Efferaldol Flas 500 Mg 16 Bucodispersible Tablets

Efferaldol Flas (500 Mg 16 Bucodispersible Tablets)

ACTION AND MECHANISM
Non-opioid analgesic and antipyretic, associated with vitamin C.
Paracetamol peripherally blocks pain impulses through the reversible inhibition of cyclooxygenase, an enzyme that is involved in the synthesis of prostaglandins. The antipyretic action is due to the inhibition of prostaglandins at the level of the thermoregulatory center located in the hypothalamus. It has shown weak anti-inflammatory properties in some non-rheumatic alterations. In other circumstances, anti-inflammatory action is not expected. At equal dose, the analgesic and antipyretic potency of paracetamol is similar to that of acetylsalicylic acid.

PHARMACKINETICS
* Orally:

- Absorption: rapid and complete after oral administration, with a bioavailability of 75-85%. After a dose of 1000 mg, a cmax of 7.7-17.6 mcg / ml is obtained after 0.5-2 h. It has an important saturable first-pass effect from a dose of 2 g.

Effect of food: food can reduce the absorption rate of paracetamol, although it does not substantially change the amount absorbed.

- Distribution: after its systemic absorption, it is widely distributed throughout most tissues, reaching concentrations similar to plasma. Your Vd is approximately 1 l / kg. It tends to accumulate especially in the liver and renal medulla. The distribution is moderately fast, with a plasma t1 / 2 of 1-3 h, and can be even faster in adolescents. It has low plasma protein binding, around 10%, and may be 20-40% in patients with acute overdose. It is able to cross the placenta and the blood brain barrier, detecting CSF concentrations of 1.5 mcg / ml after its IV infusion

- Metabolism: undergoes intense hepatic metabolism (90-95%) through conjugation reactions, mainly with glucuronic acid and sulfate.

The metabolization pathways are saturable at high doses, especially sulphation, which causes it to be metabolized by alternative pathways by cytochrome P450 (CYP2E1) that generate hepatotoxic metabolites such as N-acetyl-P-benzoquinone imine (NAPBI), which consumes glutathione in its elimination. NAPBI is subsequently metabolized to cysteine ​​and mercapturic acid.

Enzyme inducing / inhibiting ability: does not appear to have significant effects.

- Elimination: metabolism and subsequent elimination in urine, mainly in the form of glucuroconjugate metabolites (60-70%), and to a lesser extent conjugated with sulfate (20-30%) and cysteine ​​(3%). Small unchanged amounts are obtained in urine (<3%). Its elimination t1 / 2 is 1.5-3 h. It has a small excretion in bile (2.6%).

Pharmacokinetics in special situations:

- Children: neonates may have a somewhat longer t1 / 2 (4-11 h), while in older children it is similar to adults (around 1.5-4.2 h).

- Elderly: they may present a somewhat longer t1 / 2.

- Renal impairment: elimination can be decreased in patients with end-stage renal impairment (ClCr <10 ml / min).

It is partially removed by hemodialysis, hemoperfusion and peritoneal dialysis.

- Hepatic impairment: may have a somewhat longer t1 / 2, although the ability to conjugate is not modified.

INDICATIONS
- [PAIN] of mild or moderate intensity.
- [FEVER].
Alternative to acetylsalicylic acid in peptic ulcer, treatment with oral anticoagulants and allergy to salicylates.

POSOLOGY
Orally:.

- Adults: 1 tablet / 4h. It will not exceed 3 g of paracetamol / day (6 shots / day)

A dosage scheme may also be established in adult patients weighing less than 50 kg, patients with mild or moderate hepatic impairment, chronic alcoholism or chronic malnutrition (low hepatic glutathione reserves) and dehydration, not exceeding 2 g / 24 hours

POSOLOGY IN RENAL INSUFFICIENCY
FG 10-50 ml / min: 500 mg / 6h

FG <10 ml: 500 mg / 8h

POSOLOGY IN HEPATIC INSUFFICIENCY
Do not exceed 2 g / 24 hours (4 tablets of 500 mg)

RULES FOR THE CORRECT ADMINISTRATION
Let undo the tablet on the tongue

CONTRAINDICATIONS
- [PARACETAMOL ALLERGY].

- [HEPATOPATIA] (with or without liver failure), viral [HEPATITIS]: increases the risk of hepatotoxicity.

PRECAUTIONS
- [CHRONIC ALCOHOLISM]: Chronic consumption of alcoholic beverages (more than 3-4 drinks / day) can enhance the hepatic toxicity of paracetamol. Chronic alcoholics should avoid prolonged treatments or excessive doses of paracetamol (should not be administered more than 2 g / day). Increased incidence of hepatotoxicity and gastrointestinal bleeding has been observed in patients treated with fixed doses of paracetamol plus acetylsalicylic acid.

- [ANEMIA]: Due to the possible appearance of blood disorders such as thrombocytopenia, leukopenia, agranulocytosis, hemolytic anemia, etc., caution is recommended in patients with anemia, avoiding prolonged treatments. In these patients there is a risk that cyanosis does not manifest despite elevated methemoglobin levels.

Prolonged treatments in patients with cardiac or pulmonary alterations will also be avoided.

- [GLUCOSE DEFICIT ANEMIA 6 DEHYDROGENASE PHOSPHATE]: cases of hemolysis have been observed.

- Severe renal failure with creatinine clearance less than 10 ml / min, the interval between two doses will be at least 8 hours. In patients with severe or moderate renal impairment there may be accumulation of conjugated paracetamol derivatives. Prolonged treatments with high doses increase the risk of renal toxicity.

- [SALICILATOS ALLERGY]: paracetamol as an analgesic and antipyretic is a very valid alternative in patients allergic to salicylate. However, bronchospastic reactions have been observed in some asthmatic patients hypersensitive to acetylsalicylic acid or other NSAIDs. Although the incidence of cross-reaction is low (less than 5%), clinical control is advised in patients allergic to salicylates treated with paracetamol.

- [RENAL CALCULATIONS] and history of kidney stones. Ascorbic acid can acidify the urine and precipitate urate crystals, which could trigger kidney stone formation. Cautions should be taken in patients suffering from this disease.

PRECAUTIONS RELATING TO EXCIPIENTS
- This medicine contains glucose. Patients with glucose or galactose malabsorption should not take this medicine.

- This medicine contains aspartame as an excipient, so it must be taken into account by people affected by [PHENYLKETONURIA]. 100 mg of aspartame correspond to 56.13 mg of phenylalanine.

- This medicine contains sucrose. Patients with hereditary [INTRODUCTION TO FRUCTOSE], glucose or galactose malabsorption, or sucrose-isomaltase insufficiency should not take this medication.

- This medicine contains sodium salts. To know the exact sodium content, it is recommended to check the composition. Oral and parenteral dosage forms with sodium amounts greater than 1 mmol (23 mg) / maximum daily dose should be used with caution in patients with [RENAL INSUFFICIENCY] or with low sodium diets.

- This medicine contains sorbitol. Patients with hereditary [INTOLERANCE TO FRUCTOSE] should not take this medication.

- This medicine may be harmful to people with [PHENYLKETONURIA] because it contains aspartame (E-951) which is a source of phenylalanine.

- This medicine contains sucrose. The administration of amounts greater than 5 g daily should be taken into account in patients with [DIABETES].

- This medicine contains sucrose. Its use in oral fluids and pharmaceutical forms that remain in contact with the mouth for some time can harm the teeth.

PATIENT ADVICE

- High doses of paracetamol or prolonged treatments without clinical control, can cause liver disorders, especially in patients who regularly consume alcoholic beverages.
- Do not use this medicine for more than 10 days in a row without medical supervision. Prolonged treatments or high doses should be taken under doctor supervision.
- Do not exceed the recommended daily dose (maximum 4 g / day; 2 g / day in alcoholics).
- Do not use paracetamol with anti-inflammatory drugs (NSAIDs) without medical consent.
- Phenacetin (paracetamol metabolite) can darken urine.

SPECIAL WARNINGS

- During prolonged treatments it is advisable to carry out periodic checks of liver function and complete blood formula.
- Although it does not significantly reduce inflammation, very positive effects have been obtained in arthritic knee processes, probably due to its analgesic effect.
- Food delays the absorption of paracetamol.

INTERACTIONS
Paracetamol is metabolized at the liver level, leading to hepatotoxic metabolites, so it can interact with drugs that use the same metabolic pathways. Thus, there are clinical data of interactions at this level with the following drugs:

- Oral anticoagulants (acenocoumarol, warfarin): possible potentiation of the anticoagulant effect, with apparent little clinical relevance, is considered the therapeutic alternative to salicylates, when there is anticoagulant therapy. However, the dose and duration of treatment should be as low as possible, with periodic monitoring of the INR.

- Ethyl alcohol: potentiation of paracetamol toxicity, due to possible induction of hepatic production of hepatotoxic products derived from paracetamol.

- Anticonvulsants (phenytoin, phenobarbital, methylphenobarbital, primidone): decreased bioavailability of paracetamol as well as potentiation of hepatotoxicity to overdose, due to the induction of liver metabolism.

- Busulfan: as paracetamol can decrease the available glutathione, the clearance of busulfan can be reduced and its organic levels increased. It is recommended to minimize or avoid administration of paracetamol before (<72 hours) or during treatment with busulfan.

- Estrogens: decrease in plasma paracetamol levels, with possible inhibition of its effect, due to possible induction of its metabolism.

- Exenatide: the absorption of paracetamol could be diminished by exenatide, as this reduces gastric emptying. This interaction can be avoided if the analgesic is administered 1 hour before exenatide.

- Isoniazide: decrease in paracetamol clearance, with possible potentiation of its action and / or toxicity, by inhibition of its hepatic metabolism.

- Lamotrigine: decrease of the area under a curve (20%) and of the half-life (15%) of lamotrigine, with possible inhibition of its effect, due to possible induction of its hepatic metabolism.

- Propranolol: increase in plasma paracetamol levels, due to possible inhibition of liver metabolism.

- Rifampicin: increased paracetamol clearance due to possible induction of liver metabolism.

In addition, there are clinical data on interactions with other mechanisms:

- Anticholinergics (glycopyrronium, propanteline): decrease in the absorption of paracetamol, with possible inhibition of its effect, due to the decrease in gastric emptying speed.

- Ionic exchange resins (cholestyramine): decrease in the absorption of paracetamol, with possible inhibition of its effect, by fixation of paracetamol in the intestine.

- Drugs that predispose to nephrolithiasis (acetazolamide, calcium salts, saquinavir, topiramate, triamterene). Joint administration could lead to a higher incidence of nephrolithiasis. It is recommended to avoid association.

PREGNANCY
- Paracetamol: the use of short-term therapeutic oral doses is generally accepted at all stages of pregnancy.

- Ascorbic acid: accepted use at low doses (Caution at high doses).

LACTATION
Paracetamol is excreted with breast milk in low concentrations. No adverse effects have been recorded in newborns after oral maternal administration, except for an isolated case of an infant with reversible maculopapular rash in the upper trunk and face. The American Academy of Pediatrics considers the use of paracetamol compatible with breastfeeding.
The safety and efficacy of high-dose vitamin C supplements in nursing mothers have not been evaluated.

CHILDREN
Safety and efficacy in children <18 years have not been established. No data available in children

ADVERSE REACTIONS
* Paracetamol
- Blood: exceptionally, blood disorders, such as [TROMBOCITOPENIA], [LEUCOPENIA], [PANCITOPENIA], [NEUTROPENIA], [AGRANULOCITOSIS] and [HEMOLITIC ANEMIA] (in patients with G6PD deficiency).
- Dermatological: [EXANTEMATIC ERUPTIONS], [URTICARY], [ALLERGIC CONTACT DERMATITIS], [FEVER].
- Endocrine / Metabolic: exceptionally, [HYPOGLUCEMIA], especially children.
- Hepatobiliary: rarely, [ICTERICIA], [INCREASE OF TRANSAMINASES], [HEPATOTOXICITY] (associated with cases of overdose, either by the intake of 1 toxic dose or several doses of excessive doses).
- Genitourinary: it can cause [NEFROPATIA] which in turn can evolve into a picture of renal failure, [PIURIA] sterile (cloudy urine), renal adverse effects (with high doses).
- Cardiovascular: rarely, [HYPOTENSION].
* Ascorbic acid does not usually present adverse reactions, except in especially sensitive individuals.
- Digestive The most common symptom is the appearance of [DIARREA], although it usually occurs mostly at high doses, greater than 1 g for adults and 500 mg in children. This diarrhea could be due to the osmotic effects of ascorbic acid in the intestinal lumen. Also presented [NAUSEAS], [VOMITOS], [GASTRIC HYPERACIDEZ], [ABDOMINAL SPASM] and [FLATULENCE], but usually appear at doses greater than 1 g.
- Genitourinary. The administration of large amounts of vitamin C has been associated with the production of [RENAL CALCULATIONS], although these have only appeared in individuals with a history of kidney stones.
- Hematological. Cases of [HEMOLITICAL ANEMIA] have been described in patients with glucose-6-phosphate dehydrogenase deficiency, especially in neonates.

OVERDOSE
Symptoms: paracetamol can lead to very serious and life-threatening poisoning. Toxicity can begin to be experienced from single doses of 6 g in adults or 100 mg / kg in children. Doses greater than 20-25 g are potentially fatal. Chronic doses greater than 4 g / 24 h may lead to transient hepatotoxicity. However, patients treated with other hepatotoxic drugs, enzyme inducers or with chronic alcoholism may be more susceptible to their toxic effects, requiring a lower dose to produce toxicity.

Hepatotoxicity may appear at paracetamol Cp greater than 120 mcg / ml at 4 h and 30 mcg / ml at 12 h. Levels of 300 mcg / ml at 4 h after overdosing have been related to hepatotoxicity phenomena in 90% of patients.

Paracetamol overdose follows four characteristic clinical stages:

- Phase I: appears a few hours after overdosing, and until the first 24 hours. He has general malaise, nausea and vomiting, abdominal pain, paleness, excessive sweating and anorexia. Liver functionality and liver parameters are normal.

- Phase II: occurs in 24-36 hours after overdosing. Symptoms of liver damage begin to appear, such as abdominal pain in the right hypochondrium and increased levels of transaminase and bilirubin, and prothrombin time.

- Phase III: occurs at 72-96 h after overdosing, and coincides with the hepatotoxicity peak, with transaminase elevations of up to 10,000 U / l or even higher, increases in bilirubin, glucose, lactate and phosphate, as well as prothrombin time elevation. The patient may have encephalopathy and coma. Similarly, renal tubular necrosis and myocardial involvement have been reported. Death may occur due to fulminant liver failure with liver necrosis.

- Phase IV: occurs 7-8 days after overdosing. Recovery of those patients who have survived the previous stage.

The risk of severe paracetamol poisoning depends on the route of administration as well as the conditions of use of the drug. In this way, it is not expected that serious poisoning will occur in case of overdosing with suppositories (yes if swallowed, although this is not frequent), or in case of injectables (due to hospital use, with sanitary control , although serious poisonings have occurred due to confusion of the dose in the amount of paracetamol or volume of the solution for injection). However, in no case can it be discarded.

Treatment: in case of oral overdosing, and preferably within 4 hours after ingestion, gastric aspiration and washing will be carried out, together with administration of activated carbon, reducing paracetamol absorption.

N-acetylcysteine ​​is the specific antidote for paracetamol overdose. N-acetylcysteine ​​can be used orally in adults and parenterally in adults and children.

- Via iv: the dose to be administered is 300 mg / kg, for a period of 20 h and 15 minutes, according to the following schedule:

* Adults: initially 150 mg / kg (equivalent to 0.75 ml / kg of 20% aqueous solution, with pH 6.5) by IV slowly or diluted in 200 ml of 5% glucose serum, for 15 min.

Then 50 mg / kg (0.25 ml / kg of 20% aqueous solution, with pH 6.5) diluted in 500 ml of 5% glucose serum in the form of iv infusion for 4 h.

Finally, 100 mg / kg (0.50 ml / kg of 20% aqueous solution, with pH 6.5) diluted in 1,000 ml of 5% glucose serum in the form of iv infusion for 16 h.

* Children: the same guideline will be administered, although the volume of the infusion solutions will be adjusted to the child's age and weight to avoid pulmonary vascular congestion.

The efficacy of parenteral treatment with N-acetylcysteine ​​is maximal when administered at 8 h after overdosing, gradually reducing thereafter until it becomes ineffective at 15 h.

The administration of N-acetylcysteine ​​may be suspended when plasma paracetamol levels are below 200 mcg / ml.

- Oral route (for adults only): initially 140 mg / kg, followed by 17 doses of 70 mg / kg / 4 h. The dose should be diluted in water, cola drinks or orange or grape juice to a final concentration of 5%, as it has an unpleasant taste and can lead to irritation or sclerosing. In case of vomiting the dose within 1 h, its administration will be repeated.

If necessary, it will be administered diluted in water through a duodenal tube.

If the patient experiences symptoms of hepatotoxicity, liver function should be monitored every 24 h.

Leaflet Efferaldol Flas 500 Mg 16 Bucodispersible Tablets