INSTRUCTION

for medical use of the medicinal product

 

RAPIMAX FORTE

 

Composition:

active substance: paracetamol, propyphenazone; caffeine;

1 tablet contains: paracetamol 250 mg, propyphenazone 150 mg; caffeine 50 mg;

excipients: lactose monohydrate, microcrystalline cellulose, corn starch, povidone, magnesium stearate, talc, colloidal anhydrous silicon dioxide, croscarmellose sodium, pregelatinized corn starch, hydroxypropyl cellulose

 

Pharmaceutical form. Tablets.

Basic physical and chemical properties: white, flat, round tablets with a score line on one side.

 

Pharmacotherapeutic group. Paracetamol, combination without psycholeptics.

ATC code N02В Е51.

 

Pharmacological properties.

Pharmacodynamics.

The medicinal product contains caffeine, paracetamol, and propyphenazone, which have sedative and fever-reducing properties. In a study of acute toxicity in animals, the use of a combination of paracetamol and propyphenazone in a 5:3 ratio has shown a lower toxicity level than when each substance was used individually. The sedative effect of this combination develops within 30 minutes and lasts for several hours.

Pharmacokinetics.

After oral administration, paracetamol is quickly and completely absorbed. The peak concentration in blood serum is reached 30–90 minutes after application. The half-life of paracetamol is 2-3 hours on average. Thus, the administered dose of paracetamol is excreted with urine within 24 hours mainly in the form of conjugates of glucuronic and sulfuric acids.

Paracetamol penetrates through the placenta and excretes into breast milk.

Propyphenazone is rapidly and completely absorbed after oral administration. The peak concentration in the blood plasma is reached within 30 minutes.

Propyphenazone is mainly metabolized in the liver, leading to the formation of the primary metabolite N-desmethylpropyphenazone, 80% of which is excreted in the urine.

When a combination of paracetamol and propyphenazone is used in the ratio found in RAPIMAX FORTE, the half-life of propyphenazone is extended from 64 ± 10 minutes (when 150 mg of propyphenazone is used) to 77 ± 10 minutes (when 250 mg of paracetamol and 150 mg of propyphenazone are used).

The administered dose of propyphenazone is excreted in the urine over a 24-hour period, primarily in the form of glucuronic acid conjugates. Only about 1% of propyphenazone is excreted in the urine unchanged.

Propyphenazone penetrates through the placenta and excretes into breast milk.

Impairment of kidney and liver function may inhibit the metabolism and excretion of propyphenazone.

Caffeine is quickly and almost completely absorbed after oral administration.

The main metabolites of caffeine: 1-methyluric acid, l-methylxanthine and 5-actylamino-6-amino-3-methyluracil are excreted with urine.

The main metabolite excreted with faeces is 1.7-dimethyluric acid.

The half-life of caffeine is on average 4 to 6 hours, mainly with urine (86%), not more than 2% of caffeine is eliminated unchanged.

Caffeine penetrates through the placenta and excretes into breast milk.

 

Clinical particulars.

Indications.

Symptomatic treatment of headache, dental, period, postoperative and rheumatic pain; fever during colds and flu.

 

Contraindications.

Hypersensitivity to pirozolon and similar substances (phenazone, aminophenazone, metamizone), as well as to phenylbutazone, acetylsalicylic acid and to any component of the medicinal product.

Deficiency of glucose-6-phosphate dehydrogenase, liver and/or kidney dysfunction, congenital hyperbilirubinemia, alcoholism, pancreatitis, benign prostatic hyperplasia; blood disorders, severe anaemia, thrombosis, thrombophlebitis, leukopenia, acute hematoporphyria; pronounced renal dysfunction, congenital hyperbilirubinemia; agitation; sleep disorders; organic cardiovascular diseases (severe hypertension, decompensated heart failure, conduction disorder, paroxysmal tachycardia, severe atherosclerosis, tendency to vascular spasm, ischemic heart disease, acute myocardial infarction); severe arterial hypertension, glaucoma, epilepsy, hyperthyroidism; elderly (over 60 years); severe forms of diabetes; pregnancy or breastfeeding; children under 12 years of age.

Do not use along with monoamine oxidase inhibitors (MAO) and within 2 weeks after discontinuing MAO inhibitors. The medicinal product is contraindicated for patients taking tricyclic antidepressants or beta-blockers.

 

Special precautions.

The drug should not be used for a long time.

During the treatment with the drug, it is not recommended to consume an excessive amount of beverages containing caffeine (for example, tea, coffee).

Do not use with other drugs containing paracetamol.

 

Interaction with other medicinal products and other forms of interaction.

When co-administered with metoclopramide and domperidone, paracetamol absorption increases, but when used in combination with cholestyramine, it decreases. Prolonged co-administration of the drug with acetylsalicylic acid or other non-steroidal anti-inflammatory drugs may cause kidney damage. Paracetamol enhances the effect of warfarin and increases the plasma level of acetylsalicylic acid, chloramphenicol, and acetosamide. With long-term regular use of paracetamol, the anticoagulant effect of warfarin and other coumarins may be intensified, increasing the risk of bleeding.

Slow gastric emptying, as when taking propantheine, can slow down the absorption of paracetamol and delay its onset. Rapid gastric emptying, as when taking metoclopramide, increases the rate of absorption.

The toxic effect on the liver increases with concomitant use with anticonvulsant drugs  stimulating the activity of microsomal liver enzymes (including phenytoin, barbiturates, carbamazepine), rifampicin, isoniazid, hepatotoxic agents, and alcohol in excessive amounts due to an increase in the degree of transformation of the drug into hepatotoxic metabolites, even when using safe doses.

Barbiturates reduce the fever-reducing effect of paracetamol.

When combined with chloramphenicol, the elimination of this drug can be prolonged, increasing the risk of toxicity.

The co-administration of paracetamol with hepatotoxic agents increases the likelihood of paracetamol accumulation and enhances the toxic effects of paracetamol and these agents on the liver. Paracetamol in high doses with isoniazid increases the risk of hepatotoxic syndrome.

Paracetamol reduces the effectiveness of diuretics.

Cases of neutropenia occur more frequently when paracetamol is taken concurrently with zidovudine. The drug can be taken simultaneously with zidovudine only under a doctor's prescription.

Inducers of liver microsomal enzymes (rifampicin and phenobarbital) increase the toxicity of paracetamol since a large amount of a toxic epoxide is formed during its biotransformation. Paracetamol may reduce the bioavailability of lamotrigine by reducing its effect due to induction of its metabolism in the liver.

The co-administration of caffeine with MAO inhibitors may cause a dangerous increase in blood pressure. Cimetidine enhances the action of caffeine.

Caffeine enhances the effect (improves bioavailability) of analgesics-antipyretics, improves the absorption of ergotamine from the gastrointestinal tract, potentiates the effects of xanthine derivatives, alpha- and beta-adrenergic agonists, psychostimulants, and increases the thyroid effect of thyrotropic agents.

Caffeine reduces the effectiveness of opioid analgesics, anxiolytics, sedatives, and is an antagonist of central nervous system depressants (including barbiturates, antihistamines), adenosine preparations, adenosine triphosphate (ATP). It reduces the concentration of lithium in the blood. Caffeine can increase the excretion of lithium from the body. Therefore, the concurrent use of caffeine with lithium preparations is not recommended.

Caffeine improves the absorption of ergotamine from the gastrointestinal tract (GIT).

Caffeine enhances tachycardia induced by sympathomimetics (including ephedrine) and thyroxine. Interaction with broad-spectrum agents (benzodiazepine) can manifest in various forms and cannot be predicted. Oral contraceptives, cimetidine, and disulfiram reduce caffeine metabolism, while barbiturates and smoking increase it. Caffeine delays the excretion of theophylline. Caffeine increases the likelihood of substance addiction (e.g. ephedrine). The co-administration of some hydrazine inhibitors can prolong the excretion of caffeine and its metabolite, paraxanthine. It is assumed that caffeine increases the risk of analgesic addiction (e.g. paracetamol), but there is insufficient clinical data to confirm this.

The action of propyphenazone is intensified when used concurrently with sedatives. The drug enhances the action of oral antidiabetic drugs (tolbutamide, chlorpropamide, acetohexamide) and oral anticoagulants like coumarin, increasing the risk of bleeding. Therefore, patients taking oral anticoagulants should not take paracetamol for an extended period without medical supervision.

Hormonal contraceptives and isoniazid enhance the action of caffeine.

The co-administration of the drug with drugs and other remedies stimulating the central nervous system is not recommended.

Do not use with alcohol.

Although there are no clinical data on the interaction with propyphenazone, the interaction of the following groups of drugs with other nonsteroidal anti-inflammatory drugs has been reported:

• ˗ angiotensin-converting enzyme (ACE) inhibitors, beta-blockers: reduction of antihypertensive effect;
• ˗ antithrombotic agents, excluding salicylates: increased risk of bleeding;
• ˗ methotrexate: increased concentration and, accordingly, toxicity of methotrexate;
• ˗ lithium: increased serum lithium levels.

 

Precautions for use.

Before using the drug, it is necessary to consult with a doctor. Do not use the drug in combination with other products containing paracetamol. Concurrent use with other paracetamol-containing medications may lead to overdose. Paracetamol overdose can cause liver insufficiency, which may necessitate a liver transplant or result in a fatal outcome.

Patients should be informed that analgesics should not be taken for an extended period unless prescribed by a doctor. It is not recommended to take the medication for more than 7 days without consulting a physician. Do not exceed the specified doses.

Prolonged use of analgesics containing high cumulative doses of paracetamol can lead to drug-induced nephropathy or irreversible kidney failure in some cases. Patients with kidney conditions should consult a doctor before starting paracetamol usage, as dosage adjustments may be necessary. Monitoring the kidney function is essential.

Taking the drug for a longer period than recommended can lead to severe complications in the liver, such as cirrhosis. Acute or chronic overdose can result in severe hepatotoxic effects, sometimes with fatal consequences.

Patients with liver conditions or infections that affect the liver, such as viral hepatitis, should consult a doctor before using the drug. During the use of paracetamol, the level of alanine aminotransferase (ALT) in the bloodstream may increase.

Alcoholic beverages should not be consumed during the treatment. Paracetamol can be toxic to the liver in doses exceeding 6-8 g per day, but negative effects on the liver can also occur with significantly lower doses when alcohol is consumed, or when inducers of liver enzymes or other substances that have a toxic impact on the liver are used. This is also true in cases of non-cirrhotic alcoholic liver disease. Prolonged alcohol consumption significantly increases the risk of hepatotoxic effects of paracetamol. Patients with impaired liver function, as well as those who take high doses of paracetamol for an extended period are recommended to regularly undergo liver function tests.

Patients who take analgesics daily for mild arthritis should consult with a doctor before using the drug.

Prolonged use of high doses can damage the liver and kidneys. In cases where renal oxidative stress is elevated and glutathione reserves in the liver are reduced, such as in the concurrent use of multiple medications, severe exhaustion, anorexia, low body mass index, alcoholism, sepsis, or diabetes, the risk of developing hepatotoxic effects of paracetamol at therapeutic doses is increased. In patients with severe infections, such as sepsis, the use of paracetamol increases the risk of metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or difficult breathing, nausea, vomiting, and loss of appetite. Seek immediate medical attention if these symptoms occur.

The risk of neutropenia and agranulocytosis is mainly due to the presence of propyphenazone. If such a reaction occurs after taking the medication (increased temperature, throat pain, mouth ulcers, perianal abscesses, reduced granulocyte count), discontinue the medication immediately. These side effects are usually reversible and disappear within 1-2 weeks.

During the treatment with the drug, it is not recommended to consume excessive amounts of caffeine-containing beverages (coffee, tea). This can lead to sleep disorders, tremors, palpitations, discomfort in the chest, tension, and irritability. If tachycardia occurs, discontinue the drug immediately. Individuals sensitive to caffeine or those who have not consumed this substance are more prone to caffeine side effects.

Avoid using other medications containing paracetamol. Prolonged use of analgesics for headache treatment can lead to chronic headache. If headache becomes persistent, consult a doctor.

The drug should be used with special caution in patients with heart disease in combination with fluid retention and oedema, in those with a history of immediate-type hypersensitivity or bone marrow depression, in patients with gastrointestinal diseases or a history of ulcer formation. Patients with hay fever are at an increased risk of developing allergic reactions. There have been reports of isolated cases of bronchial asthma attacks and anaphylactic shock in sensitive individuals related to the use of medications containing propyphenazone and paracetamol. If symptoms persist, consult your doctor.

Before using the drug, consult with your doctor if you are taking warfarin or similar drugs with anticoagulant effects. When using oral anticoagulants along with high doses of paracetamol, prothrombin time should be monitored.

The drug may affect the results of laboratory tests for blood glucose and uric acid levels.

The drug contains lactose monohydrate. If you have intolerance to certain sugars, consult your doctor before taking the drug.

 

Pregnancy and lactation.

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

 

Effects on ability to drive and use machines.

The drug has no effect on the ability to drive vehicles or work with other mechanisms, but the possibility of dizziness should be taken into account.

 

Method of administration and dosage.

RAPIMAX FORTE is administered orally. The tablets should be taken with an adequate amount of fluid.

Adults:

1-2 tablets as a single dose. Use not more than 3 single doses per day.

Children aged 12–18 years.

1 tablet as a single dose. Use no more than 3 single doses per day.

The duration of treatment should not exceed 1 week. It is not recommended to exceed the recommended dose.

 

Children.

The drug is prescribed to children over 12 years of age.

 

Overdose.

Symptoms: pale skin, nausea, vomiting, abdominal pain, cardiac rhythm disturbances (including extrasystoles), increased sweating, low blood pressure, impaired vision and orientation.

When taking high doses may cause the following central nervous system disorders: dizziness, psychomotor excitement and disorientation, depression of the central nervous system, drowsiness or insomnia, impaired consciousness, nervousness, anxiety, tremors, hyperreflexia, convulsions; the urinary system disorders: nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis).

With long-term use of the drug in high doses, aplastic anaemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, thrombocytopenia may develop in hematopoietic organs.

In case of drug overdose, each active component can cause specific symptoms.

Paracetamol overdose.

Symptoms of paracetamol overdose within the first 24 hours may include pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage (hepatonecrosis, elevated liver transaminase activity, increased prothrombin time) can manifest 12-48 hours after overdose and usually peak around 4-6 months. In severe poisoning, it can progress and lead to the toxic encephalopathy, bleeding, hypoglycaemia, coma, and a fatal outcome.

Liver damage can occur 12-48 hours after overdose in adults who have taken 10 grams or more of paracetamol and in children who have ingested more than 150 mg/kg of body weight. In patients at risk (prolonged treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs that induce liver enzymes; regular consumption of excessive amounts of alcohol; glutathione deficiency: digestive disorders, cystic fibrosis, HIV infection, starvation), the intake of 5 grams or more of paracetamol can lead to liver damage.

Acute renal dysfunction with acute tubular necrosis can develop even in the absence of severe liver damage, which may manifest as severe lower back pain, haematuria, proteinuria, and occur even in the absence of severe liver damage.

Caffeine overdose.

High doses of caffeine can lead to pain in the epigastric region, vomiting, increased diuresis, accelerated respiration, extrasystole, tachycardia, or arrhythmia; affect the central nervous system (loss of consciousness, insomnia, restlessness, headaches, nervousness, mood swings, anxiety, tremors, seizures).

Clinically significant symptoms of caffeine overdose are also associated with serious liver damage from paracetamol, which can occur when taking such an amount of the drug that causes caffeine overdose.

 

Propyphenazone overdose can cause damage to the central nervous system (convulsions, coma).

Disorders of glucose metabolism and metabolic acidosis may occur.

In severe poisoning, hepatic insufficiency can progress to encephalopathy, hemorrhage, hypoglycemia, coma, and can be fatal. Cardiac arrhythmia and pancreatitis were also reported.

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

Treatment. Gastric lavage followed by activated charcoal administration, symptomatic therapy. Immediate medical assistance is necessary in case of overdose, even if overdose symptoms are not observed. If overdose is confirmed or even suspected, the patient should be taken to the nearest medical facility where urgent assistance and qualified treatment can be provided. This should be done even if overdose symptoms are felt due to the risk of delayed liver damage.

Plasma concentration of paracetamol should be measured 4 hours or later after intake (earlier concentrations are unreliable). Treatment with N-acetylcysteine can be administered within 24 hours after taking paracetamol, but the maximum protective effect occurs when it is administered within 8 hours after intake. The effectiveness of the antidote sharply decreases after this time. If necessary, N-acetylcysteine should be administered intravenously to the patient according to current guidelines. In the absence of vomiting, methionine can be used orally as an appropriate alternative in remote areas outside the hospital. The oral administration of methionine or intravenous administration of acetylcysteine is effective up to 48 hours after overdose. General supportive measures should also be taken. The alpha-adrenergic blockers should be used if necessary. The beta-adrenergic receptor antagonists can alleviate the cardiotoxic effect; oxygen therapy should be applied, and diazepam should be used in seizures.

 

Adverse reactions.

The following adverse reactions were identified through post-marketing observations. The information is provided voluntarily and pertains to a population of an unknown size; therefore, the frequency of these adverse reactions is unknown. However, it is likely that they are rare (< 1/10000).

Adverse reactions caused by paracetamol

The drug is usually well tolerated, but in some cases the following side effects may occur:

Blood and lymphatic system disorders: thrombocytopenia, neutropenia, leukopenia, agranulocytosis, pancytopenia, anaemia, sulfhemoglobinemia, and methemoglobinemia (cyanosis, dyspnoea, chest pain), haemolytic anaemia, bruising, and bleeding.

Cardiovascular system disorders: tachycardia, arrhythmia, high blood pressure.

Immune system disorders: anaphylaxis, hypersensitivity, including skin and mucous membrane rashes (including generalized erythematous rashes), urticaria, angioedema, Stevens-Johnson syndrome, skin itching, toxic epidermal necrolysis (Lyell's syndrome), acute generalized exanthematous pustulosis, and angioedema.

Digestive system disorders: nausea, vomiting, heartburn, epigastric pain,

Endocrine system disorders: hypoglycaemia, up to hypoglycaemic coma.

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

Hepatobiliary system disorders: impaired liver function, liver failure, liver necrosis, jaundice, increased activity of liver enzymes, usually without the development of jaundice, hepatonecrosis (dose-dependent effect).

Skin and subcutaneous tissue disorders: itching, haemorrhage, oral mucosal ulceration.

Kidneys and urinary system disorders: nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

Nervous system disorders: headache.

Adverse reactions caused by caffeine

Central nervous system disorders: nervousness, dizziness, insomnia.

Cardiovascular system disorders: increased heart rate, oedema.

Gastrointestinal tract disorders: gastrointestinal disorder, abdominal pain, diarrhea, nausea, vomiting.

Psychic disorders: insomnia, restlessness, anxiety and irritability.

Skin and subcutaneous tissues disorders: itching, rashes, sweating, purpura, urticaria.

The co-administration of the medicinal product at recommended doses with products containing caffeine may intensify the adverse effects caused by caffeine, such as dizziness, increased excitability, insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disorders, and increased heart rate.

 

Shelf life. 3 years.

 

Storage conditions.

Store in the original package at a temperature not exceeding 25 °C. Keep out of reach of children.

 

Packaging.

10 tablets in a blister, 1 blister in a carton.

10 tablets in a blister, 10 blisters in a carton.

 

Terms of dispensing.

Without prescription, package No. 10.

On prescription, package No. 100 (10×10).

 

Manufacturer.

Bafna Pharmaceuticals Ltd., India.

 

Manufacturer’s registered address.

147, Madhavaram Red Hills Road Grantlyon Village Vadakarai Chennai Tamil Nadu IN 600052, India.

 

Applicant.

SCAN BIOTECH LTD, India.

 

Applicant’s registered address.

E-4/300, Arera Colony Extension, 462016, Bhopal, India.