Adverse reactions : תופעות לוואי

4.8      Undesirable effects

Clinical trials with Combodex IV and paracetamol 500 mg/ibuprofen 150 mg film-coated tablets have not indicatedany other undesirable effects other than those for paracetamol alone or ibuprofen alone.

The adverse reactions are listed below as MedDRA preferred term by system organ class and absolute frequency:
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); Frequency not known (cannot be estimated from the available data) 

Infections and                 Very rare: Exacerbation of infection-related inflammations (e.g.
infestations                   development of necrotising fasciitis) coinciding with the use of NSAIDs has been described.
Blood and lymphatic       Uncommon: Decrease in haemoglobin and haematocrit. Although a system disorders          causal relationship has not been established, bleeding episodes (e.g.
epistaxis, menorrhagia) have been reported in during therapy with the drug.
Very Rare: Haematopoietic disorders (agranulocytosis, anaemia,
aplastic anaemia, haemolytic anaemia leucopenia, neutropenia,
pancytopenia and thrombocytopenia with or without purpura) have been reported following ibuprofen use, but were not necessarily causally related to the drug.
Immune system             Very Rare: Hypersensitivity reactions including skin rash and cross- disorders                 sensitivity with sympathomimetics have been reported.
Uncommon: Other allergic reactions have been reported but a causal relationship has not been established: Serum sickness, lupus erythematosus syndrome, Henoch-Schönlein vasculitis, angioedema.
Metabolic and nutrition   Very Rare: In the case of metabolic acidosis, causality is uncertain as disorders                 more than one drug was ingested. The case of metabolic acidosis followed the ingestion of 75 grams of paracetamol, 1.95 grams of acetylsalicylic acid, and a small amount of a liquid household cleaner.
The patient also had a history of seizures which the authors reported may have contributed to an increased lactate level indicative of metabolic acidosis.
Metabolic side effects have included hypokalaemia. Metabolic side effects including metabolic acidosis have been reported following a massive overdose of paracetamol.
Uncommon: Gynaecomastia, hypoglycaemic reaction.
Nervous system            Common: Dizziness, headache, nervousness.
disorders                 Uncommon: Depression, insomnia, confusion, emotional lability, somnolence, aseptic meningitis with fever and coma.
Rare: Paraesthesia, hallucinations, dream abnormalities.
Very Rare: Paradoxical stimulation, optic neuritis, psychomotor impairment, extrapyramidal effects, tremor and convulsions.
Eye disorders             Uncommon: Amblyopia (blurred and/or diminished vision, scotomata and/or changes in colour vision) have occurred but is usually reversed after cessation of therapy. Any patient with eye complaints should have an ophthalmological examination which includes central vision fields.
Ear and labyrinth         Very Rare: Vertigo.
disorders                 Common: Tinnitus (for medicines containing ibuprofen).
Cardiac disorders         Common: Oedema, fluid retention; fluid retention generally responds promptly to discontinuation of the drug.
Very Rare: Palpitations; tachycardia; arrhythmia and other cardiac dysrhythmias have been reported. Hypertension and cardiac failure have been reported in association with NSAID treatment.
Respiratory and           Uncommon: Thickened respiratory tract secretions. In children thoracic and              undergoing tonsillectomy, stridor has been reported. Hypoxemia has mediastinal disorders     been reported.
Very Rare: Respiratory reactivity including: asthma, exacerbation of asthma, bronchospasm and dyspnoea.
Gastrointestinal          Common: Abdominal pain, diarrhoea, dyspepsia, nausea, stomach Disorders                 discomfort and vomiting, flatulence, constipation, slight gastrointestinal blood loss that may cause anaemia in exceptional cases.
Uncommon: Peptic/gastrointestinal ulcer, perforation or gastrointestinal haemorrhage, with symptoms of melaena haematemesis sometimes fatal, particularly in the elderly. Ulcerative stomatitis and exacerbation of colitis and Crohn's disease have been reported following administration. Less frequently gastritis has been observed and pancreatitis reported. Acid peptic disease has been reported.
Very rare: Oesophagitis, formation of intestinal diaphragm-like strictures.
Hepatobiliary disorders   Very Rare: Hepatic damage, especially during long-term treatment, hepatic failure. Abnormal liver function, hepatitis and jaundice. In overdose paracetamol can cause acute hepatic failure, hepatic failure, hepatic necrosis and liver injury.
Skin and subcutaneous     Common: Rash (including maculopapular type), pruritus.
tissue disorders          Very Rare: Alopecia. Hyperhidrosis, purpura and photosensitivity.
Exfoliative dermatoses. Bullous reactions including erythema multiforme, Stevens Johnson Syndrome and Toxic Epidermal
Necrolysis. Very rare cases of serious skin reactions have been reported.
In exceptional cases, severe skin infections and soft-tissue complications may occur during varicella infection.
Not known: Drug reaction with eosinophilia and systemic symptoms
(DRESS syndrome), acute generalised exanthematous pustulosis
(AGEP).
Renal and urinary         Uncommon: Urinary retention disorders                 Rare: Kidney tissue damage (papillary necrosis), particularly in long- term therapy.
Very Rare: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, and acute and chronic renal failure.
Adverse renal effects are most often observed after overdose, after chronic abuse (often with multiple analgesics), or in association with paracetamol-related hepatotoxicity.
Acute tubular necrosis usually occurs in conjunction with liver failure, but has been observed as an isolated finding in rare cases. A possible increase in the risk of renal cell carcinoma has been associated with chronic paracetamol use as well.
One case-control study of patients with end-stage renal disease suggested that long term consumption of paracetamol may significantly increase the risk of end-stage renal disease particularly in patients taking more than 1000 mg per day.
General disorders and     Uncommon: Pyrexia administration site       Very Rare: Fatigue and malaise.
conditions
Injury, poisoning and     Uncommon: Post-operative haemorrhage following tonsillectomy has procedural                been reported.
complications
Investigations              Common: Alanine aminotransferase increased, gamma- glutamyltransferase increased and liver function tests abnormal with paracetamol.
Blood creatinine increased and blood urea increased.
Uncommon: Aspartate aminotransferase increased, blood alkaline phosphatase increased, blood creatine phosphokinase increased,
haemoglobin decreased and platelet count increased.
Rare: elevated uric acid concentrations in the blood.

Clinical studies suggest that use of ibuprofen, particularly at a high dose (2400 mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarctionor stroke) (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online formhttps://sideeffects.health.gov.il