VOLTFAST Powder for oral solution Ref.[49860] Active ingredients: Diclofenac

General

Undesirable effects may be minimised by using the lowest effective dose for the shortest possible duration necessary to control symptoms (see section 4.2 Posology and GI and cardiovascular risks below).

The concomitant use of Nigfast with systemic NSAIDs including cyclooxygenase-2 selective inhibitors, should be avoided due to the absence of any evidence demonstrating synergistic benefits and the potential for additive undesirable effects.

Caution is indicated in the elderly on basic medical grounds. especially used in frail elderly patients or those with a low body weight.

Like other NSAIDs, Nigfast may mask the signs and symptoms of infection due to its pharmacodynamic properties.

Nigfast contains a source of phenylalanine and may be therefore harmful for patients with phenylketonuria. The use of diclofenac potassium may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of diclofenac potassium should be considered.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur in rare cases with diclofenac without earlier exposure to the drug. Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction. Presenting symptoms of such reactions can include chest pain occurring in association with an allergic reaction to diclofenac.

Gastrointestinal effects

Gastrointestinal bleeding ulceration or perforation, which can be fatal has been reported with all NSAIDs, including diclofenac and may occur at any time during treatment with or without warning symptoms or a previous history of serious gastrointestinal events. The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2 Posology and method of administration). When gastrointestinal bleeding or ulceration occurs in patients receiving Nigfast, the medicinal product should be withdrawn.

As with all NSAIDs, including diclofenac, close medical surveillance is imperative and particular caution should be exercised when prescribing Nigfast in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see section 4.8 Undesirable effects). The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3 Contra-indications) The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see Section 4.2)

To reduce the risk of GI toxicity in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly, the treatment should be initiated and maintained at the lowest effective dose.

Combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol) should be considered for these patients, and also for patients requiring concomitant use of medicinal products containing low-dose acetylsalicylic acid (ASA)/aspirin or other medicinal products likely to increase gastrointestinal risk (see below and section 4.5 Interactions with other medicinal products and other forms of intraction).

Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, anti-platelet agents such as aspirin or selective serotonin-reuptake inhibitors (see section 4.5 Interaction with other medicinal products and other forme of interaction).

Close medical surveillance and caution should also be exercised in patients with ulcerative colitis or Crohn’s disease, as their condition may be exacerbated (see section 4.8 Undesirable effects). NSAIDs, including diclofenac, may be associated with increased risk of gastro-intestinal anastomotic leak. Close medical surveillance and caution are recommended when using diclofenac after gastro-intestinal surgery.

Hepatic effects

Close medical surveillance is required when prescribing Nigfast to patients with impaired hepatic function, as their condition may be exacerbated.

As with other NSAIDs, including diclofenac , values of one or more liver enzymes may increase. During prolonged treatment with diclofenac, regular monitoring of hepatic function is indicated as a precautionary measure. If abnormal liver function tests persist or worsen, if clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (e.g. eosinophilia, rash etc.), Nigfast should be discontinued. Hepatitis may occur with use of diclofenac, without prodromal symptoms.

Caution is called for when using diclofenac in patients with hepatic porphyria, since it may trigger an attack.

Renal effects

As fluid retention and oedema have been reported in association with NSAID therapy, including diclofenac, particular caution is called for in patients with impaired cardiac or renal function ,history of hypertension ,the elderly, patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and in those patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery (see section 4.3 Contraindications) .Monitoring of renal function is recommended as a precautionary measure when using Nigfast in such cases. Discontinuation of therapy is normally followed by a recovery to the pre-treatment state.

Skin Effects

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs, including Nigfast (see section 4.8 Undesirable effects). Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Nigfast should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or congestive heart failure (NYHA-1) as fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that the use of diclofenac, particularly at high doses (150 mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Patients with congestive heart failure (NYHA-1), and patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with diclofenac after careful consideration. As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient’s need for symptomatic relief and response to therapy should be re-evaluated periodically.

Patients should remain alert for the signs and symptoms of serious arteriothrombotic events (e.g. chest pain, shortness of breath, weakness, slurring of speech), which can occur without warnings. Patients should be instructed to see a physician immediately in case of such an event.

Haematological effects

Use of Nigfast is recommended only for short-term treatment. If, however, Nigfast is used for a prolonged period, monitoring of the blood count is recommended, as with other NSAIDs.

Like other NSAIDs, Nigfast may temporarily inhibit platelet aggregation. Patients with defects of haemostasis should be carefully monitored.

Pre-existing asthma

In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e. nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions on NSAIDs like asthma exacerbations (so-called intolerance to analgesics/analgesics-asthma), Quincke’s oedema or urticaria are more frequent than in other patients. Therefore, special precaution is recommended in such patients (readiness for emergency). This is applicable as well for patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.

(Including interactions observed with other dosage forms of diclofenac potassium and diclofenac sodium)

Observed Interactions to be considered

CYP2C9 inhibitors: Caution is recommended when co-prescribing diclofenac with CYP2C9 inhibitors (such as voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to diclofenac.

CYP2C9 inducers: Caution is recommended when co-prescribing diclofenac with CYP2C9 inducers (such as rifampicin), which could result in a significant decrease in plasma concentration and exposure to diclofenac.

Lithium: If used concomitantly, diclofenac may increase plasma concentrations of lithium. Monitoring of the serum lithium level is recommended.

Digoxin: If used concomitantly, diclofenac may increase plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.

Diuretics and antihypertensive drugs: Like other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensive drugs (e.g.beta-blockers, angiotensin converting enzyme (ACE) inhibitors may cause a decrease in their antihypertensive effect. Therefore, the combination should be administered with caution and patients, especially the elderly, should be periodically monitored. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity. (see section 4.4 Special warnings and precautions for use).

Ciclosporin: Diclofenac, like other NSAIDs, may increase the nephrotoxicity of ciclosporin due to the effect on renal prostaglandins. Therefore, it should be given at doses lower than those that would be used in patients not receiving ciclosporin.

Drugs known to cause hyperkalemia: Concomitant treatment with potassium-sparing diuretics, ciclosporin, tacrolimus or trimethoprim may be associated with increased serum potassium levels, which should therefore be monitored frequently (see section 4.4 Special warnings and precautions for use).

Quinolone antibacterials: There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.

Anticipated Interactions to be considered

Other NSAIDs and corticosteroids: Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding (see Section 4.4 special warnings and precautions for use).

Anticoagulant and anti-platlet agents: Caution is recommended since concomitant administration could increase the risk of bleeding see section 4.4. Although clinical investigations do not appear to indicate that diclofenac affects the action of anticoagulants, there are also reports of an increased risk of haemorrhage in patients receiving diclofenac and anticoagulants concomitantly. Close monitoring of such patients is therefore recommended.

Selective serotonin reuptake inhibitors (SSRIs): Concomitant administration of systemic NSAIDs including diclofenac and SSRIs may increase the risk of gastrointestinal bleeding (see section 4.4 Special warnings and precautions for use).

Antidiabetics: Clinical studies have shown that diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect. However, there have been isolated reports of both hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.

Methotrexate: Diclofenac can inhibit the tubular renal clearance of methotrexate hereby increasing methotrexate levels. Caution is recommended when NSAIDs including diclofenac are administered less than 24 hours before or after treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increased.

Phenytoin: When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin

Colestipol and cholestyramine: These agents can induce a delay or decrease in absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least one hour before or 4 to 6 hours after administration of colestipol/cholestyramine.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%.

The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality.

In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, diclofenac should not be given unless clearly necessary. If diclofenac is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

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

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligo-hydroamniosis; 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, diclofenac is contraindicated during the third trimester of pregnancy.

Lactation

Like other NSAIDs, diclofenac passes into the breast milk but in small amounts. Therefore, Voltfast should not be administered during breast feeding in order to avoid undesirable effects in the infant.

Fertility

As with other NSAIDs, the use of Voltfast may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Voltfast should be considered.

Patients who experience dizziness, vertigo, somnolence or other central nervous system disturbances while taking Voltfast, including visual disturbances, should not drive or operate machines.

Adverse drug reactions from clinical trials and/or spontaneous or literature cases (Table 1) are listed by MedRA system order class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention: (CIOMS III): very common (>1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000).

The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4 Special warnings and precautions for use). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of coilitis and Crohn’s disease (see section 4.4 Special warnings and precautions for use) have been reported following administration. Less frequently, gastritis has been observed.

The following table of undesirable effects include those reported with Voltfast powder for oral solution and/or other pharmaceutical forms of diclofenac, with either short-term or long-term use.

Table 1:

^* The frequency reflects data from long-term treatment with a high dose (150 mg/day).

Clinical trial and epidemiological data consistently point towards an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high doses (150 mg daily) and in long term treatment (see section 4.3 and 4.4 for Contraindications and Special warnings and special precautions for use).

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

In the absence of compatibility studies, this medicinal product must not be mixed with anything other than water.