Dolostop (1 G 10 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 understood, but it seems to be fundamentally mediated 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. There is also a possible peripheral effect due to inhibition of prostaglandin synthesis, activation of the CB1 cannabinoid receptor, modulation of serotonergic or opiate signaling pathways, inhibition of nitric oxide synthesis, or substance P-induced hyperalgesia.

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

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

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

PHARMACOKINETICS
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 rate of absorption of paracetamol, although it does not substantially modify the amount absorbed.

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

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

Metabolization pathways are saturable at high doses, especially sulfation, 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 capacity: does not appear to present significant effects.

- Elimination: metabolism and subsequent elimination in urine, mainly in the form of glucuroconjugated 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 presents 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 that in adults (around 1.5-4.2 h).

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

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

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

- Hepatic failure: they may have a slightly longer t1 / 2, although the conjugation capacity is not modified.

INDICATIONS
- [PAIN]. Symptomatic treatment of pain of mild to moderate intensity, such as:

* [HEADACHE].

* [DENTISTRY].

* [DYSMENORRHEA].

* [OSTEOMUSCULAR PAIN] such as [MUSCULAR CONTRACTURE], [TORTICOLIS], [LUMBALGIA], [ARTHROSIS] or [RHEUMATOID ARTHRITIS].

* [NEURALGIA] as [SCIATICA].

* Sore throat.

* Postoperative or postpartum pain.

- [FEVER]. Symptomatic treatment of feverish state.

DOSAGE
- Adults and adolescents over 15 years of age, oral: 1 g / 6-8 h. Maximum dose 4 g / 24 h, divided into 1 g doses at least 4 h apart.
- Elderly, oral: may require a dose reduction of up to 25% in adults.
Once the symptoms disappear, the treatment will be suspended.
In case of persistence of pain (normally 5-10 days for adults and half for children; 2 days in pharyngeal pain) or fever (normally 3 days), worsening or appearance of other symptoms should be consulted with the doctor.

DOSAGE IN RENAL INSUFFICIENCY
Oral use:

- CLcr 50-90 ml / min: does not require dosage adjustment.

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

- CLcr <10 ml / min: 500 mg / 8 h.
Due to its dose, it is recommended to avoid its use in patients with moderate to severe renal insufficiency (CLcr <50 ml / min).

DOSAGE IN LIVER INSUFFICIENCY
Use only under medical supervision, evaluating liver function at the beginning of treatment and periodically throughout it.

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

RULES FOR CORRECT ADMINISTRATION
Paracetamol can be taken with or without food. However, oral administration on an empty stomach accelerates the effects of paracetamol, although not its intensity.

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

- Tablets and capsules: take with a glass of liquid, preferably water.

CONTRAINDICATIONS
- [ALLERGY TO PARACETAMOL] or to any other component of the drug.

- Severe and active liver disease.

PRECAUTIONS
- [KIDNEY INSUFFICIENCY]. Patients treated with high doses for long periods of time could experience renal adverse reactions, therefore it is recommended to monitor renal function. Patients with end-stage renal failure (CLcr <10 ml / min) should distance the feedings at least 8 h. No special problems are expected in case of occasional use.

- [HEPATOTOXICITY]. During hepatic metabolism of paracetamol, hepatotoxic compounds such as N-acetyl-benzoquinone imine are generated. This compound is produced in small amounts through metabolism by cytochrome P450, a minor pathway for paracetamol. However, at high doses of paracetamol, saturation of the fundamental pathways (glucuron and sulfateconjugation) 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, being eliminated in urine. If benzoquinone production is excessive, glutathione depletion occurs in the hepatocyte, and consequent cell damage, which could lead to life-threatening toxicity.This hepatotoxicity is a delayed adverse reaction, symptoms usually appear 2 days after overdose and peak after 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. Likewise, it is not recommended to exceed the recommended daily doses 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, as a general rule it is recommended to avoid its use in patients with liver disease, including [HEPATIC INSUFFICIENCY], [HEPATITIS] or [HEPATIC CIRRHOSIS], as well as in patients with other risks of liver damage, such as [CHRONIC ALCOHOLISM], [HYPOVOLEMIA], [DEHYDRATION] or [MALNUTRITION] with low glutathione levels, or treated with other hepatotoxic drugs.

In those patients in whom this is not possible, it is suggested to use it under medical judgment, after careful evaluation of the benefit / risk ratio. It is recommended to evaluate liver function in these patients at the beginning of 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).

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

- [DYSCRASIAS SANGUINEAS]. Paracetamol has been associated with hematological disorders such as [LEUCOPENIA], agranulocytosis or [NEUTROPENIA]. In the case of prolonged treatment, it may be necessary to perform periodic blood counts.

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

ADVICE TO THE PATIENT
- 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 being recommended by a doctor. Stop treatment as soon as symptoms disappear.

- Consult with the doctor and / or pharmacist if 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 symptoms get worse or new ones appear.

- Those patients who regularly consume alcohol in large quantities (3 or more drinks a day) should limit the doses of paracetamol 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 considerably reduce inflammation, very positive effects have been obtained in arthritic processes of the knee, probably due to its analgesic effect.

- Monitoring:

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

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

INTERACTIONS
In general, interactions with paracetamol are not expected to be serious, due to its occasional use. Only in those patients treated with high doses, especially if there are other risk factors for hepatotoxicity, or in long-term treatment, it is expected that the interactions have clinical significance.

- NSAIDs. Paracetamol is usually used in combination with other analgesics, such as ibuprofen, for the treatment of febrile processes in children.However, it must 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 joint treatment to the bare minimum.

- Oral anticoagulants. Unlike NSAIDs and acetylsalicylic acid, paracetamol does not have antiplatelet activity nor does it affect blood coagulation per se, which is why it is used as the analgesic drug of choice in patients treated with oral anticoagulants.

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

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

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

- Chloramphenicol. Paracetamol could favor the accumulation of chloramphenicol by reducing its hepatic metabolism, with the risk of hematological toxicity. It is advisable to monitor the patient.

- Drugs that delay gastric emptying, such as anticholinergics or exenatide. This delay could slow down 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 its joint administration with other hepatotoxic drugs, as well as with alcohol.

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

- Enzyme inhibitors (imatinib, isoniazid, propranolol). Increases in paracetamol plasma levels have been reported by drugs with inhibitory activity on its metabolism.

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

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

- Ion exchange resins (cholestyramine, colestipol). Possible decreased absorption of paracetamol. 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. Neither interaction of any kind with alpha-1 adrenergic blockers (doxazosin, terazosin), furosemide, letrozole or zanamivir has been recorded.

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

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

PREGNANCY
Safety in animals: no teratogenic effects have been reported in animal studies.

Safety in humans: a large amount of data in pregnant women indicates the absence of fetal / neonatal toxicity or congenital malformations. Epidemiological studies on the neurodevelopment of children exposed to paracetamol in utero show inconclusive results.

Paracetamol crosses the placental barrier. Several cohort studies have been conducted on the safety of oral paracetamol in pregnant women. These studies did not show an increased risk of congenital malformation, heart defects, or spontaneous abortion. There are data that suggest that their employment during the last two trimesters could be related to an increased risk of wheezing in the first year of the child's 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 (the latter two fatal). However, these symptoms appeared to be due to an overdose by the mother.

Oral paracetamol, at the recommended doses and used promptly, is considered a safe analgesic / antipyretic during pregnancy. It has been used just before delivery in women with fever secondary to chorioamnionitis, with a significant improvement in the 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 its use by parenteral route, unless the expected benefits outweigh the possible risks.

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

BREASTFEEDING
Paracetamol is excreted in small amounts with human milk, reaching concentrations in milk of 10-15 mcg / ml (similar to those in plasma) after 1-2 h after a dose of 650 mg po. Exposure is estimated in the child 1-2% of the maternal dose. Paracetamol or its metabolites have not been found in the urine of the infant, nor have adverse reactions been reported in the child, except for one case of a maculopapular rash, which 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 old should be carried out under medical supervision, and its use should be limited to the minimum possible.

Due to the risks of serious, potentially fatal poisoning, it is recommended to closely monitor the dosage in children, avoiding doses higher than those recommended. In this way, the appropriate presentation must be used that allows the child to be accurately dosed, depending on their weight.

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

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

ADVERSE REACTIONS
Paracetamol is generally well tolerated, and its adverse reactions are rare.

Adverse reactions are described according to each frequency range, being considered very common (> 10%), common (1-10%), uncommon (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 IN TRANSAMINASES], [INCREASE IN ALKALINE PHOSPHATASE], [HYPERBILIRUBINEMIA]; very rare [HEPATOTOXICITY], with [JAUNDICE].

- Cardiovascular: rare [HYPOTENSION].

- Neurological / psychological: [DIZZINESS], [DISORIENTATION], [EXCITABILITY].

- Genitourinary: very rare kidney disorders such as cloudy urine and kidney disorders.

- Allergic: very rare [HYPERSENSITIVITY REACTIONS], with symptoms ranging from [EXANTEMATIC ERUPTIONS] and [URTICARIA] to [ANAPHYLAXY].

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

- Metabolic: very rare [HYPOGLYCAEMIA].

- Analytical: analytical alterations have been described such as [INCREASE IN LACTATE DEHYDROGENASE], [INCREASE IN SERIAL 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 DISASTER].

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 can lead to transient hepatotoxicity. However, patients treated with other hepatotoxic drugs, enzyme inducers or with chronic alcoholism could be more susceptible to its toxic effects, requiring a lower dose to produce toxicity.

Hepatotoxicity can appear at paracetamol Cp greater than 120 mcg / ml at 4 h and 30 mcg / ml at 12 h. Levels of 300 mcg / ml 4 h after overdose have been associated with hepatotoxicity phenomena in 90% of patients.

Paracetamol overdose follows four characteristic clinical stages:

- Phase I: appears within a few hours of overdose, and up to the first 24 hours. It presents with general malaise, nausea and vomiting, abdominal pain, paleness, excessive sweating and anorexia. Liver function and liver parameters are normal.

- Phase II: occurs within 24-36 h after overdose. Symptoms of liver damage begin to appear, such as abdominal pain in the right upper quadrant and increased levels of transaminases and bilirubin and prothrombin time.

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

- Phase IV: occurs 7-8 days after overdose. 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 overdose with suppositories (yes by ingestion of the same, although this is not frequent), or in case of injectables (due to their hospital use, with sanitary control , despite the fact that serious poisoning has occurred due to confusion of the dose in quantity of paracetamol or volume of the injectable solution). However, in no case can it be ruled out.

Treatment: in the event of oral overdose, and preferably within 4 hours after ingestion, gastric aspiration and lavage will be carried out, along with administration of activated charcoal, reducing the absorption of paracetamol.

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

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

* Adults: initially 150 mg / kg (equivalent to 0.75 ml / kg of 20% aqueous solution, with pH 6.5) by slow iv 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 as an iv infusion for 4 h.

Finally 100 mg / kg (0.50 ml / kg of 20% aqueous solution, with pH 6.5) diluted in 1000 ml of 5% glucose serum as an iv infusion for 16 h.

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

The efficacy of parenteral treatment with N-acetylcysteine ​​is greatest when administered within 8 hours after overdose, gradually reducing thereafter until ineffective at 15 hours.

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

- Oral route (only for adults): 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. If the dose is vomited 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 hours.

Dolostop 1 G 10 Tablets Leaflet