ATTROGY Film-coated tablet Ref.[115596] Active ingredients: 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.

Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors should be avoided (see section 4.5).

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If gastro-intestinal bleeding or ulceration occurs, the treatment should be withdrawn.

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. An NSAID should be given with caution and renal function should be monitored in any patient who may have mildly or moderately reduced renal reserve. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Diflunisal has not been studied in ATTR amyloidosis patients with severe renal impairment or end-stage renal disease and must not be used in these patients (see section 4.3).

Since diflunisal and its major conjugated metabolites are eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for diflunisal.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with diflunisal after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking, prolonged QTc interval).

Infections

Diflunisal should be used with extra care in the presence of existing infection, since it may mask the usual signs and symptoms of infection.

Platelet function

Diflunisal is an inhibitor of platelet function. Patients taking diflunisal who may be adversely affected by changes in platelet function, such as those with coagulation disorders or those taking anticoagulant medicines, should be carefully monitored.

Ocular effects

Because of reports of adverse eye findings with NSAIDs as listed in Section 4.8, it is recommended that patients who develop eye complaints during treatment with diflunisal have ophthalmological evaluations.

NSAIDs exacerbated respiratory disease

Diflunisal should be used with caution in patients suffering from, or with a previous history of bronchial asthma. NSAIDs have been reported to precipitate bronchospasm in some patients.

Hepatic effects

A patient on diflunisal with signs or symptoms suggesting liver disease, or in whom abnormal liver- function tests have occurred, should be evaluated for evidence of more severe effects on hepatic function. If abnormal liver tests persist or worsen, if signs or symptoms of liver disease develop, or if systemic manifestations such as eosinophilia or rash occur, diflunisal should be discontinued.

Excipients

Attrogy contains the azo colouring agent sunset yellow aluminium lake (E110) which may cause allergic reactions.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

The following combinations with diflunisal should be avoided

Acetazolamide

Case reports suggest increased risk of metabolic acidosis when acetazolamide is used concomitantly with salicylic acid derivatives. Experimental studies show that salicylic acid derivatives, such as diflunisal, increase the free pharmacologically active concentration of acetazolamide.

Anticoagulants

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Those receiving diflunisal who have pre-existing coagulation disorders or who are on concomitant anticoagulant therapy, should be carefully monitored. This applies to all anticoagulant therapies, including vitamin K antagonists (e.g. warfarin), heparins, and direct oral anticoagulants (DOACs, e.g. rivaroxaban). Adjustment of dosage of oral anticoagulants may be required.

Indomethacin

Diflunisal reduces renal clearance and glucuronidation of indomethacin which results in a substantial increase of the plasma levels of indomethacin.

Methotrexate

Diflunisal can produce renal dysfunction resulting in reduced excretion of methotrexate. Diflunisal may also compete for drug transporters responsible for excreting methotrexate (e.g. OAT1 and OAT3).

Other NSAIDs and acetylsalicylic acid

The concomitant use of diflunisal and other NSAIDs (including cyclooxygenase-2 selective inhibitors) is not recommended owing to the increased possibility of gastro-intestinal toxicity.

Corticosteroids

The risk of gastro-intestinal bleeding and ulceration associated with NSAIDs is increased when used with corticosteroids.

Tacrolimus

There is a possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs)

There is an increased risk of gastro-intestinal bleeding when used concomitantly with NSAIDs.

Combinations that require special precaution or dose adjustments

Antacids

Co-administration of aluminium hydroxide decreases the absorption of diflunisal. The medicinal products should be taken with a 2-hour interval.

Ciclosporin

Administration of NSAIDs concomitantly with ciclosporin has been associated with an increase in ciclosporin-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking ciclosporin, and renal function should be monitored carefully.

Antihypertensives

The antihypertensive effects of some antihypertensive medicinal products, including ACE inhibitors, beta-blocking agents and diuretics, may be reduced when used concomitantly with NSAIDs. Caution should, therefore, be exercised when considering the addition of NSAID therapy to the regimen of a patient taking antihypertensive therapy.

Cardiac glycosides

An increase in serum-digoxin concentration has been reported with concomitant use of acetylsalicylic acid, indomethacin and other NSAIDs. Therefore, when concomitant digoxin and NSAID therapy is initiated or discontinued, serum digoxin levels should be closely monitored.

Diuretics

NSAIDs may reduce the effect of diuretics. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Lithium

Concomitant use of indomethacin with lithium produced a clinically relevant elevation of plasma lithium and reduction in renal lithium clearance in psychiatric patients and normal subjects with steady-state plasma lithium concentrations. This effect has been attributed to inhibition of prostaglandin synthesis and the potential exists for a similar effect with other NSAIDs. As a consequence, when an NSAID and lithium are given concomitantly, the patient should be observed carefully for signs of lithium toxicity. In addition the frequency of monitoring serum lithium concentrations should be increased at the outset of such combination therapy.

Pregnancy

From the 20^th week of pregnancy onwards, diflunisal use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy, diflunisal should not be given unless clearly necessary. If treatment with diflunisal is necessary, antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be performed from gestational week 20 until the third trimester of pregnancy (week 28) when diflunisal is contraindicated. Diflunisal must be discontinued if oligohydramnios or ductus arteriosus constriction are found.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction (see above);

the mother and the neonate, at the end of pregnancy, to:

• possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses;
• inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, diflunisal is contraindicated during the third trimester of pregnancy (see section 4.3).

Breast-feeding

Diflunisal is excreted in human milk to such an extent that effects on the breastfed newborn/infant are likely. Diflunisal is contraindicated during breast-feeding (see section 4.3).

Fertility

The use of diflunisal may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation in infertility, withdrawal of diflunisal should be considered.

Diflunisal is expected to have no or negligible influence on the ability to drive and use machines.

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:

An apparent hypersensitivity syndrome has been reported in a few patients treated with diflunisal. This syndrome manifests the following symptoms: fever, chills, cutaneous reactions of different severity, changes in liver function, jaundice, leucopenia, thrombocytopenia, eosinophilia, disseminated intravascular coagulation, renal impairment, adenitis, arthralgia, myalgia, arthritis, anorexia, disorientation.

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.