hours – skin pallor, nausea, anorexia, vomiting, and abdominal pain; within 12–48 hours – kidney and liver damage leading to liver failure (increased activity of liver transaminases, dehydrogenases, elevated bilirubin and prothrombin levels); tachycardia, arrhythmias; changes in respiratory rate; pancreatitis.

Dryness of the skin and mucous membranes, increased intraocular pressure, headache, dizziness, CNS excitation, and urinary retention may also occur.

Treatment: gastric lavage should be performed, adsorbents administered, and oral methionine given (to accelerate paracetamol conjugation). The paracetamol antidote (which stimulates glutathione synthesis) – acetylcysteine (10% solution, 5 ml) – is indicated. Symptomatic therapy is required. For management of psychomotor agitation – diazepam (0.5% solution, 2 ml).

Adverse Reactions

Sigan-DBS is generally well tolerated. Adverse effects related to active ingredients contained in the medicinal product usually occur with prolonged use in high doses.

Paracetamol

Metabolism and nutrition disorders: Frequency unknown – metabolic acidosis with high anion gap.

Gastrointestinal disorders: Nausea, epigastric pain, increased liver enzyme activity, usually without development of jaundice, hepatonecrosis (dose-dependent effect), digestive disturbances.

Blood and lymphatic system disorders: Anemia, methemoglobinemia, thrombocytopenia, sulfhemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia (especially in patients with glucose-6-phosphate dehydrogenase deficiency). With prolonged use in high doses – aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia.

Renal and urinary disorders: (with intake of high doses) – nephrotoxicity, interstitial nephritis, papillary necrosis, difficulty in urination.

Immune system disorders: Anaphylaxis, hypersensitivity reactions including skin pruritus, skin and mucous membrane rashes (usually generalized rash, erythematous rash, urticaria), angioneurotic edema, multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), hypoglycemia up to hypoglycemic coma; bronchospasm in patients sensitive to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs); liver function disorders, increased liver enzyme activity, usually without development of jaundice.

Central nervous system (CNS) disorders: (usually with intake of high doses): dizziness, psychomotor agitation, and disorientation.

Other: Hypoglycemia, tinnitus, psychosis, coma, general weakness, bruising or bleeding.

Hydrochloride of dicycloverine

Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria, severe allergic reactions or drug idiosyncrasy including anaphylaxis.

Gastrointestinal disorders: Dry mouth, taste disturbances, anorexia, nausea, vomiting, flatulence, constipation, abdominal pain, digestive disturbances.

Eye disorders: Blurred vision, diplopia, mydriasis, cycloplegia (accommodation paralysis), increased intraocular pressure.

CNS and psychiatric disorders: Dizziness, sensory disturbances, headache, drowsiness, nervousness, tinnitus, psychosis, coma, dyskinesia, lethargy, insomnia, general weakness, fatigue, loss of consciousness, numbness, disorientation, transient memory loss, hallucinations, dysarthria, ataxia, euphoria, inappropriate emotional responses (symptoms decrease within 12–24 hours after dose reduction), speech disorders, confusion and/or agitation.

Cardiovascular disorders: Tachycardia, palpitations.

Renal and urinary disorders: Urination disturbances, urinary incontinence, urinary retention, difficulty in urination.

Musculoskeletal and connective tissue disorders: Muscle weakness.

Respiratory, thoracic and mediastinal disorders: Dyspnea, apnea, asphyxia, nasal congestion, sneezing, pharyngeal hyperemia.

Other: Flushing, decreased sweating.

Description of selected adverse reactions

Cases of metabolic acidosis with high anion gap as a result of pyroglutamic acidosis have been observed in patients with risk factors who used paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Shelf life

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging

No. 200: 4 tablets per strip; 1 strip per cardboard envelope; 50 envelopes per cardboard box.

No. 4: 4 tablets per strip; 1 strip per cardboard envelope.

Prescription status

Prescription only.

Manufacturer

Genome Biotech Pvt. Ltd.

Manufacturer's address and place of business

Plot No. D-121, 122, 123, MIDC Malegaon, Tal. Sinnar, Nashik 422103, Maharashtra State, India.