Aficycl

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AFICYCLE

Composition:

Active substances: paracetamol, propyphenazone, caffeine;

One tablet contains 250 mg of paracetamol, 210 mg of propyphenazone, and 50 mg of caffeine;

Excipients: magnesium stearate, sodium lauryl sulfate, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, povidone, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, sodium croscarmellose, glycerol dibehenate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, flat tablets with bevelled edges, with the manufacturer's mark «» on one side and a score line on the other.

Pharmacotherapeutic group.

Analgesics. Other analgesics and antipyretics. Anilides. Paracetamol combinations without psychotropic agents. ATC code N02BE51.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Aficycl is recognized as an effective analgesic combination, as hundreds of such combinations are used worldwide, including in countries with the most advanced pharmacology. Among the three active components of Aficycl, analgesic activity has been proven for paracetamol and propyphenazone, whereas caffeine can be considered an auxiliary agent that enhances the effect of analgesics.

Paracetamol

Paracetamol has analgesic and antipyretic effects. It is an effective and widely used analgesic for mild to moderate pain. It is also an effective antipyretic agent, and due to the association of aspirin with Reye's syndrome in children, paracetamol is the analgesic-antipyretic of choice in this population. The mechanism of action of paracetamol involves inhibition of the cyclooxygenase enzyme in the CNS, while its peripheral effects are minimal.

Propyphenazone

Propyphenazone has analgesic and antipyretic effects resulting from inhibition of the synthesis of prostaglandins E2 and F2-alpha.

Caffeine

The addition of caffeine to an analgesic combination containing paracetamol and propyphenazone is based on its ability to enhance the absorption of the other components. Caffeine is a central nervous system stimulant and a competitive inhibitor of the phosphodiesterase enzyme.

This combination allows for the benefits of analgesic synergy, enabling the use of relatively low doses of individual ingredients and minimizing potential adverse effects.

Pharmacokinetics.

The pharmacokinetics of this combined preparation, intended for use as needed, has a limited scope, as it is not intended for chronic therapy requiring maintenance of a therapeutic plasma concentration.

Paracetamol. Paracetamol is rapidly absorbed from the gastrointestinal tract; maximum plasma concentrations are reached within 30–60 minutes after oral administration. It is metabolized in the liver and primarily excreted in the urine as glucuronide and sulfate conjugates.

A minor hydroxylated metabolite (N-acetyl-p-benzoquinoneimine), normally produced in very small amounts by mixed-function oxidases in the liver and kidneys, is detoxified by conjugation with glutathione. Intentional or accidental intoxication with N-acetyl-p-benzoquinoneimine may lead to its accumulation and paracetamol overdose due to depletion of endogenous glutathione, potentially causing hepatic and renal tubular necrosis. The elimination half-life of paracetamol ranges from 1 to 3 hours.

Propyphenazone.

Propyphenazone has a similar pharmacokinetic profile, which justifies the rationality of the combination. It is rapidly absorbed from the gastrointestinal tract, with maximum plasma concentrations reached approximately 0.5–0.6 hours after oral administration. It is actively metabolized in the liver and excreted in the urine and bile as metabolites. The elimination half-life of propyphenazone ranges from 2.1 to 2.4 hours. In combination with paracetamol, propyphenazone prolongs the elimination half-life of paracetamol by 40% (to 2–3 hours), thereby extending the duration of paracetamol's effect and reducing the frequency of dosing.

Caffeine. Caffeine is rapidly and completely absorbed, distributed throughout all tissues including the brain, with maximum plasma concentrations reached approximately 15–45 minutes after administration. It is metabolized in the liver, and its elimination half-life is about 5 hours. Caffeine enhances the absorption quality of other active components in combined analgesic preparations.

Clinical Characteristics.

Indications.

Afiсycl is indicated for symptomatic and short-term treatment of pain such as headache, toothache, migraine, postoperative and post-traumatic pain, and dysmenorrhea.

Contraindications.

Hypersensitivity to the components of the drug; known hypersensitivity to pyrazolones and similar substances (phenazone, aminophenazone, metamizole), as well as to phenylbutazone or acetylsalicylic acid; severe impairment of liver and/or kidney function; viral hepatitis; congenital hyperbilirubinemia; alcoholism; pancreatitis; prostate hyperplasia; diabetes mellitus; bronchial asthma; blood disorders, pronounced anemia, leukopenia, thrombosis, thrombophlebitis, glucose-6-phosphate dehydrogenase deficiency; acute intermittent porphyria; states of increased excitation, sleep disturbances; severe arterial hypertension; organic cardiovascular diseases (decompensated heart failure, conduction disorders, severe atherosclerosis, tendency to vascular spasm, ischemic heart disease); closed-angle glaucoma; epilepsy; hyperthyroidism; advanced age.

Do not use simultaneously with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of MAOIs; contraindicated in patients taking tricyclic antidepressants or β-blockers.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of Afiсycl with products containing paracetamol may lead to paracetamol overdose.

When paracetamol is used concomitantly with hepatotoxic agents (alcohol, phenobarbital, phenytoin, carbamazepine, isoniazid, and rifampicin), the toxic effect of these drugs on the liver increases. Barbiturates reduce the antipyretic effect of paracetamol.

Paracetamol reduces the effectiveness of diuretics.

The effect of propyphenazone is enhanced when used concomitantly with sedatives.

Do not use simultaneously with alcohol. Alcohol enhances the hepatotoxicity of paracetamol.

The absorption rate of paracetamol may be increased by metoclopramide and domperidone, and decreased by cholestyramine.

In cases of delayed gastric emptying, e.g., due to propanteline, the absorption rate of paracetamol may be reduced and the onset of action delayed.

The anticoagulant effect of warfarin and other coumarins may be enhanced by long-term, regular daily use of paracetamol, increasing the risk of bleeding. Occasional use has no significant effect.

Concomitant use with nonsteroidal anti-inflammatory drugs may lead to adverse effects involving the gastrointestinal tract.

The drug enhances the action of oral antidiabetic agents (tolbutamide, chlorpropamide, acetohexamide) and oral anticoagulants such as coumarin.

Combination with chloramphenicol may prolong elimination of this drug, increasing the risk of toxicity.

Caution is advised when using paracetamol concomitantly with flucloxacillin, as this combination has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions").

Simultaneous use of the drug with medicinal products and beverages containing caffeine is not recommended.

The frequency of neutropenia (reduction in white blood cells) increases when paracetamol and AZT (zidovudine) are used concomitantly.

For substances with broad activity (e.g., benzodiazepines), interactions are possible in various forms and are unpredictable. Oral contraceptives, isoniazid, cimetidine, and disulfiram reduce the metabolism of caffeine, while smoking increases it. The drug slows the elimination of theophylline. Due to the presence of caffeine in the formulation, the action of substances similar to ephedrine is enhanced. Concurrent intake of certain CYP1A2 inhibitors may prolong the elimination of caffeine and its metabolite paraxanthine.

Caffeine enhances the action (improves bioavailability) of analgesic-antipyretic agents, potentiates the effects of xanthine derivatives, α- and β-adrenergic agonists, psychostimulants, and MAO inhibitors (furazolidone, procarbazine, selegiline).

Caffeine reduces the effectiveness of opioid analgesics, anxiolytics, hypnotics, and sedatives; it acts as an antagonist to anesthetic agents and other drugs that depress the central nervous system, and as a competitive antagonist to adenosine and ATP preparations. Concomitant use of caffeine with ergotamine improves the absorption of ergotamine from the gastrointestinal tract (GI tract); with thyrotropic agents, it increases thyroid effect. Caffeine reduces serum lithium concentration.

Special precautions.

Caution should be exercised when prescribing the drug to patients with impaired liver function. During paracetamol biotransformation, a small amount of the toxic metabolite N-acetyl-p-benzoquinone imine is formed, which may cause pathological changes in the liver. The risk of overdose increases in patients with non-cirrhotic alcoholic liver disease.

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

Prior to administration, consultation with a physician is necessary if the patient is taking warfarin or similar agents with anticoagulant effects.

Caution should be exercised when prescribing the drug to patients with impaired renal function, gastrointestinal ulcers or bleeding, as well as to patients with chronic respiratory diseases and chronic urticaria.

Precautionary measures are required in cases of reduced tolerance to analgesics, hypersensitivity to other analgesics, including acetylsalicylic acid (risk of provoking an asthma attack).

There have been isolated reports of asthmatic attacks and cases of anaphylactic shock associated with individual hypersensitivity to propiphenazone and drugs containing paracetamol.

Particular caution (reduced dosage and distribution of the daily dose into more frequent administrations) is necessary in cases of hepatitis, impaired renal function, and Gilbert's syndrome (ranging from benign secondary jaundice to glucuronyltransferase deficiency).

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoproline (pyroglutamic) acidosis have been reported in critically ill patients, such as those with severe renal insufficiency and sepsis, as well as in patients with poor nutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) who were treated with paracetamol at therapeutic doses over a prolonged period or in combination with flucloxacillin. If high anion gap metabolic acidosis 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 high anion gap metabolic acidosis in patients with multiple risk factors.

Patients who take analgesics daily for mild forms of arthritis should consult their physician.

Particular caution is required for patients with blood dyscrasias or bone marrow suppression, and careful monitoring of hematological parameters is recommended.

The risk of neutropenia and agranulocytosis is primarily associated with the presence of propiphenazone. If such a reaction occurs after taking Aficycl (e.g., elevated temperature, sore throat, oral ulcers and abscesses, perianal abscesses, and decreased granulocyte count), the drug should be discontinued immediately. These adverse effects are usually reversible and resolve within 1–2 weeks.

Special attention is also required for patients experiencing anxiety, nervousness, restlessness, tremor, as well as patients with arterial hypertension or insomnia. If tachycardia or rapid heartbeat occurs, the drug should be discontinued immediately.

During treatment with this drug, consumption of excessive amounts of beverages containing caffeine (e.g., coffee, tea) is not recommended, as this may cause sleep disturbances, tremor, and palpitations. The recommended doses should not be exceeded.

If palpitations or tachycardia occur, the drug should be discontinued immediately.
Treatment with Aficycl should not exceed 3 days without consulting a physician.
The drug should be prescribed with caution to children (aged 12 years and older).

Alcohol consumption should be avoided during treatment with Aficycl.

If symptoms persist, medical advice should be sought.

If headaches become persistent, medical advice should be sought.

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy or breastfeeding, as the active components of the drug pass into breast milk.

Ability to affect reaction speed when driving or operating machinery.

During treatment, some patients may experience drowsiness, dizziness, or excitation. This should be taken into account by patients who drive vehicles or operate complex machinery requiring concentration.

Method of Administration and Dosage.

Take orally.

Aficil, as a combined analgesic, should be used as needed and is not intended for long-term therapy.

For adults and children aged 16 years and older, the recommended dose is 1–2 tablets at a time, depending on the intensity of pain. The dose may be repeated up to 3 times daily. The maximum daily dose is 6 tablets.

For children aged 12 to 16 years, the recommended dose is ½ to 1 tablet at a time. The dose may be repeated up to 3 times daily. The maximum daily dose is 3 tablets.

The interval between doses should be at least 4 hours.

Do not exceed the recommended dose.

Do not take together with other medicinal products containing paracetamol.

Children.

The drug may be administered to children aged 12 years and older.

Overdose.

In case of overdose, each active ingredient may cause specific symptoms.

With prolonged use of high doses, the following may occur: aplastic anemia, thrombocytopenia, pancytopenia, agranulocytosis, neutropenia, leukopenia; from the central nervous system (CNS): impaired orientation and attention, CNS depression, drowsiness, consciousness disturbances, hyperreflexia, dizziness, psychomotor agitation, insomnia, tremor, nervousness, restlessness; from the kidneys and urinary system: renal colic, interstitial nephritis, papillary necrosis.

Overdose is usually caused by paracetamol and manifests as pallor, anorexia, nausea, vomiting, abdominal pain, hepatonecrosis, increased liver transaminase activity, and prolonged prothrombin index.

Liver damage may 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 with impaired consciousness, and in some cases, result in death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe kidney damage. Cardiac arrhythmia and pancreatitis have also been reported.

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

High doses of caffeine may cause epigastric pain, vomiting, increased diuresis, rapid breathing, extrasystoles, tachycardia, or cardiac arrhythmia; and may affect the central nervous system (dizziness, syndrome of increased neuropsychological excitability, headache, seizures, restlessness, loss of consciousness, insomnia, nervous excitement, irritability, affective state, anxiety, tremor, convulsions). Clinically significant symptoms of caffeine overdose may also be associated with liver damage caused by paracetamol.

Overdose of propyphenazone may cause CNS damage (seizures, coma).

In case of overdose, prompt medical assistance is required, even if symptoms are absent. Symptoms may be limited to nausea and vomiting or may not reflect the severity of the overdose or the risk of organ damage.

Treatment. Symptomatic therapy. Administration of activated charcoal should be considered if an excessive dose of paracetamol was ingested within the past 1 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 after ingestion. The efficacy of the antidote decreases significantly after this time. If necessary, intravenous N-acetylcysteine should be administered according to the established dosing schedule. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside the hospital. General supportive measures should also be implemented.

If necessary, α-adrenergic blockers should be used. β-adrenergic receptor antagonists may help alleviate cardiotoxic effects. Gastric lavage should be performed, oxygen therapy administered, and diazepam given in case of seizures.

Side effects

Therapeutic doses of the drug are generally well tolerated and do not cause dose-dependent adverse effects due to the low doses of active ingredients contained in the formulation. Possible side effects are classified according to organ system databases.

Blood and lymphatic system disorders: anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, thrombocytopenia, leukopenia, neutropenia, pancytopenia, agranulocytosis (propyphenazone – a pyrazolone derivative – is the active component of Aficidin responsible for potential cases of agranulocytosis. Aminopyrine, one of the first pyrazolone derivatives, is known to be associated with blood dyscrasias, although such reactions have also been reported with paracetamol used as monotherapy), bruising or bleeding.

Immune system disorders: anaphylactic reactions, allergic reactions including skin itching, skin and mucous membrane rashes (usually generalized rash, erythematous, urticaria), angioneurotic edema, multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Skin and subcutaneous tissue disorders: oral mucosal ulcers, purpura, allergic dermatitis.

Endocrine system disorders: hypoglycemia, up to hypoglycemic coma.

Nervous system disorders (with high-dose use): insomnia, increased excitability, dizziness, psychomotor agitation and disorientation, worsening of headache with prolonged use of the drug, tremor, paresthesia, nervousness.

Cardiovascular system disorders: increased blood pressure, arrhythmia, palpitations, tachycardia, arterial hypotension, chest pain.

Respiratory system disorders: bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs.

Metabolism and nutrition disorders: metabolic acidosis with high anion gap (frequency unknown).

Gastrointestinal disorders: nausea, vomiting, dyspepsia, constipation, digestive disturbances, heartburn, epigastric pain.

Hepatobiliary system disorders: liver function abnormalities, including liver failure (hepatotoxicity is usually associated with paracetamol overdose), increased liver enzyme activity (usually without jaundice development), hepatonecrosis (dose-dependent effect), jaundice.

Renal and urinary system disorders: kidney dysfunction.

Concomitant use of the drug at recommended doses with products containing caffeine may enhance caffeine-related side effects such as restlessness, anxiety, irritability, headache, and gastrointestinal disturbances.

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.

Tablets No. 6: 6 tablets in a perforated strip; 1 strip in a cardboard box.

Tablets No. 10: 10 tablets in a perforated strip; 1 strip in a cardboard box.

Tablets No. 12: 6 tablets in a perforated strip; 2 strips in a cardboard box.

Dispensing category.

Over-the-counter.

Manufacturer.

ALKALOID AD Skopje.

Manufacturer's address and place of business.

Boulevard Alexander the Great, 12, Skopje, 1000, North Macedonia.