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Pinex Jordgubb

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Document: Pinex Jordgubb 500 mg granules in sachets ENG SmPC change

1. NAME OF THE MEDICINAL PRODUCT


/…/ 500 mg granules in sachets


2. QUALITATIVE AND QUANTITATIVE COMPOSITION


One sachet contains 500 mg paracetamol.


Excipients with known effect:

Contains sorbitol (E420) 801 mg/sachet.

Contains sucrose 0.14 mg/sachet.


For the full list of excipients, see section 6.1.


3. PHARMACEUTICAL form


Granules in sachets


White or almost white granules.


4. Clinical particulars


4.1 Therapeutic indications


/…/ is used for symptomatic treatment of mild to moderate pain and fever.


4.2 Posology and method of administration


Posology

Doses depend on body weight and age; a single dose ranges from 10 to 15 mg/kg body weight to a maximum of 60-75 mg/kg for total daily dose.

The specific dose interval depends on the symptoms and the maximum daily dose. It should, however, not fall below 4 hours.


Don`t use /…/ longer than three days without medical advice.


500 mg sachets

Body weight (age)

single dose [sachet]

max. daily dose [sachets]

26 kg – 40 kg

(8 years -12 years)

500 mg Paracetamol (1 sachet)

1500 mg Paracetamol (3 sachets)

> 40 kg

(children over 12 years and adults)

500 - 1000 mg Paracetamol (1 – 2 sachets)

3000 mg Paracetamol ( 6 sachets of 500 mg)

Special groups of patients:


Impaired liver or kidney function

In patients with impaired hepatic or renal function or Gilbert’s syndrome, the dose must be reduced or the dosing interval prolonged.


Patients with impaired renal function

In patients with severe renal insufficiency (creatinine clearance < 10 ml/min), a dosing interval of at least 8 hours must be maintained.


Chronic alcoholism

Chronic alcohol consumption may lower the paracetamol toxicity threshold. In these patients, the length of time between two doses should be a minimum of 8 hours. 2 g paracetamol per day should not be exceeded.


Elderly patients

Dose adjustment is not required in the elderly.


Children and adolescents with small body weight

Paracetamol 500 mg sachets

Paracetamol 500 mg sachets are not suitable for children under 8 years of age and under 26 kg body weight respectively. For this patient group other formulations and dose strength are available.


For all indications:

Adults, the elderly and children aged over 12 years: The usual dose is 500 – 1000mg every 4 to 6 hours up to a maximum of 3g daily.

The dose should not be repeated more frequently than every four hours.


Renal Insufficiency

In case of renal insufficiency the dose should be reduced:

Glomerulal filtration

Dose

10 – 50 ml/min

500 mg every 6 hours

< 10 ml/min

500 mg every 8 hours

The daily effective dose must be considered, without exceeding 60 mg/kg/day (without exceeding 3 g/day) in the following situations:


Adults weighing less than 50 kg,

Hepatocellular insufficiency (mild to moderate)

Chronic alcoholism

Dehydration

Chronic malnutrition

Impaired liver or kidney function


In patients with impaired hepatic or renal function or Gilbert’s syndrome, the dose must be reduced or the dosing interval prolonged.”


The sachet is not recommended in children younger than 4 years; older children (4 – 12 years) may be given 250 – 500mg every 4 – 6 hours up to a maximum of 4 doses in 24hours


Method of administration

For oral use only. The granules should be taken directly into the mouth onto the tongue and should be swallowed without water.

Do not take /…/ at a fed state.


4.3 Contraindications


Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.


4.4 Special warnings and precautions for use


In order to avoid the risk of overdose, it should be ensured that any concurrent medication does not contain paracetamol.


Paracetamol should be administered only with particular caution under the following circumstances:


If high fever or signs of secondary infection occur or if symptoms persist for longer than 3 days, a physician should be consulted.


In general, medicinal products containing paracetamol should be taken for only a few days without the advice of a physician or dentist and not at high doses.


After long term treatment (> 3 months) of analgesics with use every second day or more frequently, headache may develop or aggravate. Headache caused by overuse of analgesics (MOH - medication-overuse headache) should not be treated by increasing the dose. In such cases the use of analgesics should be discontinued in consultation with a doctor.


In general, habitual intake of analgesics, particularly a combination of several analgesic substances, can lead to permanent renal damage with the risk of renal failure (analgesic nephropathy).


Prolonged or frequent use is discouraged. Patients should be advised not to take other paracetamol containing products concurrently. Taking multiple daily doses in one administration can severely damage the liver; in such case unconsciousness does not occur. However, medical assistance should be sought immediately. Prolonged use except under medical supervision may be harmful. In children treated with 60mg/kg daily of paracetamol, the combination with another antipyretic is not justified except in the case of ineffectiveness.


Abrupt discontinuation following long-term, high-dose, incorrect use of analgesics may lead to headaches, fatigue, muscle pain, nervousness and autonomic symptoms. These withdrawal symptoms resolve within a few days. Until this time, further intake of analgesics should be avoided and not restarted without medical advice.


Caution should be exercised when paracetamol is used in combination with CYP3A4 inducers or use of substances that induce liver enzymes such as rifampicin, cimetidine, antiepileptics such as glutethimide, phenobarbita land carbamazepine.


Caution is advised in the administration of paracetamol to patients with severe renal insufficiency (creatinine clearance 30mL/min (see section 4.2)) or hepatocellular insufficiency (mild to moderate).

Alcohol should not be used during the treatment with paracetamol.


The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Caution should be exercised in cases of chronic alcoholism. In patients with alcohol abuse the dose has to be reduced (see section 4.2). The daily dose should not exceed 2 grams in such case.


Immediate medical advice should be sought in the event of overdosage even if the patient feels well because of the risk of irreversible liver damage (see section 4.9)


Caution is advised in asthmatic patient sensitive to acetylsalicylic acid, because light reaction bronchospasm with paracetamol (cross-reaction) has been reported.


This medicinal product contains sorbitol and sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.


Doses higher than recommended entail risk for very serious liver damage. Treatment with antidote should be given as soon as possible (see section 4.9).


Paracetamol should be used with caution in cases of dehydration and chronic malnutrition.


4.5 Interaction with other medicinal products and other forms of interaction


Intake of probenecid inhibits the binding of paracetamol to glucuronic acid, thus leading to a reduction in paracetamol clearance by a factor of approximately 2. In patients concurrently taking probenecid, the paracetamol dose should be reduced.


Paracetamol is extensively metabolised in the liver, and therefore it may interact with other medicinal products that use the same metabolic pathways or which are capable of inhibiting or inducing such pathways. Chronic alcohol intake and/or use of substances that induce liver enzymes such as rifampicin, isoniazid, St. John’s wort (hypericum)and some antiepileptics (carbamazepine, phenytoin, phenobarbital, primidone)can increase the hepatotoxicity of paracetamol due to increased and more rapid formation of toxic metabolites.


Concurrent administration of paracetamol and AZT (zidovudine) enhances the tendency to neutropenia. This medicinal product should therefore be co-administered with AZT only on medical advice.


Concurrent intake of medicinal products that accelerate gastric emptying, such as metoclopramide, accelerates the absorption and onset of effect of paracetamol.


Concurrent intake of medicinal products that slow gastric emptying can delay the absorption and onset of effect of paracetamol.


Colestyramine reduces absorption of paracetamol, and should therefore not be administered within an hour following paracetamol administration.


Repeated paracetamol intake for longer than one week enhances the effect of anticoagulants, particularly warfarin. Therefore long-term administration of paracetamol in patients who are being treated with anticoagulants should only take place under medical supervision. Occasional paracetamol intake has no significant effects on bleeding tendency.


Effects on laboratory tests

Paracetamol can interfere with laboratory tests for serum uric acid using phosphotungstic acid and blood sugar tests using glucose-oxidase-peroxidase. Probenecid causes an almost 2-fold reduction in clearance of Paracetamol by inhibiting its conjugation with glucuronid acid. A reduction of the Paracetamol dose should be considered for concomitant treatment with probenecid.


Paracetamol increases the plasmatic levels of acetylsalicylic acid and chloramphenicol.


4.6 Fertility, pregnancy and lactation


Pregnancy

Epidemiological data from the use of oral therapeutic doses of paracetamol indicate no undesirable effects on the pregnancy or on the health of the fetus / newborn infant. Prospective data on pregnancies exposed to overdoses did not show an increase in malformation risk. Reproductive studies with the oral route did not show any malformation or foetotoxic effects.

Consequently under normal conditions of use, paracetamol can be use throughout the duration of pregnancy, after a benefit-risk assessment.


During pregnancy, paracetamol should not be taken for longs periods, at high doses or in combination with other medicinal products, as safety of use in such cases is not established.


Breastfeeding

After oral use, paracetamol is excreted into breast milk in small quantities. No undesirable effects on nursing infants have been reported. Therapeutic doses of this medicinal product may be used during breast-feeding.


4.7 Effects on ability to drive and use machines


Paracetamol has no influence on the ability to drive and use machines. No studies on the effects on the ability to drive and use machines have been performed.


Undesirable effects


At therapeutic doses few undesirable effects occur.


The frequency of undesirable effects is classified as follows: Very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).


System organ class

Frequency

Undesirable effects

Blood and lymphatic system disorders

Rare:

Anaemia, non-haemolysis and marrow depression, thrombocytopaenia, platelet disorders, stem cell disorders.

Very rare:

Leucopenia, neutropenia and haemolytic anaemia.

Immune system disorders

Rare:

Hypersensitivity (excluding angioedema).

Metabolism and nutrition disorders

Very rare:

Hypoglycaemia.

Psychiatric disorders

Rare:

Depression, confusion, hallucinations.

Nervous system disorders

Rare:

Tremor, headache.

Eye disorders

Rare:

Abnormal vision.

Cardiac disorders

Rare:

Oedema.

Gastrointestinal disorders

Rare:

Acute and chronic pancreatitis, haemorrhage, abdominal pain, diarrhoea, nausea, vomiting.

Hepatobiliary disorders

Rare:

Hepatic function abnormal, hepatic failure, hepatic necrosis, jaundice.

Very rare:

Hepatotoxicity

Skin and subcutaneous tissue disorders

Rare:

Anaphylactic reactions, pruritus, rash, sweating, purpura, angioedema, urticaria.

Renal and urinary disorders

Rare:

Nephropathies and tubular disorders.

Very rare:

Sterile pyuria (cloudy urine) and renal side effects

General disorders and administration site conditions

Rare:

Dizziness (excluding vertigo), malaise, pyrexia, sedation, drug interaction.

Very rare:

Hypersensitivity reaction (requiring discontinuation of treatment)

Injury, poisoning and procedural complications

Rare:

Overdose and poisoning

Paracetamol has been widely used and reports of adverse reactions are rare, and are generally associated with overdose.

Nephrotoxic effects are uncommon and have not been reported in association with therapeutic doses, except after prolonged administration.

Some cases of erythema multiforme, oedema of the larynx, anaphylactic shock, anaemia, liver alteration and hepatitis, renal alteration (severe renal impairment, nephrite interstitial, haematuria, anuresis), gastrointestinal effects and vertigo have been reported.

Very rare cases of serious skin reactions have been reported.


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 <to be completed nationally>.


4.9 Overdose


There is a risk of poisoning, particularly in elderly subjects, in young children, in patients with liver disease, in cases of chronic alcoholism, in patients with chronic malnutrition. Overdosing may be fatal in these cases.


Symptoms generally appear within the first 24 hours and comprise: nausea, vomiting, anorexia, pallor, and abdominal pain.


Overdose, 7.5g or more of paracetamol in a single administration in adults or 140 mg/kg of body weight in a single administration in children, causes liver cell necrosis likely to induce complete and irreversible necrosis, resulting in hepatocellular insufficiency, metabolic acidosis and encephalopathy which may lead to coma and death. Simultaneously, increased levels of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubine are observed together with increased prothrombin levels that may appear 12 to 48 hours after administration.


Emergency Procedure:

Immediate transfer to hospital

Blood sampling to determine initial paracetamol plasma concentration

Gastric lavage

IV (or oral if possible) administration of the antidote N-acetylcysteine (NAC) as soon as possible and before the 10th hour of the overdose. NAC may even offer protection after 10 hours but in such cases a prolonged treatment is given.


Symptomatic treatment should be implemented


Liver tests should be performed at the start of treatment and should be repeated every 24 hours. In most cases, the hepatic transaminases will return to normal within one to two weeks, with full recovery of liver function. However, in very rare cases a liver transplantation may be indicated.


5. PHARMACOLOGICAL PROPERTIES


5.1 Pharmacodynamic properties


Pharmacotherapeutic group: other analgesics and antipyretics, anilides, ATC code: N02BE01


The mechanism of analgesic action has not been fully determined. Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and, to a lesser extent, through a peripheral action by blocking pain impulse generation. The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation.


Paracetamol probably produces antipyresis by acting centrally on the hypothalamic heat regulating centre to produce peripheral vaso-dilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.


5.2 Pharmacokinetic properties


Absorption

The absorption of paracetamol by the oral route is rapid and complete. Maximum plasma concentrations are reached 30 to 60 minutes following ingestion.


Distribution

Paracetamol is distributed rapidly throughout all tissues. Concentrations are comparable in blood, saliva and plasma. Protein binding is low. Time to peak concentration, 0.5 - 2 hours; peak plasma concentrations, 5 - 20 microgram (μg)/ml (with doses up to 50mg); time to peak effect, 1- 3 hours; duration of action, 3- 4 hours.


Biotransformation

Paracetamol is metabolized mainly in the liver following two major metabolic pathways: glucuronic acid and sulfuric acid conjugates. The latter route is rapidly saturated at doses higher than the therapeutic dose. A minor route, catalyzed by the cytochrome P450, results in the formation of an intermediate reagent (N-acetyl-p-benzoquinoneimine) which under normal conditions of use is rapidly detoxified by glutathione and eliminated in the urine, after conjugation with cystein and mercaptopuric acid. Conversely, when massive intoxication occurs, the quantity of this toxic metabolite is increased.


Elimination

Elimination is essentially through the urine. 90% of the ingested dose is eliminated via the kidneys within 24 hours, principally as glucuronide (60 to 80%) and sulphate conjugates (20 to 30%). Less than 5% is eliminated in unchanged form. Elimination half life is about 2 hours.


Physiopathological variations


Renal Insufficiency: In cases of severe renal insufficiency (creatinine clearance lower than 10 ml/min) the elimination of paracetamol and its metabolites is delayed.


Elderly Subjects. The capacity for conjugation is not modified.


5.3 Preclinical safety data


In animal experiments regarding acute, subchronic and chronic toxicity of paracetamol in rats and mice, gastro-intestinal lesions, blood count changes, degeneration of liver and renal parenchyma, even necroses were observed. The causes for these changes are attributed to the mechanism of action on the one hand and on the other to the metabolism of paracetamol.


Extensive investigations showed no evidence of a relevant genotoxic risk of paracetamol at therapeutic, i.e. non-toxic doses.


Long-term studies in rats and mice yielded no evidence on relevant tumorigenic effects at non-hepatotoxic dosages of paracetamol.


Paracetamol passes through the placenta.


Animal studies yield no evidence on reproductive toxicity.


6. PHARMACEUTICAL PARTICULARS


6.1 List of excipients


Sorbitol

Talc

Basic butylated methacrylate polymer

Magnesium oxide light

Hypromellose

Carmellose sodium

Stearic acid

Sodium laurilsulfate

Magnesium stearate (Ph.Eur.)

Titanium dioxide (E 171)

Sucralose

Simeticone

N,2,3-Trimethyl-2-(propan-2-yl)butanamid

Strawberry flavour (contains Maltrodextrin, Gum arabic (E414), Natural & Nature Identical Flavouring substances, Propylenglycol (E1520), Triacetin (E1518), Maltol (E636))

Vanilla flavour (contains Maltrodextrin, Natural & Nature Identical Flavouring substances, Propylenglycol (E1520), Sucrose)


6.2 Incompatibilities


Not applicable.


6.3 Shelf life


30 months


6.4 Special precautions for storage


Do not store above 30°C.

Store in the original package in order to protect from light and moisture.


Nature and contents of container


Aluminium sachets.

10, 20 sachets


Not all pack sizes may be marketed.


6.6 Special precautions for disposal


Any unused product or waste should be disposed of in accordance with local requirements


7. MARKETING AUTHORISATION HOLDER


To be completed nationally.


8. MARKETING AUTHORISATION NUMBER(S)


To be completed nationally.


9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION


DD/MM/YYYY


10. DATE OF REVISION OF THE TEXT


2015-10-02