ACTION AND MECHANISM

- Flu.

* Paracetamol: analgesic and antipyretic, probably due to the inhibition of cyclooxygenase at the central level, especially COX-2, decreasing the synthesis of prostaglandins.

* Chlorphenamine: H1 antihistamine and anticholinergic. Reduces catarrhal symptoms such as sneezing, watery eyes, and runny nose.

* Phenylephrine: alpha-1 adrenergic agonist. Produces vasoconstriction, reducing nasal congestion.

SPECIAL WARNINGS

- If the patient experiences difficulty urinating or urinary retention, it is recommended to discontinue treatment.

- Patients who are to undergo allergy testing using allergenic extracts should discontinue treatment at least 72 hours beforehand to avoid false negatives.

SENIORS

No specific problems have been described in the elderly that require dosage adjustment.

However, these patients may be more sensitive to the side effects of this medication, so it is advisable to use it with caution, paying special attention to the appearance of anticholinergic effects.

PATIENT ADVICE

- Avoid drinking alcohol during treatment.

- Do not exceed the recommended doses. Taking other drugs with paracetamol could result in very serious poisoning.

- Consult your doctor and/or pharmacist if pain persists after 5 days of treatment, fever lasts for more than 3 days, or if symptoms worsen or new ones appear.

- Avoid driving or performing activities that require your attention until you are sure the treatment does not adversely affect you.

- Tell your doctor and/or pharmacist if you are going to undergo allergy diagnostic testing.

- Tell your doctor and/or pharmacist if you experience any of these symptoms:

* Dry mouth, visual disturbances, constipation or inability to urinate.

CONTRAINDICATIONS

- Hypersensitivity to any component of the medication, including [PARACETAMOL ALLERGY]. Cross-hypersensitivity reactions may occur between different antihistamines.

- Pathologies that could be aggravated by this medicine, such as [ARTERIAL HYPERTENSION], [PHEOCHROMOCYTOMA], [HYPERTHYROIDISM], [ISCHEMIC HEART DISEASE], [TACHYCARDIA], [GLAUCOMA] or [DIABETES].

- Severe renal impairment (CrCl < 30 ml/min) or severe hepatic impairment (Child-Pugh class C).

- [PORPHYRIA]. H1 antihistamines have been associated with the development of porphyria flares and are therefore not considered safe in these patients.

- Patients receiving treatment with an MAOI in the previous 14 days (see Interactions; antidepressants).

- Treatment with beta-blockers or other sympathomimetics.

EFFECTS ON DRIVING

May cause significant sedation due to the presence of chlorphenamine. Patients should avoid operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not adversely affect them.

PREGNANCY

FDA Category:

- Paracetamol: B.

- Chlorphenamine: C.

- Phenylephrine: C.

Animal Safety: Phenylephrine was associated with increased fetal mortality and premature delivery in rabbits, and decreased blood flow to the uterus in sheep.

Animal studies with paracetamol have not shown any malformations or fetotoxic effects.

Safety in humans: Adequate and well-controlled human studies are lacking. Its administration is only acceptable if there are no safer therapeutic alternatives, and the benefits outweigh the potential risks.

Effects on fertility: No specific studies have been conducted in humans.

INDICATIONS

- Symptomatic treatment of [COMMON COLD] or [FLU] that present with mild or moderate pain, fever, nasal congestion and discharge in adults.

INTERACTIONS

- Ethyl alcohol. Ethyl alcohol may enhance the sedative effects of this medication. Furthermore, consuming alcoholic beverages with paracetamol may cause liver damage. It is recommended to avoid alcohol during treatment. Chronic alcoholics should not administer more than 2 g of paracetamol per 24 hours.

- Alpha blockers (ergotamines for migraines, oxytocin). Their simultaneous use is not recommended because it may increase vasoconstrictive effects. Alpha blockers for hypertension or benign prostatic hyperplasia, by not blocking beta receptors, may cause an increased risk of hypotension and tachycardia.

- Inhaled anesthetics (halothane). May increase the risk of arrhythmias.

- Oral anticoagulants. In very rare cases, usually with high doses, the anticoagulant effects may be enhanced by paracetamol's inhibition of hepatic synthesis of coagulation factors. It is recommended to administer the lowest dose, with the shortest possible duration of treatment, and monitor the INR.

- Anticholinergics (antiparkinsonian drugs, tricyclic antidepressants, MAOIs, neuroleptics). Chlorphenamine may enhance the anticholinergic effects, so the combination is recommended to be avoided.

- Oral contraceptives. They may increase the plasma clearance of paracetamol, decreasing its effects.

- Tricyclic antidepressants (amitriptyline, amoxapine, clomipramine, desipramine, doxepin, maprotiline). Concomitant use may enhance the pressor effects of phenylephrine.

- Antihypertensives (beta-blockers, diuretics, guanethidine, methyldopa). Phenylephrine may antagonize the antihypertensive effects and even lead to hypertensive crises, so blood pressure monitoring is recommended. Propranolol may inhibit the metabolism of paracetamol, leading to toxic effects.

- Atropine. Blocks the reflex bradycardia caused by phenylephrine and increases the pressor response to phenylephrine.

- Activated charcoal. It can adsorb paracetamol, decreasing its absorption and pharmacological effects.

- Chloramphenicol. Chloramphenicol toxicity may be enhanced, probably by inhibiting its metabolism.

- Digitalis. The risk of cardiac arrhythmias associated with phenylephrine may be increased.

- Diuretics that can cause hypokalemia (furosemide). Hypokalemia may be exacerbated and arterial sensitivity to vasopressors such as phenylephrine may be decreased.

- Nerve stimulants (amphetamines, cocaine, xanthines). Nerve stimulation may be enhanced, leading to intense excitability.

- Thyroid hormones. Potentiation of the effects of both drugs may occur, with a risk of high blood pressure and coronary artery disease.

- MAOIs. MAOIs may enhance the effects of phenylephrine by inhibiting norepinephrine metabolism, increasing the risk of hypertensive crises and other cardiac events. It is recommended that patients treated with MAOIs within the previous 14 days avoid this medication.

- Enzyme inducers. Medications such as barbiturates, carbamazepine, hydantoin, isoniazid, rifampicin, or sulfinpyrazone may induce paracetamol metabolism, decreasing its effects and increasing the risk of hepatotoxicity.

- Lamotrigine. Paracetamol may reduce serum concentrations of lamotrigine, resulting in a decreased therapeutic effect.

- Levodopa. The administration of levodopa with sympathomimetics increases the risk of cardiac arrhythmias, so a reduction in the dose of the adrenergic agonist may be necessary.

- Metoclopramide and domperidone. They increase the absorption of paracetamol in the small intestine due to their effect on gastric emptying.

- Probenecid. Increases the plasma half-life of paracetamol by decreasing the degradation and urinary excretion of its metabolites.

- Ion exchange resins (cholestyramine). Decreased absorption of paracetamol, with possible inhibition of its effect, due to its binding in the intestine.

- Nitrates. Phenylephrine may antagonize the antianginal effects of nitrates, so it is recommended to avoid the combination.

- Sedatives (opioid analgesics, barbiturates, benzodiazepines, antipsychotics). Sedative effects may be enhanced.

- Sympathomimetics. Potentiation of side effects, both nervous and cardiovascular, may occur.

- Zidovudine. Although potential potentiation of zidovudine toxicity (neutropenia, hepatotoxicity) has been reported in isolated patients, no kinetic interaction between the two drugs appears to exist.

LACTATION

Excretion in milk:

- Paracetamol: small amounts (similar to maternal cp).

- Chlorphenamine: unknown. Other antihistamines do.

- Phenylephrine: limited excretion and reduced oral bioavailability.

The potential consequences for the infant are unknown. It is recommended to avoid administration during breastfeeding.

CHILDREN

Its use is not recommended in children and adolescents under 18 years of age because the doses of paracetamol are not adjusted for this age.

RULES FOR CORRECT ADMINISTRATION

- Sachets: dissolve the contents of the sachet in half a glass of liquid, preferably water.

Administration with food: can be taken with or without food.

POSOLOGY

- Adults: 1 sachet/6-8 h. Maximum dose 4 sachets/24 h.

- Children and adolescents < 18 years: not recommended because the paracetamol content is not adjusted for this age.

- Elderly: No specific dosage recommendations have been made. Use with caution.

Duration of treatment: Consult your doctor and/or pharmacist if symptoms persist for more than 3 days (fever) or 5 days (pain and other symptoms), or if new symptoms appear. Stop treatment when symptoms disappear.

Missed dose: Administer the missed dose as soon as possible, unless it is almost time for the next dose. Administer the next dose at the regular time. Do not double the next dose.

DOSAGE IN LIVER FAILURE

- Mild to moderate hepatic impairment (Child-Pugh classes A and B): maximum dose 2 sachets/24 h, with a minimum interval between doses of 8 h.

- Severe hepatic impairment (Child-Pugh class C): contraindicated.

DOSAGE IN KIDNEY FAILURE

It is not recommended since the paracetamol content exceeds the recommended dose in these patients.

PRECAUTIONS

- [RENAL FAILURE]. In general, use is not recommended in patients with renal failure, as it requires a dosage adjustment that would not be possible with this medicine (see Dosage in renal failure for further information).

- [HEPATOTOXICITY]. Paracetamol has been associated with hepatotoxicity when used at high doses (> 4 g/24 h) or for prolonged periods of time.

Assess its use in cases of [LIVER FAILURE], [HEPATITIS] or [LIVER CIRRHOSIS], as well as in patients with other risks of liver damage, such as [CHRONIC ALCOHOLISM], [HYPOVOLEMIA], [DEHYDRATION] or [MALNUTRITION] with low glutathione levels, or treated with other hepatotoxic drugs.

Paracetamol doses should generally not exceed 3 g/24 h.

Avoid taking other medications containing paracetamol, as well as consuming alcoholic beverages during treatment.

- [SALICYLATE ALLERGY]. Patients allergic to acetylsalicylic acid do not usually experience cross-hypersensitivity reactions with paracetamol, but cases of mild bronchospasm have been reported, so caution is advised in cases of [ASTHMA].

- Patients with pathologies that could be aggravated by anticholinergic or sympathomimetic effects, such as [CONSTIPATION], [INTESTINAL OBSTRUCTION], [HIATAL HERNIA], [GASTROESOPHAGEAL REFLUX DISEASE], stenosing [PEPTIC ULCER], [ULCERATIVE COLITIS], [HEART FAILURE], [ATHEROSCLEROSIS], [PERIPHERAL ARTERY DISEASE], [ANEURYSM], [PROSTATIC HYPERPLASIA] or other causes of [URINARY RETENTION].

- Skin tests for hypersensitivity to allergenic extracts. Due to their antihistamine effects, these extracts may cause false negative results in diagnostic tests. It is recommended to discontinue administration at least 72 hours before performing the test.

- Situations that could raise body temperature. Anticholinergic drugs could interfere with the body's thermoregulatory capacity, and could therefore promote the development of heat stroke in patients exposed to extreme heat, especially the elderly, who perform intense physical exercise in inappropriate clothing or at inappropriate times, or who are being treated with drugs such as diuretics or others that promote [DEHYDRATION].

ADVERSE REACTIONS

Adverse reactions are described according to each frequency interval, considering very frequent (>10%), frequent (1-10%), unfrequent (0.1-1%), rare (0.01-0.1%), very rare (<0.01%) or of unknown frequency (cannot be estimated from the available data).

Paracetamol RAM:

- Hepatic: rare [elevated transaminases], [elevated alkaline phosphatase], [hyperbilirubinemia]; very rare [hepatotoxicity], with [jaundicity].

- Cardiovascular: rare [HYPOTENSION].

- Neurological/psychological: [DIZZINESS], [DISORIENTATION], [EXCITABILITY].

- Genitourinary: very rare renal disorders such as urine turbidity and kidney disorders; frequency unknown [increased serum creatinine], increased ammonia levels, [increased urea nitrogen].

- Allergic: very rare [HYPERSENSITIVITY REACTIONS], with symptoms ranging from [EXANTHEMATOUS ERUPTIONS] and [URTICARIA] to [ANAPHYLAXIS].

- Hematological: very rare [THROMBOCYTOPENIA], [AGRANULOCYTOSIS], [LEUKOPENIA], [NEUTROPENIA], [HEMOLYTIC ANEMIA], [METAHEMOGLOBINEMIA]. Prothrombin time may be increased, although this does not appear to be significant.

- Metabolic: very rare [HYPOGLYCEMIA]; frequency unknown [LACTATE DEHYDROGENASE INCREASED].

- General: rare [GENERAL MALAISE].

Chlorphenamine RAM:

- Digestive: unknown frequency [NAUSEA], [VOMITING], [DIARRHEA], [CONSTIPATION], [ABDOMINAL PAIN], [DRY MOUTH].

- Liver: frequency unknown [HEPATITIS], [CHOLESTASIS].

- Cardiovascular: unknown frequency [PALPITATIONS], [HYPOTENSION], [ARTERIAL HYPERTENSION].

- Neurological/psychological: frequency unknown [DROWSINESS], [DIZZINESS], [DYSKINESIA] facial, [ATAXIA], [TREMOR], [PARESTHESIA], [DYSGEUSIA], [PAROSMIA].

In children and the elderly, paradoxical reactions of excitability may occur, with [AGITATION], [INSOMNIA], [NERVOUSNESS], [DELIRIUM], [CONVULSIONS].

- Respiratory: unknown frequency [DRY NOSE] or throat, [SORE THROAT], thickening of mucus, [CHEST TIGHTNESS], [WHEEZING].

- Genitourinary: unknown frequency [URINARY RETENTION] or difficulty urinating, [SEXUAL IMPOTENCE], early menstruation.

- Dermatological: frequency unknown [HYPERHIDROSIS].

- Allergic: frequency unknown [HYPERSENSITIVITY REACTIONS], with symptoms such as [COUGH], [DYSPHAGIA], [TACHYCARDIA], [URTICARIA], facial [EDEMA] or [ANGIOEDEMA], [DYSPNEA], [FATIGUE]. Also [PHOTOSENSITIVITY REACTIONS].

- Musculoskeletal: frequency unknown [MYASTHENIA].

- Ophthalmological: unknown frequency [BLURRED VISION], [DIPLOPIA].

- Otics: frequency unknown [TINNITUS], [LABYRINTHITIS].

- Hematological: unknown frequency [AGRANULOCYTOSIS], [LEUKOPENIA], [APLASTIC ANEMIA], [THROMBOCYTOPENIA], [HEMORRHAGY].

- Metabolic: frequency unknown [ANOREXIA].

- General: frequency unknown [FATIGUE], [EDEMA].

Phenylephrine RAM:

- Digestive: unknown frequency [VOMITING], [HYPERSALIVATION].

- Cardiovascular: unknown frequency [ARTERIAL HYPERTENSION], [HYPOTENSION], [FLUSHING], [BRADYCARDIA], [TACHYCARDIA], [ANGINA PECTORIA], [PALPITATIONS], [CARDIAC ARREST].

- Neurological/psychological: frequency unknown [HEADACHE], [CEREBRAL HEMORRHAGE], [VERTIGO], [DIZZINESS], [DUMBNESS].

- Respiratory: unknown frequency [DYSPNEA], [PULMONARY EDEMA].

- Genitourinary: unknown frequency [HESITANEOUS URINATION], [URINARY RETENTION].

- Dermatological: unknown frequency [HYPERHIDROSIS], [PARESTHESIA].

- Metabolic: frequency unknown [HYPERGLYCEMIA], [HYPOGLYCEMIA].

- General: unknown frequency sensation of coldness on the skin.

OVERDOSE

Symptoms: Overdose with paracetamol-containing products is a very serious and potentially fatal poisoning. Symptoms may not appear immediately and may take up to three days to appear. These symptoms include confusion, excitability with restlessness, nervousness and irritability, dizziness, nausea and vomiting, loss of appetite, and liver damage. Hepatotoxicity usually manifests within 48–72 hours with nausea, vomiting, anorexia, malaise, sweating, jaundice, abdominal pain, diarrhea, and liver failure.

In children, drowsiness and changes in gait also occur.

In the most severe cases, death may occur due to hepatic necrosis or acute renal failure.

The minimum toxic dose of paracetamol is 6 g in adults and 100 mg/kg in children. Doses above 20-25 g of paracetamol are potentially fatal.

In addition to the symptoms of paracetamol overdose, symptoms of chlorphenamine overdose (deep sedation, anticholinergic symptoms) and phenylephrine overdose (excitability, seizures, tachycardia, high blood pressure) may also occur.

Treatment: In case of an overdose, seek medical attention immediately, as paracetamol poisoning can be fatal, even if symptoms are asymptomatic. Early identification of paracetamol overdose is especially important in children, due to the severity of the condition and the availability of treatment options.

In any case, gastric lavage and aspiration of the stomach contents should be performed initially, preferably within four hours of ingestion. The administration of activated charcoal may reduce the amount absorbed.

There is a specific antidote for paracetamol poisoning: N-acetylcysteine. The recommended dose is 300 mg/kg of N-acetylcysteine, equivalent to 1.5 ml/kg of a 20% aqueous solution with a pH of 6.5, intravenously, over a period of 20 hours and 15 minutes, according to the following schedule:

- Adults. A loading dose of 150 mg/kg (0.75 ml/kg of 20% solution) should be administered initially by slow intravenous injection over 15 minutes, either directly or diluted in 200 ml of 5% dextrose.

A maintenance dose of 50 mg/kg (0.25 ml/kg of 20% solution) in 500 ml of 5% dextrose will then be started by slow intravenous infusion over 4 hours.

Finally, 100 mg/kg (0.50 ml/kg of 20% solution) in 1000 ml of 5% dextrose will be administered by slow intravenous infusion over 20 hours.

- Children. The same amounts per unit of weight should be administered as for adults, but the dextrose volume should be adjusted based on the child's age and weight to avoid vascular congestion.

The antidote's effectiveness is greatest if administered within 8 hours of ingestion. Its effectiveness gradually decreases thereafter and is ineffective after 3 hours.

Administration of 20% N-acetylcysteine may be discontinued when blood paracetamol levels are below 200 mcg/ml.

In addition to administering the antidote, symptomatic treatment will be initiated, keeping the patient under clinical surveillance.

In the event of hepatotoxicity, liver function testing is recommended and the test should be repeated at 24-hour intervals.