Apiretal 500 Mg 24 Bucodispersible Tablets

Apiretal 500 Mg 24 Bucodispersible Tablets

ACTION AND MECHANISM

- Paracetamol is a derivative of para-aminophenol, with analgesic and antipyretic activity.

* Analgesic effect. Its mechanism of action is not fully clarified, but it seems to be mediated primarily by the inhibition of cyclooxygenase at the central level, especially COX-2, decreasing the synthesis of prostaglandins. It also has a certain peripheral effect by blocking the generation of the painful nerve impulse. A possible peripheral effect is also posed by inhibition of prostaglandin synthesis, activation of CB1 cannabinoid receptor, modulation of serotonergic or opioid signaling pathways, inhibition of nitric oxide synthesis or hyperalgesia induced by substance P.

* Antipyretic effect. It acts on the hypothalamic thermoregulatory center, inhibiting the synthesis of prostaglandins and the effects of endogenous pyrogen, resulting in peripheral vasodilation, increased blood flow to the skin and increased sweating, which contribute to heat loss.

At equal dose it is considered to have an analgesic and antipyretic potency similar to acetylsalicylic acid (ASA). The effects are maximum at 1-3 h and last for 3-4 h.

Unlike AAS and other NSAIDs, it does not show appreciable anti-inflammatory activity, except in some non-rheumatic diseases, although it is not important. An advantage over NSAIDs is that it not only does not inhibit the synthesis of prostaglandins at the gastric level, but seems to increase it, so it does not give rise to gastrolesive effects. Similarly, it lacks platelet antiaggregant effects.

PHARMACKINETICS

Oral, parenteral, rectal route:

- Absorption: the therapeutic cp is about 10 mcg / ml.

* Oral route: rapid and complete absorption 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]. Symptomatic treatment of pain of mild to moderate intensity, such as:

* [CEFALEA].

* [ODONTALGIA].

* [DISMENORREA].

* [OSTEOMUSCULAR PAIN] such as [MUSCLE CONTRACTURE], [TORTICOLIS], [LUMBALGIA], [ARTROSIS] or [Rheumatoid ARTHRITIS].

* [NEURALGIA] as [CIATICA].

* Sore throat.

* Postoperative or postpartum pain.

- [FEVER]. Symptomatic treatment of febrile state.

POSOLOGY

- Patients> 40 kg, oral: 500 mg / 4 h. Maximum dose 3 g / 24 h.

- Patients 27-39 kg, oral: 500 mg / 6 h. Maximum dose 2 g / 24 h.

Once the symptoms disappear, the treatment will be suspended.

In case of persistence of pain (usually 5-10 days for adults and half for children; 2 days in pharyngeal pain) or fever (usually 3 days), worsening or occurrence of other symptoms should be consulted with the doctor.

POSOLOGY IN RENAL INSUFFICIENCY

Orally:

- CLcr 50-90 ml / min: no dose adjustment is required.

- CLcr 10-50 ml / min: 500 mg / 6 h.

- CLcr <10 ml / min: 500 mg / 8 h.

It is considered that timely use does not require special precautions. However, renal adverse reactions may occur in patients under treatment with high and long-term doses, therefore monitoring renal function is recommended.

POSOLOGY IN HEPATIC INSUFFICIENCY

Use only under medical control, evaluating liver functionality at the beginning of treatment and periodically throughout it.

It is recommended to avoid doses greater than 2 g / 24 h (orally) or 3 g (iv), with a minimum interval of at least 8 h.

RULES FOR THE CORRECT ADMINISTRATION

Paracetamol can be taken with or without food. However, fasting orally accelerates the effects of paracetamol, although not its intensity.

If a faster effect is required, it is recommended to take without food.

- Orodispersible tablets: let the tablet disintegrate on the tongue, swallowing once discarded. Alternatively it could be dispersed in water.

CONTRAINDICATIONS

- [PARACETAMOL ALLERGY] or any other component of the medicine.

- Severe and active liver disease.

PRECAUTIONS

- [RENAL INSUFFICIENCY]. Patients treated with high doses for long periods of time may experience renal adverse reactions, so it is recommended to monitor renal functionality. Patients with end-stage renal impairment (CLcr <10 ml / min) should distance the shots at least 8 h. No special problems are expected in case of timely use.

- [HEPATOTOXICITY]. During hepatic metabolism of paracetamol, hepatotoxic compounds such as N-acetyl-benzoquinone imine are generated. This compound is produced in small quantities through metabolism by cytochrome P450, a minor route for paracetamol. However, at high doses of paracetamol, saturation of the fundamental pathways (glucurono and sulfate conjugation) can occur, increasing the role of this cytochrome, and the consequent production of benzoquinone. This substance is rapidly detoxified with reduced glutathione expenditure, transforming into cysteine ​​and mercapturic acid, eliminating in urine. If the production of benzoquinone is excessive, there is a depletion of glutathione in the hepatocyte, and the consequent cellular damage, which could lead to life-threatening toxicity. This hepatotoxicity is a delayed adverse reaction, the symptoms usually appear within 2 days of the overdose and are maximum at 4-6 days.

In general, self-medication should be limited, and paracetamol should not be used for more than 10 days without medical advice, and as long as the symptoms that motivated its use persist. It is also not advised to exceed the recommended daily dose of 4 g in adults or 60 mg / kg in children.

Due to its hepatotoxic effects, and taking into account its indications and the alternative of other analgesics and antipyretics, it is generally recommended to avoid its use in patients with liver disease, including [HEPATIC INSUFFICIENCY], [HEPATITIS] or [HEPATIC CIRROSIS], as well as in patients with other risks of liver damage, such as [CHRONIC ALCOHOLISM], [HYPOVOLEMIA], [DEHYDRATION] or [NUDE] with low levels of glutathione, or treated with other hepatotoxic drugs.

In those patients in whom this is not possible, it is suggested to use it under medical criteria, after a careful evaluation of the benefit / risk ratio. It is recommended to evaluate in these patients the liver functionality at the beginning of the treatment and periodically throughout it. Likewise, the maximum doses to be used should not exceed 2 g / 24 h (po) or 3 g / 24 h (iv).

- Salicylate allergy: Patients allergic to acetylsalicylic acid do not usually have hypersensitivity reactions with paracetamol. However, cases of mild bronchospasm have been reported in patients allergic to acetylsalicylic acid treated with paracetamol.

- [BLOOD DISCRASIAS]. Paracetamol has been associated with hematological abnormalities such as [LEUCOPENIA], agranulocytosis or [NEUTROPENIA]. In case of prolonged treatments, periodic blood count may be necessary.

- Determination of pancreatic functionality. Paracetamol can interfere with the bentiromide test, because it is metabolized to arylamine, leading to a false increase in para-aminobenzoic acid. It is recommended to discontinue treatment with paracetamol at least three days before the test.

PRECAUTIONS RELATING TO EXCIPIENTS

- 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.

PATIENT ADVICE

- It can be taken with or without food. Administration without food accelerates the analgesic effects, but not their intensity.

- Do not exceed the recommended doses, or use for more than 10 days without a doctor's recommendation. Stop treatment as soon as symptoms disappear.

- Consult with the doctor and / or pharmacist in case the pain continues after 5-10 days of treatment (3-5 days in children; 2 days in case of pharyngeal pain), the fever lasts for more than 3 days, or the symptoms worsen or new ones appear.

- Those patients who regularly consume alcohol in significant amounts (3 or more drinks daily) should limit paracetamol doses to avoid liver damage.

- In case of overdose, consult a doctor and / or pharmacist, even if no symptoms appear.

SPECIAL WARNINGS

- Although it does not significantly reduce inflammation, very positive effects have been obtained in arthritic knee processes, probably due to its analgesic effect.

- Monitoring:

* Renal functionality and blood count in patients treated for prolonged periods of time.

* Hepatic functionality at baseline and periodically in patients at high risk of hepatotoxicity.

INTERACTIONS

In general, paracetamol interactions are not expected to be serious, due to their punctual use. Only in those patients treated with high doses, especially if there are other risk factors for hepatotoxicity, or in long-term treatments are the interactions expected to have clinical significance.

- NSAID. Paracetamol is usually used in combination with other analgesics, such as ibuprofen, for the treatment of febrile processes in children. However, it should be taken into account that its administration together with NSAIDs or salicylates at high doses and for prolonged periods of time could increase the risk of kidney damage. It is therefore recommended not to exceed the recommended doses and limit the joint treatment to the indispensable minimum.

- Oral anticoagulants. In contrast to NSAIDs and acetylsalicylic acid, paracetamol has no platelet antiaggregant activity nor does it affect blood clotting per se, which is why it is used as the analgesic drug of choice in patients treated with oral anticoagulants.

However, in case of prolonged treatments and at high doses, but without entering into toxic doses, a slight hepatotoxic effect could occur, characterized by the decrease in the production of hepatic coagulation factors, so that the INR of these patients could be increased , at risk of bleeding.

Therefore, it is recommended to monitor this parameter in these patients treated with high doses. The risk seems insignificant in case of specific treatments or prolonged treatments with doses <2 g / 24 h.

- Busulfan. Risk of toxicity by busulfan, by reducing paracetamol glutathione levels, substance with which busulfan is conjugated in its elimination. It is recommended to avoid administration of paracetamol, or to limit exposure if not possible, in the 72 hours before and during busulfan treatment.

- Chloramphenicol. Paracetamol may favor the accumulation of chloramphenicol due to a decrease in liver metabolism, with a risk of hematological toxicity. It is advised to monitor the patient.

- Drugs that delay gastric emptying, such as anticholinergics or exenatide. This delay could slow the absorption of paracetamol and the onset of the effect, rather than its intensity.

- Hepatotoxic drugs. Paracetamol at high doses exerts a hepatotoxic effect. It is recommended to avoid co-administration with other hepatotoxic drugs, as well as with alcohol.

- Enzymatic inducers (estrogen, barbiturate, contraceptives, carbamazepine, phenytoin, rifampicin oral contraceptives). Paracetamol is partially metabolized by cytochrome P450, so that its plasma levels and therapeutic effects could be reduced in case of administration together with a potent inducing drug of the hepatic microsomal system. On the other hand, in case of paracetamol overdose, the inducer could increase liver toxicity as a result of increased production of toxic metabolites generated by this enzyme system.

- Enzymatic inhibitors (imatinib, isoniazid, propranolol). Increases in plasma paracetamol levels have been reported by drugs that inhibit their metabolism.

- Reverse transcriptase inhibitors (didanosine, zidovudine). Paracetamol may potentiate the hematological toxicity of zidovudine. On the other hand, both didanosine and zidovudine could favor paracetamol hepatotoxicity.

- Lamotrigine. Paracetamol could increase the metabolism of lamotrigine, reducing its therapeutic effects.

- Ionic exchange resins (cholestyramine, colestipol). Possible decrease in paracetamol absorption. Distance the administration one hour.

Studies have shown the absence of significant pharmacokinetic interaction with adefovir, amantadine, h3 antihistamines or proton pump inhibitors, argatroban, chloroquine, erythromycin, lithium, methotrexate, oseltamivir, sucralfate, telmisartan or zolmitriptan. There has also been no interaction of any kind with alpha-1 adrenergic blockers (doxazosin, terazosin), furosemide, letrozole or zanamivir.

Paracetamol slightly reduces the urinary excretion of diazepam, although plasma levels remain unchanged.

Paracetamol does not affect the immunogenicity of influenza vaccines, and could reduce the symptoms of adverse reactions.

PREGNANCY

No reproduction studies have been performed with the intravenous form of paracetamol in animals. However, studies with the oral route showed no malformations or fetotoxic effects.

Paracetamol crosses the placental barrier. Several cohort studies have been conducted on the safety of oral paracetamol in pregnant women. In these studies there was no increase in the risk of congenital malformation, heart defects or spontaneous abortion. There are data that suggest that their employment during the last two quarters could be related to an increased risk of wheezing in the child's first year of life.

There have been some specific cases of serious adverse reactions in children of mothers who received paracetamol during pregnancy, including severe anemia, hepatotoxicity and nephrotoxicity (these last two fatal). However, these symptoms seemed to be due to an overdose by the mother.

Paracetamol orally, at the recommended doses and used promptly, is considered a safe analgesic / antipyretic during pregnancy. It has been used just before childbirth in women with fever secondary to chorioamnionitis, with a significant improvement in fetal and newborn status, after normalization of maternal temperature. However, its use at high doses or for longer periods of time could be related to fetal hepatotoxicity phenomena.

On the contrary, due to the lack of safety and efficacy data in pregnant women, it is recommended to avoid their use parenterally, unless the expected benefits outweigh the possible risks.

Effects on fertility: in animal trials, paracetamol resulted in testicular atrophy and decreased spermatogenesis at high doses. It is unknown if these data can be extrapolated to humans.

LACTATION

Paracetamol is excreted in small quantities with breast milk, reaching concentrations in milk of 10-15 mcg / ml (similar to plasma) after 1-2 h after a dose of 650 mg po It is estimated exposure in the child 1-2% of the maternal dose. No paracetamol or its metabolites have been found in the infant's urine, nor have adverse reactions been reported in the child, except for a case of maculopapular rash, which was resolved without sequelae when the mother discontinued paracetamol.

The American Academy of Pediatrics and the World Health Organization consider paracetamol compatible with breastfeeding.

CHILDREN

Paracetamol is an analgesic-antipyretic drug commonly used in children, including young children. However, as a general precautionary measure, its use in children under 3 years should be under medical supervision, and limit its use to the minimum possible.

Due to the risks of serious, potentially fatal poisoning, it is recommended to closely monitor the dosage in children, avoiding higher doses than recommended. Thus, the appropriate presentation should be used to accurately dose the child, depending on their weight.

It is advisable to consult the dosage of the different presentations for more information about their use in children.

ELDERLY

In elderly patients there has been a reduction in elimination. Certain manufacturers recommend reducing the dose by 25% compared to young adults, but others do not consider this precaution necessary.

ADVERSE REACTIONS

Paracetamol is usually well tolerated, and its adverse reactions are rare.

Adverse reactions are described according to each frequency range, being considered very frequent (> 10%), frequent (1-10%), rare (0.1-1%), rare (0.01-0.1%) , very rare (<0.01%) or of unknown frequency (cannot be estimated from the available data).

The following have been described orally:

- Hepatic: rare [INCREASE OF TRANSAMINASES], [INCREASE OF ALKALINE PHOSPHATASE], [HYPERBILYRUBINEMIA]; very rare [HEPATOTOXICITY], with [ICTERICIA].

- Cardiovascular: rare [HYPOTENSION].

- Neurological / psychological: [MAREO], [DESORIENTATION], [EXCITABILITY].

- Genitourinary: very rare renal disorders such as turbidity of urine and renal disorders.

- Allergic: very rare [HYPERSENSITIVITY REACTIONS], with symptoms from [EXANTEMATIC ERUPTIONS] and [URTICARY] to [ANAFILAXIA].

- Hematologic: very rare [THROMBOCYTOPENIA], [AGRANULOCITOSIS], [LEUCOPENIA], [NEUTROPENIA], [HEMOLITIC ANEMIA], [METAHEMOGLOBINEMIA]. Prothrombin time could be increased, although it does not seem significant.

- Metabolic: very rare [HYPOGLUCEMIA].

- Analytical: analytical alterations have been described as [INCREASE OF LACTATE DEHYDROGENASE], [INCREASE IN SERIC CREATININE], increase in ammonia levels, [INCREASE IN UREIC NITROGEN].

On the other hand, paracetamol could interfere with the analytical determination of uric acid and glucose, as well as with the monitoring of theophylline. It can also give false positives in the determination of 5-hydroxy-indoleacetic acid when nitrosonaphthol is used as a reagent.

- General: rare [GENERAL DISCOMFORT].

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:

*