4.1 Therapeutic indication
For treatment of fever associated with cold, nasal congestion in adults.
4.2 Posology and method of administration
For oral administration.
Adults: 1 tablet to be administered 3 to 4 times daily.
Doses of Individual Ingredients:
As a nasal decongestant, Phenylephrine Hydrochloride may be given in usual oral doses of 10 mg every four hours (up to a maximum of 60 mg daily) or 12 mg up to four times daily.
The usual oral dose of Paracetamol is 0.5 to 1 g every 4 to 6 hours up to a maximum of 4 g daily.
Diphenhydramine Hydrochloride is given in usual oral doses of 25 to 50 mg three or four times daily.
The recommended dosage of Caffeine as an adjuvant analgesic is from 15 to 65 mg/dose.
Do not exceed the recommended dose, as paracetamol may cause liver toxicity with overdose. Maxtra Cold Plus Tablets should be preferably administered with or after food. The tablet should be swallowed whole with water or, as prescribed by the physician.
4.3 Contraindications
Maxtra Cold Plus Tablets are contraindicated in the following:
- Known hypersensitivity to paracetamol or to phenylephrine or to caffeine or to diphenhydramine or to any component of the formulation.
- In patients who have been treated with monoamine oxidase (MAO) inhibitors within the last 14 days.
- In patients who are currently receiving other sympathomimetic drugs.
- Cardiovascular disorders.
- In patients with peripheral vascular insufficiency.
- Severe hepatic and renal impairment.
- In patients with hyperthyroidism.
- In patients with glaucoma.
- In patients with prostate problems (such as hypertrophy).
- Pheochromocytoma.
4.4 Special warnings and precautions for use
Paracetamol
Significant overdose of paracetamol can lead to hepatotoxicity in some patients. Thus, do not exceed the recommended dose. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.
Do not take with any other paracetamol-containing products, so as to avoid the chances of overdose.
Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment.
Chronic heavy alcohol abusers may be at increased risk of liver toxicity from excessive paracetamol use.
Phenylephrine
Sympathomimetic amines should be used with caution in patients with hypertension, diabetes mellitus, heart disease (angina), peripheral vascular disease, increased intraocular pressure, hyperthyroidism, or prostatic hypertrophy.
Phenylephrine should not be used with other sympathomimetics (such as decongestants, appetite suppressants, and amphetamine-like psychostimulants).
Sympathomimetics may act as cerebral stimulants giving rise to insomnia, nervousness, hyperpyrexia, tremor, and epileptiform convulsions.
Diphenhydramine
Subjects with moderate to severe renal or hepatic dysfunction should exercise caution while using diphenhydramine.
Diphenhydramine should not be taken by individuals with narrow-angle glaucoma or symptomatic prostatic hypertrophy.
Caution should be exercised in patients with glaucoma and urinary retention.
Should be used with caution in patients with myasthenia gravis or seizure disorders, bronchitis or chronic obstructive pulmonary disease (COPD).
Tolerance may develop with continuous use.
Diphenhydramine may exacerbate tinnitus in existing tinnitus sufferers.
Caffeine
Excessive intake of caffeine (e.g., coffee, tea and some canned drinks) should be avoided while taking this product.
Caffeine should be administered with caution in patients with a history of peptic ulcers.
Prolonged, high intake of caffeine may produce tolerance and habituation. Physical signs of withdrawal, such as headaches, irritation, nervousness, anxiety, and dizziness may occur upon abrupt discontinuation.
4.5 Drug interactions
Paracetamol
Cholestyramine: The rate of absorption of paracetamol is reduced by cholestyramine. Therefore, cholestyramine should not be taken within one hour, if maximal analgesia is required.
Metoclopramide and Domperidone: The absorption of paracetamol is increased by metoclopramide and domperidone. However, concurrent use need not be avoided.
Warfarin: The anti-coagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.
Chloramphenicol: Concurrent administration of paracetamol and chloramphenicol may markedly retard the elimination of chloramphenicol and thus, increases plasma concentration of chloramphenicol which leads to risk of its harmful effects. Monitoring of chloramphenicol plasma levels is recommended while combining paracetamol with chloramphenicol injection.
Alcohol, Anticonvulsants, and Isoniazid: Concomitant administration of alcohol, anticonvulsants, and isoniazid with paracetamol may increase risk of hepatotoxicity.
Phenylephrine MAO Inhibitors: Hypertensive interactions occur between sympathomimetic amines such as phenylephrine and MAO inhibitors, thus concomitant use is contraindicated.
Sympathomimetic Amines: Concomitant use of phenylephrine with other sympathomimetic amines can increase the risk of cardiovascular side effects.
Beta-Blockers and Other Antihypertensives (Including Debrisoquine, Guanethidine, Reserpine, and Methyldopa): Phenylephrine may reduce the efficacy of beta-blocking drugs and antihypertensive drugs. The risk of hypertension and other cardiovascular side effects may be increased.
Tricyclic Antidepressants (Amitriptyline): Concomitant use of phenylephrine with amitriptyline may increase the risk of cardiovascular side effects.
Ergot Alkaloids (Ergotamine and Methylsergide): Concomitant use of phenylephrine with these drugs increases risk of ergotism.
Digoxin and Cardiac Glycosides: Co-administration of phenylephrine with these drugs increases risk of irregular heartbeat or heart attack.
Diphenhydramine Drugs Acting on Central Nervous System (CNS): Diphenhydramine may potentiate the effects of alcohol, codeine, antihistamines and other CNS depressant drugs.
Anticholinergic Agents: As diphenhydramine possesses some antimuscarinic activity, the effects of anticholinergics (e.g., tricyclic antidepressants and atropine) may be potentiated by diphenhydramine. This may result in tachycardia, dry mouth, gastrointestinal disturbances (e.g., colic), urinary retention and headache.
MAO Inhibitors: MAO inhibitors prolong and intensify the anticholinergic effects of diphenhydramine. Thus, diphenhydramine should be used with caution with MAO inhibitors or within 2 weeks of stopping MAO inhibitor.
Drugs Metabolized by CYP 2D6: Diphenhydramine is an inhibitor of the cytochrome P450 isoenzyme CYP2D6. Therefore, there is a potential for interaction with drugs which are primarily metabolised by CYP2D6, such as metoprolol and venlafaxine.
Caffeine
Drugs Metabolized by Cytochrome P450 1A2: Cytochrome P450 1A2 (CYP1A2) is known to be the major enzyme involved in the metabolism of caffeine. Therefore, caffeine has the potential to interact with drugs that are substrates for CYP1A2, inhibit CYP1A2, or induce CYP1A2. Lower doses of caffeine may be needed following co-administration of drugs which are reported to decrease caffeine elimination (e.g., cimetidine and ketoconazole) and higher caffeine doses may be needed following co-administration of drugs that increase caffeine elimination (e.g., phenobarbital and phenytoin). Caffeine may also increase the metabolism of other drugs such as phenobarbital and aspirin.
Ephedrine: Caffeine and ephedrine are both CNS stimulant drugs. Co-administration of caffeine with ephedrine might cause too much stimulation and sometimes serious side effects and heart problems. Do not administer caffeine-containing products and ephedrine at the same time.
Theophylline: Caffeine works similar to theophylline. Inter-conversion between caffeine and theophylline has been reported. Caffeine may decrease metabolism and excretion of theophylline and thus, might increase the effects and side effects of theophylline. The concurrent use of these drugs is not recommended.
Beta-Adrenergic Agonists: Caffeine may enhance the cardiac inotropic effects of beta-adrenergic stimulating agents. Co-administration of caffeine with these drugs should be avoided, as it might cause serious problems including increased heart rate and high blood pressure.
Disulfiram: Co-administration of caffeine and disulfiram may lead to a substantial decrease in caffeine clearance. Co-administration of caffeine with disulfiram might increase the effects and side effects of caffeine including jitteriness, hyperactivity, and irritability.
Quinolone Antibiotics: Caffeine accumulation may occur when products or foods containing caffeine are consumed concomitantly with quinolones such as ciprofloxacin. Co-administration of these antibiotics with caffeine can increase the risk of side effects including jitteriness, headache, increased heart rate, and other side effects.
4.6 Use in special populations
Pregnant Women
The safety of this formulation during pregnancy has not been established. Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage. There is a possible association of fetal abnormalities with first trimester exposure to phenylephrine. In addition, there is a potential for increased uterine contractility and vasoconstriction, with the possibility of fetal hypoxia. Phenylephrine may also reduce placental perfusion, thus, it should not be used in patients with a history of pre-eclampsia. The half-life of caffeine is prolonged when used during pregnancy. Caffeine is not recommended for use during pregnancy due to the possible increased risk of lower birth weight and spontaneous abortion associated with its consumption. Diphenhydramine crosses the placental barrier and has been reported to cause jaundice and extrapyramidal symptoms in infants whose mothers received the drug during pregnancy. Use of sedating antihistamines during the third trimester of pregnancy may result in reactions in the newborn or premature neonates. Thus, diphenhydramine is not recommended during pregnancy. Use of Maxtra Cold Plus Tablets should be avoided during pregnancy.
Lactating Women
Paracetamol and phenylephrine are excreted in breast milk, but not in a clinically significant amount. Caffeine appears in breast milk. Caffeine in breast milk may potentially have a stimulating effect on breast fed infants. Irritability and poor sleeping pattern in the infant have been reported. Diphenhydramine has been detected in breast milk. If administered during breast feeding there is an increased risk of adverse effects of antihistamine, such as unusual excitation or irritability in infants. Thus, diphenhydramine hydrochloride is not recommended for use during lactation in nursing mothers. Due to the caffeine and diphenhydramine content of this formulation, Maxtra Cold Plus Tablets should not be administered to a nursing mother. Accordingly, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Paediatric Patients
Safety and effectiveness of this formulation in paediatric patients below 12 years of age have not been established. Thus, Maxtra Cold Plus Tablets are not recommended in this age group.
Geriatric Patients
Elderly patients with normal renal and hepatic function should be given the same dose as recommended for adults. Side effects are more likely to occur in the elderly. The risk of toxic reactions with this formulation may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
4.7 Effects on ability to drive and use machines
Diphenhydramine content of this formulation has a major influence on the ability to drive and use machines. It may cause drowsiness or sedation soon after the dose has been taken or up to 8 hours of ingestion. Diphenhydramine may also cause dizziness, blurred vision, cognitive and psychomotor impairment which may adversely affect patient's ability to concentrate and react. Thus, while on this medicine, patients are advised not to drive a vehicle or operate machinery.
4.8 Undesirable effects
Paracetamol
Adverse effects of paracetamol are rare. However, hypersensitivity including skin rash and fixed drug eruption (FDE) may occur. There have been reports of blood dyscrasias including thrombocytopenic purpura, methaemoglobenemia and agranulocytosis, but these were not necessarily related to paracetamol. Overdosage with paracetamol can result in severe hepatotoxicity and sometimes acute renal tubular necrosis. If there is a pre-existing liver insufficiency, paracetamol can be hepatotoxic even in normal dosage. Increased levels of aspartate aminotransferase and hepatic transaminases may occur. Nausea, vomiting, abdominal pain, diarrhea, constipation, dyspepsia, dry mouth, heartburn have also been reported commonly with the use of paracetamol.
Phenylephrine
Phenylephrine may elevate blood pressure with headache, vomiting and rarely palpitations, tachycardia or reflex bradycardia, tingling and coolness of the skin. There have been rare reports of allergic reactions.
Diphenhydramine
Diphenhydramine may cause drowsiness, dizziness, gastrointestinal disturbance, dry mouth, difficulty in urination or blurred vision. Less frequently diphenhydramine may also cause palpitations, tremor, convulsions or parasthesia. Hypersensitivity reactions have been reported with the use of diphenhydramine, in particular, skin rashes, erythema, urticaria and angioedema.
Caffeine
Caffeine may cause CNS adverse effects such as insomnia, dizziness, restlessness, excitability, anxiety, irritability, nervousness and mild delirium. Caffeine may also cause gastrointestinal adverse effects such as nausea, vomiting and gastric irritation. High doses of caffeine can cause tremor and palpitations.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com
Website: https://www.zuventus.com/drug-safety-reporting
By reporting side effects, you can help provide more information on the safety of this medicine.
4.8 Overdose
Paracetamol
Symptoms: Ingestion of 5 gram or more of paracetamol may lead to liver damage. Symptoms of paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycaemia, cerebral edema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, hematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.
Treatment: Immediate treatment is essential in the management of paracetamol overdose. Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine (FDA approved antidote) may be used up to 24 hours after ingestion of paracetamol. However, the maximum protective effect is obtained up to 8 hours post ingestion.
Phenylephrine
Symptoms: Overdose symptoms may include hypertension and possibly reflex bradycardia. In severe cases confusion, hallucinations, seizures, and arrhythmias may occur.
Treatment: Treatment measures include early gastric lavage and symptomatic and supportive measures. The hypertensive effects may be treated with an α-receptor blocking agent (such as phentolamine mesylate, 6 to 10 mg) given intravenously, and the bradycardia treated with atropine, preferably only after the pressure has been controlled.
Diphenhydramine
Symptoms: The symptoms of diphenhydramine overdose may include drowsiness, hyperpyrexia and anticholinergic effects. With higher doses, and particularly in children, symptoms of CNS excitation including hallucinations and convulsions may appear; with massive doses, coma or cardiovascular collapse may follow.
Treatment: Treatment of overdose should be symptomatic and supportive. Measures to promote rapid gastric emptying (ipecac-induced emesis or gastric lavage) and, in cases of acute poisoning, the use of activated charcoal may be useful. Seizures may be controlled with diazepam or thiopental sodium. The intravenous use of physostigmine may be efficacious in antagonising severe antichlolinergic symptoms.
Caffeine
Symptoms: Common features include CNS stimulation; anxiety, nervousness, restlessness, insomnia, excitement, muscle twitching, confusion, convulsions. Cardiac symptoms include tachycardia, cardiac arrhythmia. Gastric symptoms include abdominal or stomach pains. Other symptoms of caffeine overdose include diuresis and facial flushing.
Treatment: Treatment of caffeine overdose is primarily symptomatic and supportive. Diuresis should be treated by maintaining fluid and electrolyte balance and CNS symptoms can be controlled by intravenous administration of diazepam.
