Attrogy

Posology The recommended dose of diflunisal is one 250 mg tablet taken twice daily. 4). Special populations Elderly Diflunisal should be used with caution in elderly patients who are more prone to adverse reactions. 4). Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs.

Renal impairment Since diflunisal and its major metabolites are eliminated primarily by the kidneys, its half-life is extended in patients with reduced renal function. 4). No dose adjustment is required in patients with mild or moderate renal impairment.

Hepatic impairment No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh A or B). 3). 3 Paediatric population There is no relevant use of diflunisal in the paediatric population in the hATTR amyloidosis indication.

Method of administration It is recommended that the tablets are swallowed whole, not crushed or chewed, due to the bitter taste. Patients who are taking antacids should leave a 2-hour interval between taking diflunisal and taking antacid medicines.

Summary of the safety profile The most common and most important adverse reactions reported for diflunisal are gastro-intestinal. Tabulated list of adverse reactions Adverse reactions are listed below by MedDRA System Organ Class (SOC) and frequency categories using the standard convention: 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) and Not known (frequency cannot be estimated from the available data).

Table 1 Tabulated list of adverse reactions System Organ Class Very common Common Uncommon Very rare Infections and infestations Viral gastroenteritis Blood and lymphatic system disorders Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia 8 System Organ Class Very common Common Uncommon Very rare Immune system disorders Acute anaphylactic reaction with bronchospasm, angioedema, hypersensitivity vasculitis, hypersensitivity syndrome Psychiatric disorders Depression, hallucinations, nervousness, confusion Nervous system disorders Headache, dizziness, somnolence, insomnia Vertigo, light headedness, paraesthesiae Eye disorders Ocular hypertension Transient visual disturbances including blurred vision Ear and labyrinth disorders Tinnitus Cardiac disorders Cardiac failure Palpitations, syncope Vascular disorders Hypertension Allergic vasculitis Respiratory, thoracic and mediastinal disorders Dyspnoea Rhinitis, asthma Gastrointestinal disorders Dyspepsia Gastrointestinal pain, diarrhoea, nausea, vomiting, constipation, flatulence, gastrointestinal perforation and bleeding, gastroesophageal reflux disease Peptic ulcer, anorexia, gastritis, haematemesis, melaena, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease Hepatobiliary disorders Jaundice sometimes with fever, cholestasis, liver- function abnormality, hepatitis Raised transaminases Skin and subcutaneous tissue disorders Rash, sweating, dermatitis, erythema Pruritus, dry mucous membranes, stomatitis, photosensitivity, urticaria, erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis Musculoskeletal and connective tissue disorders Muscle cramps Renal and urinary disorders Renal failure, proteinuria Dysuria, renal impairment, interstitial nephritis, haematuria, nephritic syndrome 9 System Organ Class Very common Common Uncommon Very rare General disorders and administration site conditions Fatigue, oedema, peripheral oedema, chest pain, early satiety, Asthenia, loss of apetite Investigations Occult blood positive, haematocrit decreased An apparent hypersensitivity syndrome has been reported in a few patients treated with diflunisal.

Patients treated with NSAIDs long-term, such as diflunisal, should undergo regular medical supervision to monitor for adverse reactions. Older patients are particularly susceptible to the adverse reactions of NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal.

Prolonged use of NSAIDs in these patients is not recommended. Where prolonged therapy is required, patients should be monitored regularly. 5). Gastro-intestinal effects Diflunisal should be used with caution in patients having a history of gastro-intestinal haemorrhage, or ulcers.

In patients with active peptic ulcers, the treatment should only be initiated if the potential benefit of treatment outweighs the potential risk of adverse reactions. Gastro-intestinal bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious gastro-intestinal events.

Close monitoring and standard prophylactic care, such as proton-pump inhibitors, to reduce risk of gastro-intestinal effects caused by NSAIDs should be considered for patients at risk of gastro-intestinal side-effects. If gastro-intestinal bleeding or ulceration occurs, the treatment should be withdrawn.

4 Renal effects There have been reports of acute interstitial nephritis with haematuria, proteinuria, and occasionally nephrotic syndrome in patients receiving diflunisal. In patients with reduced renal blood flow where renal prostaglandins play a major role in maintaining renal perfusion, administration of an NSAID may precipitate overt renal decompensation.

Patients at greatest risk of this reaction are those with renal or hepatic dysfunction, diabetes mellitus, advanced age, extracellular volume depletion, congestive heart failure, sepsis, or concomitant use of any nephrotoxic medicinal product.

1. Previous acute asthmatic attacks, urticaria, rhinitis or angioedema precipitated by acetylsalicylic acid or other NSAIDs, due to risk of cross-reaction. Active gastro-intestinal bleeding. 4). 4). 4). 6).