Fludrex syrup is used for the relief of symptoms associated with colds and flu; including relief of nasal congestion, runny nose, fever, headache and pains.

The usual dose is as follows, to be taken orally:

Children 6-12 years: Two teaspoonful (10 ml), 3 times daily (every 8 hours).

For patients 12 years old and above: one FLUDREX tablet 3 times daily (every 8 hours) or according to physician’s prescription.

Do not exceed the stated dose

Known hypersensitivity to Chlorpheniramine maleate, paracetamol and pseudoephedrine or to any of the excipients listed in section 6.1. Concomitant use of other sympathomimetic decongestants, beta-blockers (see section 4.5) or monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOI treatment (see section 4.5). The concomitant use of MAOIs may cause a rise in blood pressure or hypertensive crisis. Cardiovascular disease including hypertension Diabetes mellitus Phaeochromocytoma Hyperthyroidism Closed angle glaucoma Severe renal impairment Not to be used in children under the age of 6 years.

As both Chlorpheniramine maleate and pseudoephedrine have been associated with central nervous system adverse events (see section 4.8), there is a possibility that the risk of experiencing such adverse events may be increased by use of the combination.

Chlorpheniramine maleate may enhance the sedative effects of central nervous system depressants including alcohol, sedatives, opioid analgesics, antipsychotics and tranquilizers. Alcoholic beverages should be avoided while taking this product.

If any of the following occur, Fludrex syrup should be stopped

• Hallucinations

• Restlessness

• Sleep disturbances

Severe Skin reactions: Severe skin reactions such as acute generalized exanthematous pustulosis (AGEP) may occur with pseudoephedrine-containing products. This acute pustular eruption may occur within the first 2 days of treatment, with fever, and numerous, small, mostly non-follicular pustules arising on a widespread oedematous erythema and mainly localized on the skin folds, trunk, and upper extremities. Patients should be carefully monitored. If signs and symptoms such as pyrexia, erythema, or many small pustules are observed, administration of this medicine should be discontinued, and appropriate measures taken if needed.

Ischaemic colitis: Some cases of ischaemic colitis have been reported with pseudoephedrine. Pseudoephedrine should be discontinued and medical advice sought if sudden abdominal pain, rectal bleeding or other symptoms of ischaemic colitis develop.

There have been rare cases of posterior reversible encephalopathy syndrome (PRES) / reversible cerebral vasoconstriction syndrome (RCVS) reported with sympathomimetic drugs, including pseudoephedrine. Symptoms reported include sudden onset of severe headache, nausea, vomiting, and visual disturbances. Most cases improved or resolved within a few days following appropriate treatment. Pseudoephedrine should be discontinued, and medical advice sought immediately if signs or symptoms of PRES/RCVS develop.

Patients with the following conditions should be advised to consult a physician before using this product:

• Acute or chronic asthma, a persistent or chronic cough such as occurs with chronic bronchitis or emphysema or where cough is accompanied by excessive secretions

• Prostatic hyperplasia, urinary retention

• Patients with thyroid disease who are receiving thyroid hormones

Use with caution in patients with susceptibility to angle-closure, moderate to severe renal impairment, severe hepatic impairment (particularly if accompanied by cardiovascular disease) or occlusive vascular disease. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.

Do not use with any other product containing Chlorpheniramine maleate, including topical formulations used on large areas of skin.

Taking this product with other paracetamol-containing products could lead to overdose and should therefore be avoided.

May cause drowsiness (see section 4.8). This product should not be used to sedate a child.

This medicine contains Sunset yellow (E110). This may cause allergic reactions.

 CNS depressants: Chlorpheniramine maleate may enhance the sedative effects of CNS depressants including barbiturates, hypnotics, opioid analgesics, anxiolytic sedatives, antipsychotics and alcohol.

• Antimuscarinic drugs: Chlorpheniramine maleate may have an additive muscarinic action with other drugs, such as atropine and tricyclic antidepressants. This may result in tachycardia, mouth dryness, gastrointestinal disturbances (e.g. colic), urinary retention and headache.

• MAOIs (see section 4.3) and/or RIMAs: Pseudoephedrine exerts its vasoconstricting properties by stimulating α -adrenergic receptors and displacing noradrenaline from neuronal storage sites. Since monoamine oxidase inhibitors (MAOIs) impede the metabolism of sympathomimetic amines and increase the store of releasable noradrenaline in adrenergic nerve endings, MAOIs may potentiate the pressor effect of pseudoephedrine. This product should not be used in patients taking MAOIs or within 14 days of stopping treatment as there is a risk of serotonin syndrome (diphenhydramine) or hypertensive crisis (pseudoephedrine).

• Moclobemide: risk of hypertensive crisis.

• Antihypertensives: because of its pseudoephedrine content, this product may partially reverse the hypotensive action of antihypertensive drugs which interfere with sympathetic activity including bretylium, betanidine, guanethidine, debrisoquine, methyldopa, adrenergic neurone blockers and beta-blockers Cardiac glycosides: increased risk of dysrhythmias

• Ergot alkaloids (ergotamine & methysergide): increased risk of ergotism

• Appetite suppressants and amphetamine-like psychostimulants Concomitant use of this product with sympathomimetic agents, such as decongestants, tricyclic antidepressants, appetite suppressants and amphetamine-like psychostimulants, may cause a rise in blood pressure. Oxytocin – risk of hypertension

• Anaesthetic agents: Concurrent use with halogenated anaesthetic agents such as chloroform, cyclopropane, halothane, enflurane or isoflurane may provoke or worsen ventricular arrhythmias

Chronic alcohol intake can increase the hepatotoxicity of paracetamol overdose and may have contributed to the acute pancreatitis reported in one patient who had taken an overdose of paracetamol. Acute alcohol intake may diminish an individual's ability to metabolise large doses of paracetamol, the plasma half-life of which can be prolonged.

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone, and absorption reduced by colestyramine.

The anticoagulant 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.

The use of drugs which induce hepatic microsomal enzymes, such as anticonvulsants and oral contraceptive steroids, may increase the extent of metabolism of paracetamol, resulting in reduced plasma concentrations of the drug and a faster elimination rate

Pregnancy

This medicine, like most medicines should not be used during pregnancy unless the potential benefit of treatment to the mother outweighs any possible risk to the developing foetus.

Paracetamol, pseudoephedrine and Chlorpheniramine maleate have been in widespread use for many years without any apparent ill consequence. A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency. The safety of pseudoephedrine in pregnancy has not been established. Chlorpheniramine maleate is known to cross the placenta and, therefore should only be used during pregnancy if considered essential by a doctor.

Breast-feeding

Pseudoephedrine is excreted in breast milk in small amounts, but the effect of this on breast-fed infants is not known. It has been estimated that approximately 0.4 to 0.7% of a single 60mg dose of pseudoephedrine ingested by a nursing mother will be excreted in the breast milk over 24 hours.

Data from a study of lactating mothers taking 60 mg pseudoephedrine every 6 hours suggests that from 2.2 to 6.7% of the maximum daily dose (240 mg) may be available to the infant from a breastfeeding mother.

Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding. A pharmacokinetic study of paracetamol in 12 nursing mothers revealed that less than 1% of a 650mg oral dose of paracetamol appeared in the breast-milk. Similar findings have been reported in other studies, therefore maternal ingestion of therapeutic doses of paracetamol does not appear to present a risk to the infant.

Chlorpheniramine maleate is excreted into human breast milk, but levels have not been reported. Although the levels are not thought to be sufficiently high enough after therapeutic doses to affect the infant, the use of Chlorpheniramine maleate during breast-feeding is not recommended.

Fludrex syrup may cause drowsiness. If patients are affected they should not drive or use machinery

Adverse drug reactions (ADRs) identified during clinical trials and post-marketing experience with Chlorpheniramine maleate, paracetamol, pseudoephedrine or the combination are included below by System Organ Class (SOC).

The frequencies are defined according to the following convention:

Very common ≥1/10

Common ≥1/100 and < 1/10

Uncommon ≥1/1,000 and <1/100

Rare ≥1/10,000 and <1/1,000

Very rare <1/10,000

Not known (cannot be estimated from the available data)

ADRs are presented by frequency category based on 1) incidence in adequately designed clinical trials or epidemiology studies, if available, or 2) when incidence cannot be estimated, frequency category is listed as 'Not known'.

 

 

System Organ Class (SOC)	Frequency	Adverse Drug Reaction (Preferred Term)
Blood and lymphatic system disorders	Rare	Blood disorders, blood dyscrasias (including thrombocytopenia and agranulocytosis) have been reported following paracetamol use, but were not necessarily causally related to the drug
Immune system disorders	Rare	Hypersensitivity ( cross-sensitivity may occur with other sympathomimetics
Psychiatric disorders	Rare	Hypersensitivity ( cross-sensitivity may occur with other sympathomimetics)
	Common	Insomnia Nervousness
	Uncommon	Confusional state Irritability
	Rare	Depression Sleep disorder
	Not known	Anxiety Euphoric mood Excitability Hallucinations Paranoid delusions Restlessness
Nervous system disorders	Very common	Headache Somnolence Sedation
	Common	Dizziness Paradoxical stimulation Psychomotor impairment
	Rare	Extrapyramidal disorder Seizure Tremor
	Not known	Cerebrovascular accident Paraesthesia Posterior reversible encephalopathy syndrome (PRES)/reversible cerebral vasoconstriction syndrome (RCVS) Psychomotor hyperactivity
Eye disorders	Common	Vision blurred
Ear and labyrinth disorders	Uncommon	Tinnitus
Cardiac disorders	Rare	Palpitations
	Not known	Dysrhythmias Myocardial infarction/myocardial ischaemia Tachycardia
Vascular disorders	Rare	Hypotension
	Not known	Hypertension
Respiratory, thoracic and mediastinal disorders	Common	Increased viscosity of bronchial secretions
	Not known	Dyspnoea Nasal dryness
Gastrointestinal disorders	Common	Dry mouth Gastrointestinal disorder Nausea
	Not known	Ischaemic colitis Vomiting
Hepato-biliary disorders	Rare	Liver disorder
Skin and subcutaneous tissue disorders	Uncommon	Rash
	Not known	Angioedema Erythema Pruritus Rash pruritic Serious skin reactions, including acute generalised exanthematous pustulosis (AGEP) Urticaria
Renal and urinary disorders	Common	Urinary retention (in men in whom prostatic enlargement could have been an important predisposing factor)
	Not known	Dysuria
General disorders and administration site conditions	Common	Asthenia
	Not known	Chest discomfort

 

To report any side effect(s):

·   Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC) § Fax: +966-11-205-7662 § Call NPC at: +966-11-2038222, Ext.: 2317-2356-2353-2354-2334-2340. § Toll free phone: 8002490000 § E-mail: npc.drug@sfda.gov.sa                                                   Website: www.sfda.gov.sa/npc

·   In massive over dosage exceeding 10 g of paracetamol may cause liver damage. Early symptoms may include pallor, nausea, vomiting, (diaphoresis) and general malaise.

·   Clinical and laboratory evidence of liver damage may not be apparent until 48 to 72 hours past ingestion. Overdose should be promptly treated by gastric lavage followed by intravenous

N-acetylcysteine or methionine without waiting for the results of plasma paracetamol levels.

·   Additional antidote therapy is normally considered in light of further plasma paracetamol levels and the time elapsed since ingestion. In all cases of suspected overdose, prompt medical attention is critical for adults as well as for children, even if you do not notice any signs or symptoms.

Mode of Action of each ingredient:

ATC code:

·   Paracetamol:  N02BE01  

·   Pseudoephedrine: R01BA02

·   Chlorphenamine maleate: R06AB04 

 

Paracetamol: based on the inhibition of prostaglandin biosynthesis.

Pseudoephedrine: has direct and indirect sympathomimetic activity and is an effective upper respiratory decongestant. Pseudoephedrine is less potent than ephedrine in producing both tachycardia and elevation of systolic blood pressure and is also less potent in causing stimulation of the central nervous system. Pseudoephedrine produces its decongestant effect within 30 minutes, persisting for at least 4 hours.

Chlorphenamine maleate: potent antihistamine (H1-antagonist). Antihistamines diminish or abolish the actions of histamine in the body by competitive reversible blockade of histamine H1-receptor sites on tissues. Chlorphenamine also has anticholinergic activity.

Antihistamines act to prevent the release of histamine, prostaglandins and leukotrienes and have been shown to prevent the migration of inflammatory mediators. The actions of chlorphenamine include inhibition of histamine on smooth muscle, capillary permeability and hence reduction of oedema and wheal in hypersensitivity reactions such as allergy and anaphylaxis

ABSORPTION

Paracetamol: is rapidly and almost completely absorbed from the gastrointestinal tract.

Pseudoephedrine: the C max of pseudoephedrine was approximately 180 ng/ml with tmax occurring at approximately 1.5 hours for the syrup after drug administration.

Chlorphenamine maleate: is well absorbed from the gastro-intestinal tract, following oral administration. The effects develop within 30 minutes, are maximal within 1 to 2 hours and last 4 to 6 hours. The plasma half-life has been estimated to be 12 to 15 hours

 

DISTRIBUTION

The apparent volume of distribution of pseudoephedrine (Vd/F) was approximately 2.8 l/kg.

 

METABOLISM AND ELIMINATION

Paracetamol: The concentration in plasma reaches a peak in 30 to 60 minutes and the plasma half-life is 1 - 4 hours after therapeutic doses. Paracetamol is relatively uniformly distributed throughout most body fluids. Binding of the drug to plasma proteins is variable; 20 to 30% may be bound at the concentrations encountered during acute intoxication. Following therapeutic doses 90 - 100% of the drug may be recovered in the urine within the first day. However, practically no paracetamol is excreted unchanged and the bulk is excreted after hepatic conjugation.

Pseudoephedrine: the t½ was approximately 5.5 hours. Pseudoephedrine is partly metabolised in the liver by N-demethylation to norpseudoephedrine, an active metabolite. Pseudoephedrine and its metabolite are excreted in the urine; 55% to 90% of a dose is excreted unchanged. The apparent total body clearance of pseudoephedrine (Cl/F) was approximately 7.5 ml/min/kg. The elimination rate constant (Kel) was approximately 0.13 h-1. The rate of urinary elimination is accelerated when the urine is acidified. Conversely, as the urine pH increases, the rate of urinary elimination is slowed.

Chlorphenamine: is metabolised to the monodesmethyl and didesmethyl derivatives. About 22% of an oral dose is excreted unchanged in the urine.

 

There is insufficient information available to determine whether some of the active ingredients have mutagenic, carcinogenic, teratogenic potential, or the potential to impair fertility.

Citric acid monohydrate

Sodium Benzoate

Disodium Edetate

Saccharin Sodium

Sucrose

Glycerol

Povidone K25

Sorbitol solution 70%

cherry flavor

Erythrosine E127

banana flavor

Purified water

None reported.

3 years from the manufacturing date. The expiry date refers to the last day of the month.

·   Keep in a safe place, out of the reach and sight of children.

·   Store below 30º C, Protect from light.

It is available in an amber colored type III glass bottle and provided with child resistant cap.

No special requirements.