Trifedrin® ic

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRIPHEDRIN® IC (TRIPHEDRIN IC)

Composition:

Active substances: anhydrous theophylline, ephedrine hydrochloride, phenobarbital;

Each tablet contains 100 mg (0.1 g) of anhydrous theophylline, 12 mg (0.012 g) of ephedrine hydrochloride, and 10 mg (0.01 g) of phenobarbital;

Excipients: potato starch, calcium stearate, sodium croscarmellose, copovidone, talc.

Pharmaceutical form. Tablets.

Main physicochemical properties: white-colored, flat cylindrical tablets with beveled edges; the company trademark is printed on one side of the tablet, a score line is present on the other side.

Pharmacotherapeutic group. Agents for systemic use in obstructive respiratory diseases. Xanthines in combination with adrenergic agents. Theophylline in combination with adrenergic agents. ATC code R03DB04.

Pharmacological Properties.

A combined medicinal product that exerts bronchodilator, central nervous system stimulant, and cardiac activity-enhancing effects.

Pharmacodynamics.

Theophylline belongs to the methylxanthine group. Its mechanism of action is due to blockade of adenosine receptors, inhibition of phosphodiesterase, increased intracellular cAMP levels, and decreased intracellular calcium ion concentration, resulting in relaxation of bronchial smooth muscle and development of a pronounced bronchodilator effect. It stimulates the respiratory center and exhibits a diuretic effect.

Phenobarbital is a derivative of barbituric acid. It exerts spasmolytic and myorelaxant effects. In the composition of the drug, it provides mild and prolonged sedative action and contributes to correction of the psychoemotional state in patients with broncho-obstructive syndrome of various etiologies.

Ephedrine is a mixed-action sympathomimetic agent. It exerts a spasmolytic effect on bronchial smooth muscle due to pronounced stimulation of β2-adrenergic receptors. It increases arterial blood pressure and heart rate. It produces a stimulant effect on the central nervous system and stimulates the respiratory center.

Pharmacokinetics.

All components of the drug are readily and almost completely absorbed in the gastrointestinal tract.

After oral administration, the therapeutic blood level of theophylline is reached within 1–1.5 hours and maintained for 6–12 hours. Theophylline is metabolized in the liver to inactive metabolites and is primarily excreted by the kidneys. The elimination half-life of theophylline in adults is 6.5–10 hours.

Ephedrine hydrochloride is well absorbed. After oral administration, maximum effect is achieved within 1 hour and lasts approximately 4 hours (2–8 hours). Ephedrine is almost completely excreted unchanged in urine, together with a small amount of metabolites formed in the liver. The elimination half-life is 3–6 hours.

Phenobarbital is uniformly distributed in the body's organs and tissues. It is approximately 45% bound to plasma proteins and is only partially metabolized in the liver. It penetrates through histohematogenous barriers and into breast milk and crosses the placenta readily. It is excreted both unchanged (up to 25% of the dose in urine) and as metabolites. The elimination half-life in adults is 2–4 days.

Clinical characteristics.

Indications.

Respiratory tract diseases accompanied by bronchospasm: bronchial asthma, chronic obstructive pulmonary disease (COPD).

Contraindications.

Hypersensitivity to any component of the drug or to other xanthine derivatives (theobromine, pentoxifylline). Severe cardiovascular diseases (acute myocardial infarction, decompensated heart failure, acute cardiac arrhythmias, severe arterial hypertension, severe arterial hypotension, severe atherosclerosis of coronary and cerebral vessels), glaucoma, pheochromocytoma, myasthenia gravis, severe respiratory depression, prostatic hyperplasia with urinary retention, diabetes mellitus, hyperthyroidism, severe liver and kidney diseases with impaired function, sleep disorders, depressive disorders with suicidal tendencies, alcoholism, drug or narcotic dependence.

Interaction with other medicinal products or other types of interactions.

The use of alcoholic beverages, food and drinks containing methylxanthines (coffee, tea, cocoa, chocolate, Coca-Cola and similar tonic drinks), and medicinal products that stimulate the central nervous system (CNS) (caffeine, theobromine, pentoxifylline) during treatment may enhance the CNS-stimulating effects of theophylline and ephedrine. Concurrent use of the drug with oral antidiabetic agents may reduce their hypoglycemic effect.

The effect of theophylline may be enhanced when used concomitantly with allopurinol, cimetidine, disulfiram, phenylbutazone, fluvoxamine, fluoroquinolones, furosemide, imipenem, α-interferon, isoniazid, calcium channel blockers, lincomycin, macrolides, amiodarone, mexiletine, paracetamol, pentoxifylline, oral contraceptives, probenecid, propafenone, propranolol, ranitidine, tacrine, thiabendazole, ticlopidine, viloxazine, influenza vaccine, ciprofloxacin, enoxacin. In patients receiving one or more of the above-mentioned drugs concurrently with Trifedrin® IS, serum theophylline concentration should be monitored and the dose reduced if necessary. The drug effect may be reduced when used concomitantly with β-receptor antagonists, antiepileptic agents (e.g., phenytoin, carbamazepine, primidone), isoproterenol, magnesium hydroxide, moricizine, rifampicin, ritonavir, sulfinpyrazone. The effect of the drug may also be reduced in smokers. In patients receiving one or more of the above-mentioned drugs concurrently with Trifedrin® IS, serum theophylline concentration should be monitored and the dose increased if necessary. Theophylline may enhance the effects of β-receptor agonists, diuretics, and reserpine. Theophylline may reduce the efficacy of adenosine, lithium carbonate, and β-receptor antagonists. Halothane anesthesia may cause severe cardiac arrhythmias in patients receiving theophylline.

Hypokalemia may occur during theophylline therapy, particularly when used concomitantly with α-receptor agonists, thiazide diuretics, furosemide, corticosteroids, and in conditions of hypoxemia; therefore, periodic monitoring of serum potassium levels is recommended.

Phenobarbital induces hepatic enzymes and thus may accelerate the metabolism of certain drugs metabolized by these enzymes (including paracetamol, salicylates, indirect anticoagulants, cardiac glycosides (digoxin), antimicrobials (chloramphenicol, doxycycline, metronidazole, rifampicin), antivirals, antifungals (griseofulvin, itraconazole), antiepileptics (anticonvulsants), psychotropic agents (tricyclic antidepressants, clonazepam), hormones (estrogens, progestogens, corticosteroids, thyroid hormones), immunosuppressants (glucocorticoids, cyclosporines, cytostatics), antiarrhythmics, antihypertensives (β-blockers, calcium channel blockers), oral hypoglycemic agents, etc.). Phenobarbital may accelerate the metabolism of oral contraceptives, leading to loss of contraceptive effect. Phenobarbital enhances the action of analgesics, local anesthetics, and drugs that depress the central nervous system. Concurrent use of phenobarbital with sedative drugs leads to enhanced sedative and hypnotic effects and may be accompanied by respiratory depression. Phenobarbital may influence the blood concentration of phenytoin, as well as carbamazepine and clonazepam. Medicinal products with acidic properties (ascorbic acid, ammonium chloride) enhance the action of barbiturates and shorten the elimination half-life of ephedrine, which is also a component of Trifedrin® IS. Patients receiving concomitant treatment with valproate and phenobarbital should be monitored for signs of hyperammonemia. In half of the reported cases, hyperammonemia was asymptomatic and did not necessarily lead to encephalopathy. MAO inhibitors (including furazolidone, procarbazine, selegiline) prolong the action of phenobarbital and potentiate the pressor effect of ephedrine (risk of hypertensive crisis). Therefore, the drug should not be used concomitantly with MAO inhibitors or within 2 weeks after discontinuation of such agents. Rifampicin may reduce the effect of phenobarbital. When used concomitantly with gold preparations, the risk of kidney damage increases. Long-term use in combination with nonsteroidal anti-inflammatory drugs increases the risk of gastric ulceration and bleeding. Concurrent administration of phenobarbital with zidovudine enhances the toxicity of both drugs.

Due to the presence of ephedrine in Trifedrin® IS, the drug should not be used in combination with medicinal products that, when used concomitantly with ephedrine, increase the risk of intoxication, dangerous arrhythmias, or severe and acute arterial hypertension: cardiac glycosides, quinidine, oxytocin, tricyclic antidepressants, non-selective adrenergic blockers (propranolol), antihypertensive agents (guanethidine), ergot alkaloids (ergometrine, ergotamine, methylergometrine), reserpine, anti-Parkinson agents (levodopa, bromocriptine), and vasodilators (tolazoline).

Special precautions for use.

Due to the presence of theophylline, the drug should be administered with caution and only in cases of acute necessity to patients with unstable angina, arterial hypertension, epilepsy, porphyria, as well as to patients with impaired renal and hepatic function, and to those with peptic ulcer (including history of peptic ulcer disease). Restrictions regarding the use of the drug in gastroesophageal reflux are associated with the effect of theophylline on smooth muscles of the cardioesophageal sphincter, which may worsen the condition in gastroesophageal reflux by enhancing reflux. If administration is necessary, the dose of the drug should be carefully monitored.

The dose of the drug should be reduced in patients with decreased oxygen concentration in the blood (hypoxemia), with persistently elevated body temperature, in patients with pneumonia, viral infections (especially influenza), and in acute severe conditions. Theophylline may alter certain laboratory parameters: it may increase the levels of free fatty acids and catecholamines in urine.

The drug contains phenobarbital; therefore, it should be administered with caution in patients with hyperkinesias, adrenal hypofunction, acute and chronic pain, and acute drug intoxication. Phenobarbital is associated with a withdrawal syndrome, especially after prolonged use; therefore, discontinuation of the drug should be carried out gradually.

Prolonged use of the drug should be avoided due to the risk of phenobarbital accumulation and development of drug dependence.

The risk of developing Stevens-Johnson syndrome or Lyell's syndrome is highest during the first weeks of treatment.

The presence of ephedrine in the drug composition may lead to a positive result in doping tests in athletes.

The drug should be used under medical supervision in patients with occlusive vascular diseases predisposing to an increased risk of peripheral ischemia, in patients with prostate disorders who may be at increased risk of urinary retention, and in patients with sepsis.

Children and patients aged 60 years and older are more sensitive to the effects of the drug; therefore, the drug should be used with caution in these age groups.

Use during pregnancy or breastfeeding.

Active components of the drug can cross the placental barrier and may affect the fetus; therefore, the drug should not be used during pregnancy. If it is necessary to use the drug, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

During treatment, patients should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage.

Administer orally after meals. To avoid disruption of night sleep, it is advisable to take the drug in the first half of the day. For adults and children aged 12 years and older, the recommended dose is ½–1 tablet once daily. In severe cases, the dose for adults may be increased up to the maximum dose of 5 tablets per day, divided into 2–3 doses. For children aged 6 to 12 years, the recommended dose is ½ tablet per day.

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

Children.

Do not use in children under 6 years of age.

Overdose.

An overdose may intensify the manifestations of adverse reactions.

Symptoms: nausea, weakness, decreased body temperature, respiratory depression with risk of respiratory arrest, acute heart failure, depression of cardiovascular function including arrhythmias, bradycardia, a sharp drop in arterial blood pressure up to collapse; reduced diuresis, toxic psychosis, central nervous system (CNS) depression progressing to coma. Seizures and dangerous cardiac rhythm disturbances (tachyarrhythmia) may occur suddenly without prior warning signs.

Treatment. In most cases, reducing the dose or temporarily discontinuing the drug is sufficient. In severe cases of overdose or intoxication, perform gastric lavage, administer activated charcoal, and provide symptomatic therapy (primarily monitoring of vital functions such as respiration, pulse, and blood pressure). Theophylline can be rapidly and effectively removed by hemoperfusion or hemodialysis.

Adverse Reactions

Adverse reactions occur very rarely when the drug is used at recommended doses and depend on the dose and duration of treatment.

The active substances of the drug are associated with the following adverse reactions.

Nervous system side effects: headache, dizziness, slowed reaction time, impaired motor coordination, ataxia, tremor, seizures, hyperkinesia (in children), nystagmus, mydriasis, weakness.

Psychiatric disorders: paradoxical excitation, irritability, sleep disturbances (insomnia, drowsiness), increased fatigue, cognitive impairments (including reduced concentration, confusion, hallucinations, delirium), depression.

Gastrointestinal tract side effects: sensation of fullness or epigastric pain, nausea, vomiting, diarrhea or constipation. If serum concentrations of the drug components exceed therapeutic levels, pre-existing gastroesophageal reflux may worsen.

Hepatobiliary system side effects: with prolonged use of phenobarbital – liver function disorders.

Cardiovascular system side effects: palpitations, arrhythmias (including bradycardia), increased frequency of angina attacks, fluctuations in blood pressure (including arterial hypotension), impaired peripheral circulation.

Blood and lymphatic system side effects: if serum concentrations of the drug components exceed therapeutic levels, agranulocytosis, thrombocytopenia, anemia, leukocytosis, leukopenia may occur.

Metabolic side effects: if serum concentrations of the drug components exceed therapeutic levels, hypokalemia and/or hypercalcemia, hyperglycemia and hyperuricemia, metabolic acidosis may occur.

Urinary and reproductive system side effects: increased urine output; urinary retention may occur in patients with benign prostatic hyperplasia.

Musculoskeletal system side effects: prolonged use of phenobarbital may impair osteogenesis and lead to rickets.

General disorders: dry mouth, loss of appetite, asthenia.

Immune system side effects: hypersensitivity reactions, including anaphylactic reactions, angioedema, fever, bronchospasm, rhabdomyolysis, collapse.

Skin and mucous membranes side effects: skin rashes (including urticaria), pruritus, facial skin hyperemia, Lyell’s syndrome (toxic epidermal necrolysis), polymorphic exudative erythema (including Stevens-Johnson syndrome), exfoliative dermatitis, photosensitization.

Antiepileptic hypersensitivity syndrome (AHS): rash, fever, lymphadenopathy, lymphocytosis.

Other side effects: dyspnea; with prolonged use of phenobarbital – folate deficiency, impotence, drug dependence, withdrawal syndrome, which usually may occur after abrupt discontinuation of the drug and may be accompanied by nightmares and nervousness.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister; 1, 3 or 5 blisters per carton.

Prescription category.

Prescription only.

Manufacturer.

Limited liability company "INTERKHIM".

Manufacturer's address and location of business activity.

40-A, 21st km, Starokyivska Road, Odesa, Ukraine, 65025.