NEW AMFELU^® DAY TIME + C

Prescription only.

Keep out of the reach of children.

Read carefully the enclosed insert before use.

In case of any unexpected reaction consult your doctor or pharmacist.

PART I. INFORMATION LEAFLET FOR PATIENT

1. COMPOSITION: Each film coated tablet contains:

Active ingredients:

Acetaminophen…………………………. 500 mg

Guaifenesin………………………………. 200 mg

Phenylephrine HCl……………………. 10 mg

Dextromethorphan HBr……………… 15 mg

Vitamin C………………………………… 100 mg

Excipients: Maize starch, pregelatinized starch, povidone K30, sodium starch glycolate, talc, magnesium stearate, colloidal silicon dioxide (aerosil 200), anhydrous citric acid, sunset yellow lake, opadry orange AMB.

2. DESCRIPTION OF PRODUCT:

Orange, oblong-shaped, film coated tablet, printed                   in black on both sides.

3. DESCRIPTION OF PACKAGING:

Box of 1 blister x 10 film coated tablets.

Box of 10 blisters x 10 film coated tablets.

Box of 20 blisters x 10 film coated tablets.

4. WHAT IS THE MEDICINE USED FOR:

It is used to relieve the symptoms of flu and common cold:

– Fever             – Aches and pains        – Headache

– Cough           – Sore throat          – Nasal congestion (stuffy), runny nose

– Helps loosen phlegm (mucus) and thin bronchial secretions to make coughs more productive.

5. HOW MUCH AND HOW OFTEN SHOULD YOU USE THIS MEDICINE:

Administration: Oral administration.

Dosage:

– Adults and children from 12 years and older: Take 1 tablet every 6 hours. Do not take more than 6 tablets in 24 hours.

– Children (6-12 years): ½ tablet every 6 hours, not to exceed 3 tablets in 24 hours

6. WHEN SHOULD YOU NOT TAKE THIS MEDICINE:

Do not use this drug if you:

– Known hypersensitivity to any ingredients of this product.

– Receiving MAOIs (see Drug interaction section).

– Coronary disease and severe hypertension.

– G6DP insufficiency.

– Severe hepatic failure, nephrolithiasis, hyperoxaluria and disorders of oxalate metabolism.

– Children under 6 years.

7. SIDE EFFECTS:

There are rare cases of allergy such as: Skin rash, erythema, urticaria. Other side effects are restlessness, insomnia, hypertension, hyperoxaluria, arrhythmia, heart failure, thrombocytopenia, haemolytic anaemia, hepatic failure, dizziness, headache, nausea, vomiting, gastric irritation, tremor, weakness, hallucinations and difficulty breathing.

8. WHAT OTHER MEDICINE OR FOOD SHOULD BE AVOIDED WHILST TAKING THIS MEDICINE:

Consult your doctor before using this drug if you are taking one of the following medicines:

• Monoamine oxidase inhibitors (MAOIs) (certain drugs for depression, psychiatric or emotional conditions, or parkinson’s disease), or for 2 weeks after stopping the MAOI drug.
• Anticonvulsants (phenytoin, barbiturate, carbamazepine), isoniazid.
• Other sympathomimetic amines.
• Beta-blocking drugs and antihypertensive drugs (including debrisoquine, guanethidine, reserpine, methyldopa).
• Tricyclic antidepressants (e.g. amitriptyline, imipramine).
• Ergot alkaloids (ergotamine and methylsergide).
• Central nervous system inhibitors.
• Preparation containing elemental iron.
• Vitamin B12.

9. WHAT SHOULD YOU DO IF YOU MISS A DOSE:

If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

10. HOW SHOULD YOU KEEP THIS MEDICINE:

Store at temperature from 15^oC to 30^oC, in a dry place and protect from light.

11. SIGNS AND SYMPTOMS OF OVERDOSE:

Symptoms of acetaminophen overdose: Nausea, vomiting and abdominal pain (normally settle within 24 hours of ingestion). After 24 hours symptoms may include right subcostal pain and tenderness, usually indicates development of hepatic necrosis. Liver damage is greatest 3-4 days after ingestion and may lead to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death.

Symptoms of phenylephrine HCl overdose: Hypertension, headache, convulsions, cerebral haemorrhage, palpitation, slow heart rate.

Symptoms of dextromethorphan HBr overdose: Nausea, vomiting, somnolence, blurred vision, nystagmus, urinary retention, euphoria, hallucination, ataxia, respiratory failure and convulsion

Symptoms of Vitamin C overdose: Nephrolithiasis, nausea, gastritis and diarrhea.

An overdose of Guaifenesin is not likely to cause life-threatening symptoms.

12. WHAT TO DO WHEN YOU HAVE TAKEN MORE THAN THE RECOMMENDED DOSAGE:

Talk to your doctor or go to a hospital straight away.

Remember to take medicine that is left with you or medicine pack so the doctor knows what you have taken.

13. PRECAUTIONS THAT SHOULD BE TAKEN WHEN TAKING THIS MEDICINE:

• Can cause rare but serious skin reactions, can cause death including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), or Lyell Syndrome, acute generalized exanthematous pustulosis (AGEP).
• Description of above syndromes:

+ Steven-Johnson syndrome (SJS): drug allergies can be bullous, bullae localize around the natural cavities: the face, nose, mouth, ears, genitals and anus. Also may include high fever, pneumonia, liver, kidney dysfunction. Diagnosis of Steven-Johnson syndrome (SJS) when at least two natural cavities injured.

+ Toxic epidermal necrolysis (TEN) is the most severe allergic reactions can include:

• The diversity in skin lesions: morbilliform erythema, scarlatinoid erythema, erythema or bullous erythema, the lesions rapidly spread throughout the body;
• Ophthalmic mucosa lesions: corneal inflammation, purulent conjunctivitis, corneal ulcer.
• Injury to gastrointestinal mucosa: stomatitis, erosive oral mucosa, ulceration of pharynx, throat, esophagus, stomach, intestines;
• Injury to the genital, urinary mucosa.
• There are also the serious systemic symptoms such as fever, gastrointestinal bleeding, pneumonia, glomerulonephritis, hepatitis,… high mortality rate: 15-30%.

+ Acute generalized exanthematous pustulosis (AGEP): small, sterile pustules, arising within large areas of erythema. Lesions usually appear in the folds like the underarms, groin and face, then can spread throughout the body. Usual systemic symptoms of fever, neutrophilia in blood test

When detecting first signs of skin rash or any other hypersensitivity reaction, patients should stop using the drug. Patients with history of severe skin reaction caused by acetaminophen, do not take again, inform the medical staff when having medical care.

Do not use with any other product containing acetaminophen.

Ask a doctor before use if you have: Heart disease, liver disease, diabetes, hyperthyroidism. Cough that occurs with too much phlegm (mucus), high blood pressure, renal failure, glaucoma, hyperoxaluria, trouble urinating due to enlarged prostate gland. Chronic cough that lasts as occurs with smoking, asthma, chronic bronchitis or emphysema.

Stop use and ask a doctor if:

– New symptoms occur.

– Redness or swelling is present.

– Pain, nasal congestion, or cough gets worse or lasts more than 7 days.

– Fever gets worse or lasts for more than 3 days.

– You get nervous, dizzy or sleepless.

– Cough comes back or occurs with fever, rash or headache that lasts.

These could be signs of a serious condition.

– Vitamin C – Related: Do not take high dose of vitamin C which exceeds 1g/24 hours. Due to a mild stimulant effect, it is preferable not to take the drug at the end of the day.

This drug contains: Sunset yellow lake which may cause allergic reactions.

Pregnancy: Do not use this medicine during pregnancy.

Lactation: Do not use this medicine during breastfeeding.

Effects on ability to work: Cautiously use when driving vehicle, operating machinery, working at height and other activities.

14. WHEN SHOULD YOU CONSULT YOUR DOCTOR OR PHARMACIST:

In case of overdosage or adverse drug reactions.

When you are taking other drugs or foods.

For further information, consult your doctor or pharmacist.

15. SHELF-LIFE OF DRUG: 36 months from manufacturing date. Do not use after expiry date.

PART II. INFORMATION LEAFLET FOR HEALTHCARE PROFESSIONALS

1. PHARMACODYNAMICS:

Pharmacotherapeutic group and ATC code:

Acetaminophen: Analgesics and antipyretics; N02BE01.

Guaifenesin: Expectorants; R05CA03.

Phenylephrine HCl: α₁ sympathomimetic agent; R01BA03.

Dextromethorphan HBr: Cough suppressants; R05DA09.

Vitamin C: Vitamin; A11GA01.

Acetaminophen is the active metabolite of phenacetin, exhibits analgesic action by peripheral blockage of pain impulse generation. It produces antipyresis by inhibiting the hypothalamic heat-regulating centre.

Guaifenesin is an expectorant, the action of which promotes or facilitates the removal of secretions from the respiratory tract.

Phenylephrine HCl is a sympathomimetic with mainly direct effects on alpha₁ adrenergic receptors, causes vasoconstriction, reduces nasal congestion and sinusitis.

Dextromethorphan HBr is a cough suppressant, which has a central action on the cough centre in the medulla. It has no analgesic properties and little sedative activity.

Vitamin C, a water-soluble vitamin, is essential for the synthesis of collagen and connective tissue components. Ascorbic acid is capable of reducing in many biological redox reactions, including the biosynthesises of collagen, carnitin, catecholamines, tyrosine, corticosteroids and aldosterone. ascorbic acid can regulate prostaglandin synthesis for the effects of bronchodilator, vasodilatation, anticoagulation and aggregation, the ability to convert folic acid into folinic acid, carbohydrate metabolism, synthesis of lipids, proteins, resistance to infections and cellular respiration.

2. PHARMACOKINETICS:

Acetaminophen is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 30 to 60 minutes after oral dose. Acetaminophen is distributed into most body tissues. It crosses placenta and is present in breast milk. Plasma protein binding is negligible at usual therapeutic concentration but increases with increasing concentrations. The elimination half-time varies from about 1 to 3 hours. Acetaminophen is metabolised predominantly in the liver and excreted in the urine mainly as the glucuronide (about 60-80%) and sulfate (about 20-30%) conjugates. Less than 5% is excreted as unchanged acetaminophen. A minor (below 4%) metabolite is usually produced in very small amounts by cytochrom P450.

Guaifenesin is well absorbed from the gastrointestinal tract. It is metabolised and then excreted in the urine.

Phenylephrine HCl is irregularly absorbed from the gastrointestinal tract and undergoes first-pass metabolism by monoamine oxidase in the gut and liver. It is almost entirely excreted in the urine.

Dextromethorphan HBr is rapidly absorbed from the gastrointestinal tract and has effect in 15 – 30 minutes after oral doses, duration is about 6-8 hours. It is metabolised in the liver and excreted in the urine as unchanged dextromethorphan and demethylated metabolites including dextrorphan, which has some cough suppressant activity.

Vitamin C is easily absorbed after oral dose. Vitamin C is widely distributed in body tissues with about 25% of the vitamin C in plasma is bound to proteins. Vitamin C crosses the placenta and is distributed into the breast milk. Vitamin C is reversibly oxidized to dehydroascorbic acid. Some vitamin C is metabolized to inactive compounds including ascorbic acid-2-sulfate and oxalic acid which are excreted in the urine. Vitamin C in excess of the body’s needs is rapidly eliminated in the urine.

3. INDICATIONS:

It is indicated to relieve the symptoms of flu and common cold:

– Fever             – Aches and pains        – Headache

– Cough           – Sore throat            – Nasal congestion (stuffy), runny nose

– Helps loosen phlegm (mucus) and thin bronchial secretions to make coughs more productive.

4. DOSAGE AND ADMINISTRATION:

Administration: Oral administration

Dosage:

– Adults and children from 12 years and older: Take 1 tablet every 6 hours. Do not take more than 6 tablets in 24 hours.

– Children (6-12 years): ½ tablet every 6 hours, not to exceed 3 tablets in 24 hours.

5. CONTRAINDICATIONS:

– Patients with known hypersensitivity to any ingredients of this product.

– Patients who are receiving MAOIs (see Drug interaction section).

– Patients with coronary disease and severe hypertension.

– G6DP insufficiency.

– Patients with severe hepatic failure, nephrolithiasis, hyperoxaluria and disorders of oxalate metabolism.

– Children under 6 years.

6. WARNINGS AND PRECAUTIONS:

Special precaution and warning when using medication containing acetaminophen: The doctor must warn the patients about the symptoms of serious skin reactions including: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), or Lyell Syndrome, acute generalized exanthematous pustulosis (AGEP).

Do not use with any other product containing acetaminophen.

Ask a doctor before use if you have: Heart disease, liver disease, diabetes, hyperthyroidism. Cough that occurs with too much phlegm (mucus), high blood pressure, renal failure, glaucoma, hyperoxaluria, trouble urinating due to enlarged prostate gland. Chronic cough that lasts as occurs with smoking, asthma, chronic bronchitis or emphysema.

Stop use and ask a doctor if:

– New symptoms occur.

– Redness or swelling is present.

– Pain, nasal congestion, or cough gets worse or lasts more than 7 days.

– Fever gets worse or lasts for more than 3 days.

– You get nervous, dizzy or sleepless.

– Cough comes back or occurs with fever, rash or headache that lasts.

These could be signs of a serious condition.

– Vitamin C – Related: Do not take high dose of vitamin C which exceeds 1g/24 hours. Due to a mild stimulant effect, it is preferable not to take the drug at the end of the day.

This drug contains: Sunset yellow lake which may cause allergic reactions.

Pregnancy:

Acetaminophen: Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use.

Guaifenesin: The safety of guaifenesin in pregnancy has not been fully established but this constituent is not thought to be hazardous. However the product should only be used in pregnancy when considered essential by the doctor.

Phenylephrine HCl: Due to the vasconstrictive properties of phenylephrine, the product should be used with caution in patients with a history of pre-eclampsia. Phenylephrine may reduce placental perfusion and the product should be used in pregnancy only if the benefits outweigh this risk. The safety of phenylephrine during pregnancy has not been established.

Dextromethorphan HBr: There is no or inadequate evidence of the safety of dextromethorphan in human pregnancy and therefore dextromethorphan should not be used during this period.

Vitamin C: Vitamin C crosses the placenta, concentration of vitamin C in umbilical cord blood higher 2 – 4 times than the maternal blood. No matter what happens in human if you take vitamin C according to normal daily requirement. However, ingestion of large amounts of vitamin C during pregnancy may result in increased requirements and scurvy in neonate.

Lactation:

Acetaminophen: Paracetamol is excreted in breast milk but not in a clinically significant amount. This product should not be used whilst breast feeding without medical advice.

Guaifenesin: The safety of guaifenesin in pregnancy has not been fully established but this constituent is not thought to be hazardous.

Phenylephrine HCl: Phenylephrine is excreted in breast milk but not in a clinically significant amount. There is no information on use in lactation. This product should not be used whilst breast feeding without medical advice.

Dextromethorphan HBr: No information is available on the secretion of dextromethorphan into breast milk and it is recommended that the product should not be used by breast feeding mothers.

Vitamin C: Vitamin C is distributed into breast milk. Problems in neonate have not been documented with intake of normal requirements containing 40 – 70 micrograms vitamin C/ml to lactating women.

Effects on ability to work: Cautiously use when driving vehicle, operating machinery, working at height and other activities.

7. INTERACTIONS:

• Do not take this product if you are now taking a prescription of monoamine oxidase inhibitors (MAOIs) (certain drugs for depression, psychiatric or emotional conditions, or parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.
• Anticonvulsants (phenytoin, barbiturate, carbamazepine), isoniazid may increase the hepatotoxicity of acetaminophen.
• Concomitant use of phenylephrine with other sympathomimetic amines can increase the risk of cardiovascular side effects.
• Phenylephrine may reduce the efficacy of beta-blocking drugs and antihypertensive drugs (including debrisoquine, guanethidine, reserpine, methyldopa). The risk of hypertension and other cardiovascular side effects may be increased.
• Tricyclic antidepressants (e.g. amitriptyline, imipramine): May increase the risk of cardiovascular side effects with phenylephrine.
• Concomitant use of phenylephrine with ergot alkaloids (ergotamine and methylsergide): Increase the risk of ergotism.
• Concomitant use of phenylephrine with digoxin: Increase the risk of irregular heartbeat or heart attack.
• Concomitant use of phenylephrine with atropine will block the reflex bradycardia that phenylephrine causes.
• Concomitant use of dextromethorphan and CNS inhibitors may increase the CNS inhibition of these drugs.
• Quinidine inhibits cytochrome P450 2D6 and markedly increases the plasma levels of dextromethorphan which causes increased side effects of dextromethorphan.
• Concurrent administration of more than 200 mg of vitamin C and 30 mg of elemental iron increases the absorption of iron from the GI tract.
• Increased urinary excretion of vitamin C and decreased excretion of aspirin occur when the drugs are administered concurrently.
• Concurrent administration of vitamin C and fluphenazine may result in decreased plasma concentration of fluphenazine.
• Large dose of vitamin C may destroy vitamin B12.

8. SIDE EFFECTS

There are rare cases of allergy such as: Skin rash, erythema, urticaria. Other side effects are restlessness, insomnia, hypertension, hyperoxaluria, arrhythmia, heart failure, thrombocytopenia, haemolytic anaemia, hepatic failure, dizziness, headache, nausea, vomiting, gastric irritation, tremor, weakness, hallucinations and difficulty breathing.

9. OVERDOSE AND TREATMENT:

Acetaminophen

Symptoms: Nausea, vomiting and abdominal pain (normally settle within 24 hours of ingestion). After 24 hours symptoms may include right subcostal pain and tenderness, usually indicates development of hepatic necrosis. Liver damage is greatest 3-4 days after ingestion and may lead to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death.

Treatment: Treatment is based on plasma concentration. Acetylcysteine protects the liver if administered within 24 hr after ingestion (most effective if given within 8 hours). Dose: 140 mg/kg orally (loading) followed by 70 mg/kg every 4 hours for 17 doses. Activated charcoal or gastric lavage may be treated to decrease absorption of acetaminophen.

Phenylephrine HCl

Symptoms: Hypertension, headache, convulsions, cerebral haemorrhage, palpitation, slow heart rate.

Treatment: Should provide symptomatic and supportive care

Dextromethorphan HBr

Symptoms Nausea, vomiting, somnolence, blurred vision, nystagmus, urinary retention, euphoria, hallucination, ataxia, respiratory failure and convulsion.

Treatment: Symptomatic and supportive treatment, can administer intravenous injection of naloxon 2 mg, to be repeat if necessary.

Vitamin C

Symptoms: Nephrolithiasis, nausea, gastritis and diarrhea.

Treatment: Forced diuresis by infusion may be effective after taking large doses.

An overdose of Guaifenesin is not likely to cause life-threatening symptoms.

10. SIGNS SHOULD BE NOTED AND RECOMMENDATIONS:

Do not exceed recommended dosage.