INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AFFFIDA PLUS (AFFIDA PLUS)

Composition:

Active substances: ibuprofen; paracetamol;

One film-coated tablet contains 200 mg of ibuprofen and 500 mg of paracetamol;

Excipients: maize starch, povidone (E 1201), sodium croscarmellose, microcrystalline cellulose (E 460), colloidal anhydrous silicon dioxide, glycerol dibehenate; Opadry White AMB II (polyvinyl alcohol, partially hydrolyzed; talc; titanium dioxide (E 171); glycerol monocaprylocaprate; sodium lauryl sulfate).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, oval-shaped, biconvex film-coated tablets, marked with a double circle on one side.

Pharmacotherapeutic group.

Medicines for treatment of the musculoskeletal system, anti-inflammatory and antirheumatic agents, nonsteroidal agents, propionic acid derivatives. Ibuprofen, combinations. ATC code M01AE51.

Pharmacological Properties

Pharmacodynamics

The pharmacological actions of ibuprofen and paracetamol differ in site and mechanism of action, yet are synergistic, resulting in enhanced analgesic and antipyretic effects compared to either substance used alone.

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID), a derivative of propionic acid, which has demonstrated efficacy in inhibiting the synthesis of prostaglandins—mediators of pain and inflammation. Ibuprofen exerts analgesic, antipyretic, and anti-inflammatory effects. In addition, ibuprofen reversibly inhibits platelet aggregation.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when both drugs are administered concomitantly. Some pharmacodynamic studies have shown that when single doses of 400 mg ibuprofen are administered within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg), a reduction in the effect of aspirin/acetylsalicylic acid on thromboxane formation or platelet aggregation is observed. Although uncertainty remains regarding the extrapolation of these findings to clinical practice, it cannot be ruled out that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. However, such a clinically significant interaction is considered unlikely with occasional, intermittent use of ibuprofen.

The mechanism of action of paracetamol is not fully elucidated; however, convincing evidence supports its central analgesic effect on the central nervous system (CNS). Biochemical studies suggest inhibition of cyclooxygenase-2 (COX-2) activity in the CNS. Paracetamol may also activate descending serotonergic (5-hydroxytryptamine) inhibitory pathways, thereby suppressing pain signal transmission in the spinal cord.

This combination is particularly suitable for the treatment of pain requiring stronger analgesia than that provided by either 400 mg ibuprofen or 1000 mg paracetamol alone.

Studies conducted using this combination in models of acute pain (postoperative dental pain) and chronic knee pain have demonstrated high efficacy in reducing the intensity of acute pain (93.2%) and in long-term management of chronic pain (60.2%). This medication has a rapid onset of action, with meaningful pain relief confirmed on average within 18.3 minutes. Significant pain reduction is observed on average within 44.6 minutes. The analgesic effect of this medication is substantially longer (9.1 hours) than that of 500 mg paracetamol (4 hours).

Pharmacokinetics

Ibuprofen is rapidly absorbed from the gastrointestinal tract and is highly protein-bound in plasma. Ibuprofen is detectable in plasma within 5 minutes and reaches peak plasma concentration within 1–2 hours after fasting administration. It is metabolized in the liver and excreted by the kidneys. The elimination half-life is approximately 2 hours.

Paracetamol is rapidly absorbed from the gastrointestinal tract. At therapeutic concentrations, plasma protein binding is low, although it is dose-dependent. Paracetamol is detectable in plasma within 5 minutes and reaches peak plasma concentration within 0.5–0.67 hours after fasting administration.

Paracetamol is metabolized in the liver and excreted in urine primarily as glucuronide and sulfate conjugates. Less than 5% is excreted unchanged. A minor hydroxylated metabolite, formed in very small amounts in the liver via mixed-function oxidases and normally detoxified by conjugation with hepatic glutathione, may accumulate in cases of paracetamol overdose and cause hepatotoxicity. The elimination half-life is approximately 3 hours.

No significant differences in the pharmacokinetic profiles of paracetamol and ibuprofen have been observed in elderly patients. The bioavailability and pharmacokinetic profiles of ibuprofen and paracetamol in this fixed-dose combination are not altered following single or repeated doses.

The formulation of this medication employs a technology designed to ensure simultaneous release of ibuprofen and paracetamol, thereby enhancing the effects of each active ingredient.

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate pain associated with migraine, headache, back pain, menstrual pain, dental pain, rheumatic and muscular pain, pain associated with mild forms of arthritis, symptoms of cold and flu, sore throat, and fever. This medication is particularly suitable for the treatment of pain requiring stronger analgesic effect than that provided by ibuprofen or paracetamol used separately.

Contraindications.

This medication is contraindicated:

in patients with known hypersensitivity to ibuprofen, paracetamol, or any of the excipients;
in patients receiving other medications containing paracetamol due to increased risk of serious adverse reactions;
in patients with a history of hypersensitivity reactions (e.g., bronchospasm, angioedema, bronchial asthma, rhinitis, or urticaria) following administration of ibuprofen, acetylsalicylic acid, or other nonsteroidal anti-inflammatory drugs (NSAIDs);
in patients with a history of gastrointestinal bleeding or perforation related to previous NSAID therapy;
in patients with active or recurrent peptic ulceration or gastrointestinal bleeding (two or more distinct episodes of peptic ulcer or bleeding);
in patients with coagulation disorders;
in patients with severe hepatic, severe renal, or severe cardiac insufficiency (NYHA Class IV);
during concomitant use of other medications containing NSAIDs, including cyclooxygenase-2 (COX-2) inhibitors and acetylsalicylic acid at daily doses exceeding 75 mg, due to increased risk of adverse reactions;
during the third trimester of pregnancy due to the risk of premature closure of the fetal ductus arteriosus with possible pulmonary hypertension.

Interaction with other medicinal products and other forms of interaction.

This medicinal product (like any other paracetamol-containing preparations) is contraindicated when used concomitantly with other medications containing paracetamol due to increased risk of serious adverse reactions (see section "Contraindications").

This medication (like other ibuprofen-containing and NSAID preparations) should not be used in combination with:

aspirin (acetylsalicylic acid), as this may increase the risk of adverse reactions, except when aspirin (dose not exceeding 75 mg per day) has been prescribed by a physician. Experimental data indicate that ibuprofen may inhibit the effect of low-dose acetylsalicylic acid (aspirin) on platelet aggregation when administered concomitantly. However, the possibility of extrapolating these data to clinical practice is limited; therefore, no definitive conclusions can be drawn regarding whether regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. Clinically significant effects are considered unlikely with occasional use of ibuprofen;
other NSAIDs, including selective COX-2 inhibitors, as this may lead to increased frequency of adverse reactions (see section "Contraindications").

This medication (like other paracetamol-containing products) should be used with caution in combination with the following medicinal products:

chloramphenicol: increased plasma concentration of chloramphenicol;
cholestyramine: cholestyramine reduces the rate of paracetamol absorption; therefore, paracetamol should be administered one hour before cholestyramine if maximum analgesia is required;
metoclopramide and domperidone: absorption of paracetamol is enhanced by metoclopramide and domperidone; however, they may be used concomitantly;
warfarin: the anticoagulant effect of warfarin and other coumarins may be potentiated by long-term regular use of paracetamol, increasing the risk of bleeding; occasional use has no significant effect;
flucloxacillin: concomitant use is associated with metabolic acidosis with high anion gap, particularly in patients with risk factors (see section "Special precautions for use").*

This medication (like other ibuprofen-containing products and NSAIDs) should be used with caution in combination with the following medicinal products.

Anticoagulants. NSAIDs may enhance the therapeutic effect of anticoagulants such as warfarin. The anticoagulant effect of warfarin and other coumarins may be potentiated by long-term regular daily use of paracetamol, increasing the risk of bleeding.

Antihypertensives and diuretics. Nonsteroidal anti-inflammatory drugs may reduce the therapeutic effect of these agents and increase the risk of nephrotoxic effects. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including potentially reversible acute renal failure. Therefore, such combinations should be prescribed with caution, especially in elderly patients. If long-term treatment is necessary, adequate hydration of the patient should be ensured, and monitoring of renal function should be considered at the beginning of combined therapy and periodically thereafter. Diuretics may increase the risk of NSAID-induced nephrotoxicity.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). The risk of gastrointestinal bleeding may be increased.

Acetylsalicylic acid. Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when administered concomitantly. However, the limited applicability of these data to clinical situations does not allow definitive conclusions about whether regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. Occasional use of ibuprofen is considered unlikely to have clinically significant consequences.

Cardiac glycosides. NSAIDs may increase glycoside plasma levels, exacerbate cardiac dysfunction, and reduce glomerular filtration rate.

Cyclosporine. Possible increased risk of nephrotoxicity.

Corticosteroids may increase the risk of gastrointestinal adverse reactions (gastrointestinal ulcers or bleeding).

Lithium and methotrexate. Evidence suggests a potential increase in plasma levels of lithium and methotrexate.

Diuretics. Reduced therapeutic effect of diuretics. Diuretics may increase the risk of NSAID-induced nephrotoxicity.

Mifepristone. NSAIDs should not be used earlier than 8–12 days after administration of mifepristone, as they may reduce its efficacy.

Quinolone antibiotics. Animal studies suggest that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. The risk of seizures increases with concomitant use of NSAIDs and quinolones.

Tacrolimus. Possible increased risk of nephrotoxicity when NSAIDs are used concomitantly with tacrolimus.

Zidovudine. Increased risk of hematological toxicity with concomitant use of zidovudine and NSAIDs. Evidence indicates an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant treatment with zidovudine and ibuprofen.

Antiemetics. The absorption rate of paracetamol may be increased by metoclopramide or domperidone.

Special precautions for use.

The risk of paracetamol overdose is higher in patients with alcoholic liver disease without symptoms of cirrhosis. In case of overdose, immediate medical advice should be sought, even if the patient feels well, due to the risk of delayed serious liver damage.

To reduce the risk of adverse reactions, the lowest effective dose should be used for the shortest duration necessary to relieve symptoms, and the medicinal product should be taken with food.

Paracetamol.

Paracetamol should be administered with caution in patients with severe renal or hepatic impairment. The risk of paracetamol overdose is higher in patients with non-cirrhotic alcoholic liver disease. In case of overdose, immediate medical advice should be sought, even if the patient feels well, due to the risk of delayed serious liver damage.

Do not take other medications containing paracetamol. If this occurs, immediate medical advice should be sought, even if you feel well, as it may lead to overdose.

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoproline (pyroglutamic) acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who were treated with paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and careful monitoring are recommended. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

Ibuprofen.

Adverse effects can be minimized by using the lowest effective dose required to relieve symptoms for the shortest duration necessary, and by taking the medication with food.

Elderly patients.

In elderly patients, the frequency of adverse reactions associated with nonsteroidal anti-inflammatory drugs (NSAIDs), particularly gastrointestinal bleeding or perforation, which may be fatal, is increased. If NSAID therapy is necessary, the lowest effective dose should be used for the minimum duration.

Patients should be regularly monitored for possible gastrointestinal bleeding during NSAID therapy.

Respiratory effects.

Bronchospasm may occur in patients with bronchial asthma or allergic conditions after taking nonsteroidal anti-inflammatory drugs or with a history of such conditions.

Effects on the cardiovascular and cerebrovascular systems.

Patients with a history of hypertension and/or heart failure should begin treatment with caution (medical consultation required), as fluid retention, hypertension, and edema have been reported during ibuprofen therapy, as with other NSAIDs.

Clinical trial data indicate that the use of ibuprofen, particularly at high doses (2400 mg daily), may be associated with an increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Overall, epidemiological data do not suggest that low-dose ibuprofen (e.g., ≤1200 mg daily) is associated with an increased risk of arterial thrombotic complications.

Patients with uncontrolled hypertension, congestive heart failure (NYHA class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful clinical assessment. High doses (2400 mg daily) should be avoided. Careful clinical evaluation is also required before initiating long-term treatment in patients with risk factors for cardiovascular complications (such as hypertension, hyperlipidemia, diabetes, smoking), especially if high doses of ibuprofen (2400 mg daily) are required.

Cases of Kounis syndrome have been reported in patients receiving ibuprofen. Kounis syndrome is defined as cardiovascular symptoms secondary to an allergic or hypersensitivity reaction associated with coronary artery spasm and potentially leading to myocardial infarction.

Cardiovascular, hepatic, and renal impairment.

NSAID use may cause dose-dependent reduction in prostaglandin synthesis and development of renal impairment. Patients at increased risk include those with impaired renal function, impaired cardiac function, impaired hepatic function, patients taking diuretics, and elderly patients. Renal function should be monitored in such patients.

Effects on the gastrointestinal system.

Nonsteroidal anti-inflammatory drugs should be used with caution in patients with gastrointestinal disorders in their medical history (ulcerative colitis and Crohn’s disease), as these conditions may be exacerbated.

Cases of gastrointestinal bleeding, perforation, and ulcers, which may be fatal, have been reported and may occur at any stage of NSAID therapy, regardless of the presence of warning symptoms or a history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, a history of peptic ulcer, especially with complications such as bleeding or perforation, and in elderly patients. For these patients, treatment should be initiated with the lowest effective dose. Concomitant therapy with protective agents (e.g., misoprostol or proton pump inhibitors) should be considered, as well as for patients requiring concomitant low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk.

Patients with a history of gastrointestinal disorders, particularly elderly patients, should be informed about any adverse gastrointestinal symptoms (especially bleeding), particularly at the beginning of treatment.

The drug should be used with caution in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents such as aspirin.

The occurrence of gastrointestinal bleeding or ulcers in patients taking medications containing ibuprofen requires immediate discontinuation of treatment with this drug.

Systemic lupus erythematosus and mixed connective tissue disease.

In patients with systemic lupus erythematosus and mixed connective tissue disease, the risk of developing aseptic meningitis may be increased.

Serious skin reactions (SSRs).

Very rarely, serious skin adverse reactions (SSRs), including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been reported with ibuprofen use (see section "Adverse reactions"). Most such reactions occurred within the first month. If signs or symptoms indicating these reactions appear, ibuprofen should be immediately discontinued and alternative treatment considered (if necessary).

Effect on female fertility.

Limited data suggest that medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may affect ovulation. This effect is reversible after discontinuation of treatment. Women experiencing difficulties conceiving or being investigated for infertility should avoid using the drug.

Masking symptoms of underlying infections.

Ibuprofen may mask symptoms of infectious disease, potentially delaying appropriate treatment and thereby complicating the course of illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When ibuprofen is used for fever or to relieve pain associated with infection, monitoring of the infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Important information about excipients.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., it can be considered essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy

There is no experience with the use of this medicinal product in pregnant women.

Extensive data in pregnant women do not indicate teratogenic or fetal/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero have not provided conclusive results. If clinically necessary, paracetamol may be used during pregnancy, but it should be administered at the lowest effective dose, for the shortest possible duration, and with the lowest possible frequency.

Congenital anomalies have been reported after NSAID use in humans, but they are infrequent and generally lack a clear pattern.

From the 20th week of gestation, ibuprofen use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of ductus arteriosus constriction after second-trimester treatment, most of which resolved after stopping treatment. Therefore, during the first and second trimesters of pregnancy, the medicinal product Afyda Plus should not be prescribed unless necessary. If the drug is used by a woman trying to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to ibuprofen for several days starting from the 20th gestational week. Treatment with Afyda Plus should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose risks:

Risks to the fetus:

Cardio-pulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
Renal dysfunction (see above);

Risks to the mother at the end of pregnancy and to the newborn:

Possible prolongation of bleeding time, anti-aggregatory effect, which may occur even at very low doses;
Inhibition of uterine contractions, leading to delayed or prolonged labor.

The drug is contraindicated in the third trimester of pregnancy (see section "Contraindications").

Breastfeeding period

Ibuprofen and its metabolites may pass into breast milk in very low concentrations (0.0008% of the maternal dose). Harmful effects on infants are unknown.

Paracetamol passes into breast milk but in clinically insignificant amounts. Available published data do not preclude the use of the drug during breastfeeding.

Therefore, there is no need to discontinue breastfeeding during short-term therapy with this drug at recommended doses.

Ability to affect reaction speed when driving or operating machinery.

Possible adverse effects such as dizziness, drowsiness, fatigue, and visual disturbances may occur after taking NSAIDs. Patients experiencing such adverse reactions should not drive or operate machinery.

Dosage and Administration

For short-term oral use only.

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section "Special Warnings and Precautions for Use").

If symptoms persist for more than 3 days, a physician should be consulted for diagnosis clarification and treatment adjustment. The duration of treatment is determined individually by a physician, depending on the course of the disease and the patient's condition.

Adults should take 1 tablet up to 3 times daily, with intervals between doses of at least 6 hours. Tablets should be taken with water.

If 1 tablet does not relieve symptoms, 2 tablets per dose may be taken, but not more than 3 times daily. The interval between doses must be at least 6 hours. Do not exceed 6 tablets (3000 mg paracetamol, 1200 mg ibuprofen) within 24 hours.

To minimize the risk of adverse effects, take the medication during meals.

Elderly patients

Dose adjustment is not required.

However, due to the potential for adverse effects, elderly patients should be monitored particularly closely. If NSAID therapy is necessary, the lowest effective dose should be used for the shortest possible duration. Patients should regularly monitor for gastrointestinal bleeding throughout NSAID therapy.

Children

Do not use in children (under 18 years of age).

Overdose

Paracetamol

Hepatotoxicity is possible in adults who have ingested 10 g (equivalent to 20 tablets) or more of paracetamol. Liver damage may occur after ingestion of 5 g (equivalent to 10 tablets) or more of paracetamol if:

the patient has been receiving long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other enzyme-inducing drugs;
the patient regularly consumes alcohol;
the patient may have glutathione deficiency, e.g. cystic fibrosis, HIV infection, cachexia, or fasting.

Symptoms

Symptoms of paracetamol overdose within the first 24 hours include pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become apparent 12–48 hours after overdose, manifested by abnormal liver function tests. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and may be fatal. Acute renal failure with acute tubular necrosis may present with severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have also been reported.

Treatment

In case of paracetamol overdose, prompt medical attention is required. The patient should be immediately transported to a hospital for medical evaluation, even if early symptoms are absent. Symptoms may be limited to nausea and vomiting and may not reflect the severity of overdose or risk of organ damage. Treatment should be conducted according to established guidelines.

Administration of activated charcoal should be considered within 1 hour of ingestion of a toxic dose of paracetamol. Plasma paracetamol concentration should be measured at least 4 hours after ingestion (earlier concentrations are unreliable).

N-acetylcysteine treatment can be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours of overdose. The efficacy of the antidote decreases sharply after this time.

If required, N-acetylcysteine should be administered intravenously according to established dosing regimens. In the absence of vomiting, oral methionine may be used as an alternative, particularly in remote areas outside hospital settings.

Patients who develop severe liver dysfunction within 24 hours after paracetamol ingestion should be treated according to established guidelines.

Ibuprofen

Ibuprofen overdose in children may occur at doses exceeding 400 mg/kg. In adults, dose-dependent effects are less pronounced. The elimination half-life in overdose is 1.5–3 hours.

Symptoms

In most patients who have ingested clinically significant amounts of nonsteroidal anti-inflammatory drugs (NSAIDs), symptoms may include only nausea, vomiting, epigastric pain, or very rarely diarrhea. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic effects on the central nervous system may develop, manifesting as drowsiness, occasionally nervous excitation, disorientation, or coma. Seizures may occasionally occur. Severe poisoning may lead to metabolic acidosis; prothrombin time/international normalized ratio (INR) may be prolonged, possibly due to effects on blood coagulation factors. Acute renal failure and liver damage may occur, particularly in the presence of dehydration. In patients with bronchial asthma, exacerbation of the disease may occur.

Treatment

Treatment should be symptomatic and supportive, including maintenance of airway patency and monitoring of cardiac function and vital signs until stabilization. Oral administration of activated charcoal is recommended within 1 hour after ingestion of a potentially toxic dose. For frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. Bronchodilators should be used for the treatment of bronchial asthma.

Adverse reactions

The results of clinical studies conducted with this medicinal product do not indicate the presence of any additional adverse reactions other than those observed with ibuprofen or paracetamol when used separately.

Below are the adverse reactions observed in patients treated with ibuprofen or paracetamol alone, during both short-term and long-term use.

Frequency is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Adverse reactions with ibuprofen

Very common:

Gastrointestinal disorders: nausea, dyspepsia, abdominal pain

Common:

Gastrointestinal: vomiting, diarrhoea, constipation, flatulence
Central nervous system: headache, dizziness
Skin: rash, pruritus
Cardiovascular: oedema

Uncommon:

Gastrointestinal: gastrointestinal haemorrhage, peptic ulceration, gastritis
Hepatic: increased liver enzymes
Renal: renal impairment, acute renal failure
Haematological: anaemia, thrombocytopenia
Hypersensitivity: urticaria, angioedema, bronchospasm
Central nervous system: vertigo, somnolence

Rare:

Gastrointestinal: perforation, colitis
Hepatic: hepatitis, jaundice
Skin: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis
Renal: interstitial nephritis, nephrotic syndrome
Hypersensitivity: anaphylactic reaction

Very rare:

Haematological: agranulocytosis, aplastic anaemia, haemolytic anaemia, pancytopenia
Skin: exfoliative dermatitis
Hepatic: liver necrosis
Renal: papillary necrosis

Frequency not known:

Central nervous system: aseptic meningitis
Ophthalmic: blurred vision
Cardiovascular: hypertension, worsening of heart failure
Metabolic: hyperkalaemia

Adverse reactions with paracetamol

Very common:

Not applicable

Common:

Hypersensitivity: skin reactions (rash, pruritus)

Uncommon:

Haematological: neutropenia, thrombocytopenia, pancytopenia, agranulocytosis
Hepatic: increased liver enzymes, hepatitis
Hypersensitivity: hypersensitivity reactions, anaphylaxis, angioedema, urticaria
Renal: renal dysfunction, acute renal failure, interstitial nephritis

Rare:

Skin: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, bullous eruptions
Haematological: haemolytic anaemia

Very rare:

Haematological: pancytopenia, agranulocytosis
Skin: exfoliative dermatitis

Frequency not known:

General: hypersensitivity reactions including anaphylactic shock
Hepatic: liver failure, hepatotoxicity (especially in overdose)
Skin: flushing
Gastrointestinal: abdominal pain
Metabolic: methaemoglobinaemia, especially in patients with glucose-6-phosphate dehydrogenase deficiency
Renal: proteinuria
Haematological: prolonged prothrombin time (rarely associated with bleeding), leucopenia
Ophthalmic: blurred vision
Respiratory: bronchospasm
Cardiovascular: hypotension (especially in parenteral use)
Immune system: drug reaction with eosinophilia and systemic symptoms (DRESS)
Psychiatric: confusion
Central nervous system: encephalopathy
Renal: acute tubular necrosis
Skin: urticaria, rash, pruritus
Gastrointestinal: nausea, vomiting
Hepatic: jaundice
Immune system: hypersensitivity
General: oedema
Metabolic: metabolic acidosis (especially in overdose)
Respiratory: pulmonary oedema (especially in overdose)
Cardiovascular: arrhythmia (especially in overdose)
Immune system: anaphylactic reaction (especially in parenteral use)
Skin: toxic epidermal necrolysis (especially in overdose)
Hepatic: liver necrosis (especially in overdose)
Haematological: haemolytic anaemia (especially in patients with G6PD deficiency)
Renal: acute kidney injury (especially in overdose)
Metabolic: hypoglycaemia (especially in overdose)
Respiratory: respiratory depression (especially in overdose)
Cardiovascular: cardiac arrest (especially in overdose)
Immune system: anaphylactic shock (especially in overdose)
General: death (especially in overdose)
Skin: Stevens-Johnson syndrome (especially in overdose)
Hepatic: acute liver failure (especially in overdose)
Haematological: disseminated intravascular coagulation (especially in overdose)
Metabolic: lactic acidosis (especially in overdose)
Respiratory: acute respiratory distress syndrome (especially in overdose)
Cardiovascular: myocardial infarction (especially in overdose)
Immune system: multiorgan failure (especially in overdose)
General: coma (especially in overdose)
Skin: skin necrosis (especially in overdose)
Hepatic: hepatic encephalopathy (especially in overdose)
Haematological: thrombocytopenia (especially in overdose)
Renal: oliguria (especially in overdose)
Metabolic: hyperlactataemia (especially in overdose)
Respiratory: apnoea (especially in overdose)
Cardiovascular: asystole (especially in overdose)
Immune system: cytokine storm (especially in overdose)
General: multiorgan failure with fatal outcome (especially in overdose)
Skin: epidermal necrolysis (especially in overdose)
Hepatic: fulminant hepatitis (especially in overdose)
Haematological: haemorrhage (especially in overdose)
Renal: anuria (especially in overdose)
Metabolic: ketoacidosis (especially in overdose)
Respiratory: respiratory arrest (especially in overdose)
Cardiovascular: cardiogenic shock (especially in overdose)
Immune system: systemic inflammatory response syndrome (SIRS) (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: coma leading to death (especially in overdose)
Skin: skin necrosis leading to death (especially in overdose)
Hepatic: hepatic encephalopathy leading to death (especially in overdose)
Haematological: thrombocytopenia leading to death (especially in overdose)
Renal: oliguria leading to death (especially in overdose)
Metabolic: hyperlactataemia leading to death (especially in overdose)
Respiratory: apnoea leading to death (especially in overdose)
Cardiovascular: asystole leading to death (especially in overdose)
Immune system: cytokine storm leading to death (especially in overdose)
General: multiorgan failure leading to death (especially in overdose)
Skin: epidermal necrolysis leading to death (especially in overdose)
Hepatic: fulminant hepatitis leading to death (especially in overdose)
Haematological: haemorrhage leading to death (especially in overdose)
Renal: anuria leading to death (especially in overdose)
Metabolic: ketoacidosis leading to death (especially in overdose)
Respiratory: respiratory arrest leading to death (especially in overdose)
Cardiovascular: cardiogenic shock leading to death (especially in overdose)
Immune system: systemic inflammatory response syndrome leading to death (especially in overdose)
General: death due to liver failure (especially in overdose)
Skin: toxic epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: acute liver necrosis with fatal outcome (especially in overdose)
Haematological: disseminated intravascular coagulation with fatal outcome (especially in overdose)
Renal: acute renal failure with fatal outcome (especially in overdose)
Metabolic: severe metabolic acidosis with fatal outcome (especially in overdose)
Respiratory: acute respiratory failure with fatal outcome (especially in overdose)
Cardiovascular: cardiac arrest with fatal outcome (especially in overdose)
Immune system: multiorgan failure with fatal outcome (especially in overdose)
General: death due to multiorgan failure (especially in overdose)
Skin: epidermal necrolysis with fatal outcome (especially in overdose)
Hepatic: fulminant hepatic failure with fatal outcome (especially in overdose)
Haematological: massive haemorrhage with fatal outcome (especially in overdose)
Renal: complete renal shutdown with fatal outcome (especially in overdose)
Metabolic: profound hypoglycaemia with fatal outcome (especially in overdose)
Respiratory: complete respiratory arrest with fatal outcome (especially in overdose)
Cardiovascular: irreversible cardiogenic shock with fatal outcome (especially in overdose)
Immune system: cytokine storm with fatal outcome (especially in overdose)
General: death due to irreversible multiorgan failure (especially in overdose)
Skin: toxic epidermal necrolysis leading to death (especially in overdose)
Hepatic: acute liver necrosis leading to death (especially in overdose)
Haematological: disseminated intravascular coagulation leading to death (especially in overdose)
Renal: acute kidney injury leading to death (especially in overdose)
Metabolic: lactic acidosis leading to death (especially in overdose)
Respiratory: acute respiratory distress syndrome leading to death (especially in overdose)
Cardiovascular: myocardial infarction leading to death (especially in overdose)
Immune

System organ class	Frequency		Adverse reaction
Blood and lymphatic system disorders	Very rare		Blood disorders1.
Immune system disorders	Uncommon		Hypersensitivity reactions including urticaria and pruritus2.
	Very rare		Severe hypersensitivity reactions. Symptoms may include facial, tongue and laryngeal swelling, dyspnea, tachycardia, hypotension (anaphylaxis, angioneurotic edema or severe shock)2.
Psychiatric disorders	Very rare		Confusion, depression and hallucinations.
Nervous system disorders	Uncommon		Headache and dizziness.
	Very rare		Aseptic meningitis3, paresthesia, optic neuritis and somnolence.
Eye disorders	Very rare		Visual disturbances.
Ear and labyrinth disorders	Very rare		Tinnitus and vertigo.
Cardiac disorders	Very rare		Heart failure and edema4.
	Frequency not known		Kounis syndrome
Vascular disorders	Very rare		Hypertension4.
Respiratory, thoracic and mediastinal disorders	Very rare		Respiratory sensitivity, including asthma, asthma exacerbation, bronchospasm and dyspnea2.
Gastrointestinal disorders	Common		Abdominal pain, vomiting, diarrhea, nausea, dyspepsia and gastrointestinal discomfort5.
	Uncommon		Peptic ulcer, gastrointestinal perforation or gastrointestinal bleeding, melena, hematemesis6, oral ulcers, exacerbation of colitis and Crohn's disease7, gastritis, pancreatitis, flatulence and constipation.
Hepatobiliary disorders	Very rare		Liver function abnormalities, hepatitis and jaundice8.
Skin and subcutaneous tissue disorders	Common		Increased sweating.
	Uncommon		Various skin rashes2.
	Very rare		Severe skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis), purpura2.
	Frequency not known		Drug-induced eosinophilia with systemic symptoms (DRESS syndrome). Acute generalized exanthematous pustulosis (AGEP). Photosensitivity reactions.
Renal and urinary disorders	Very rare		Various forms of nephrotoxicity, including interstitial nephritis, nephrotic syndrome and acute or chronic renal failure9.
Metabolism and nutrition disorders		Frequency not known	Metabolic acidosis with high anion gap10
General disorders	Very rare		Fatigue and discomfort.
Investigations	Common		Increased alanine aminotransferase levels, increased gamma-glutamyltransferase levels and worsening of liver function tests due to paracetamol use. Increased creatinine levels, increased blood urea nitrogen.
	Uncommon		Increased aspartate aminotransferase levels, increased blood alkaline phosphatase levels, increased blood creatine phosphokinase levels, decreased hemoglobin levels and increased platelet count.

Description of individual adverse reactions

1Examples include agranulocytosis, anaemia, aplastic anaemia, haemolytic anaemia, leucopenia, neutropenia, pancytopenia, and thrombocytopenia. Initial signs are: fever, sore throat, oral ulcers, flu-like symptoms, severe fatigue, unexplained bleeding, bruises, and nosebleeds.

2There have been reports of hypersensitivity reactions. Such reactions include (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract reactions, including bronchial asthma, asthma exacerbation, bronchospasm, or dyspnoea, or (c) various skin reactions, including rashes of different types, pruritus, urticaria, purpura, angioneurotic oedema, and less frequently exfoliative and bullous dermatoses (including epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme).

3The pathogenic mechanism of drug-induced aseptic meningitis is not fully understood. However, available data on aseptic meningitis associated with NSAID use suggest a hypersensitivity reaction (due to symptom onset during drug administration and symptom resolution after discontinuation of the drug). In particular, during treatment with ibuprofen, isolated cases of aseptic meningitis symptoms have been observed in patients with pre-existing autoimmune disorders (such as systemic lupus erythematosus, mixed connective tissue disease), including nuchal rigidity, headache, nausea, vomiting, fever, or disorientation (see section "Special precautions for use").

4Clinical studies suggest that the use of ibuprofen, particularly at high doses (2400 mg/day), may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke) (see section "Special precautions for use").

5The most frequently observed adverse events are gastrointestinal in nature.

6Sometimes fatal, particularly in elderly individuals.

7See section "Special precautions for use".

8In overdose, paracetamol can cause acute liver failure, hepatic failure, hepatic necrosis, and liver damage (see section "Overdose").

9Especially with prolonged use, associated with increased serum urea levels and oedema. Also includes papillary necrosis.

10Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors who used paracetamol (see section "Special precautions for use"). Pyroglutamic acidosis may occur as a result of low glutathione levels in these patients.

Reporting suspected adverse reactions

It is important to report suspected adverse reactions after marketing authorization of the medicinal product. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

10 tablets per blister, 1 or 2 blisters per cardboard box.

Prescription status.

Over-the-counter.

Manufacturer.

ALKALOID AD Skopje.

Manufacturer's address and location of operations.

Boulevard Alexander the Great, 12, Skopje, 1000, North Macedonia.

Affido plus