Diclofast®
Diclofenac Potassium

Diclofast^® Powder for Oral Solution.

DESCRIPTION:

Diclofast contains diclofenac potassium, a non-steroidal anti-inflammatory drug. Inactive Ingredients: Glycerol dibehenate, potassium hydrogen carbonate, sucralose, lemon flavor, mint flavor, mannitol

PHARMACOLOGY:

Diclofenac, the active substance of Diclofast, is a non-steroidal compound with analgesic, anti-inflammatory and antipyretic properties.

Inhibition of prostaglandin biosynthesis has been demonstrated experimentally and is considered fundamental to the mechanism of action of diclofenac. Prostaglandins play a major causative role in inflammation, pain and fever.

In vitro, at concentrations equivalent to those attained in humans, diclofenac does not suppress proteoglycan biosynthesis in cartilage.

Indications:

Short- term treatment (maximum 3 days) of the following acute conditions:

Postoperative inflammation and pain e.g. following dental or orthopaedic surgery. Painful post-traumatic inflammatory states, e.g. due to sprains. Painful and/or inflammatory gynecological conditions, e.g. primary dysmenorrhea or adnexitis.

Migraine attacks, with or without aura. As an adjunct in severe, painful, inflammatory infections of the ear, nose or throat e.g. pharyngotonsillitis, otitis. Painful syndromes of the vertebral column. Non-articular rheumatism. In keeping with standard therapeutic principles, the underlying disease should be treated with specific therapy as appropriate. Fever alone is not an indication.

Contraindications:

Hypersensitivity to the active substance or to any of the excipients. A history of bronchospasm, urticaria, acute rhinitis, nasal polyps or allergy- like symptoms after taking acetylsalicylic acid or other non-steroidal anti-inflammatory drugs. Third trimester of pregnancy. Active gastric and/or duodenal ulcers, gastrointestinal bleeding or perforation. Inflammatory bowel disease (such as Crohn’ s disease or ulcerative colitis). Severe hepatic dysfunction (Child-Pugh class C) (cirrhosis of the liver and ascites). Severe renal impairment (creatinine clearance < 30 ml/minute). Severe heart failure (NYHA III-IV) . Treatment of postoperative pain after coronary bypass surgery (or use of a heart -lung machine). Children under 14 years of age.

SIDE EFFECTS:

The following adverse effects include those reported with all dosage forms of diclofenac during either short-term or long-term use.

Frequencies:

Very common (≥ 1/10); common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000), very rare (<1/10000). Blood and lymphatic system disorders Very rare: Thrombocytopenia, leukopenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis.

Immune system disorders

Rare: Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock). Very rare: Angioedema (including facial oedema).

Psychiatric disorders

Very rare: Disorientation, depression, insomnia, nightmares, irritability, psychotic disorders.

Nervous system disorders

Common: Headache, dizziness.

Rare: Somnolence.

Very rare: Paraesthesia, memory impairment, convulsions, anxiety, tremor, aseptic meningitis, dysgeusia, cerebrovascular accidents.

Eye disorders

Very rare: Visual disturbances, visual impairment, diplopia.

Ear and labyrinth disorders

Common: Vertigo.

Very rare: Tinnitus, impaired hearing.

Cardiac disorders

Very rare: Palpitations, chest pain, cardiac failure, myocardial infarction, hypertension.

Vascular disorders

Very rare: Vasculitis.

Respiratory disorders

Rare: Asthma (including dyspnoea).

Very rare: Pneumonitis.

Gastrointestinal disorders

Common: Nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, flatulence, decreased appetite.

Rare: Gastritis, gastrointestinal haemorrhage, haematemesis, hemorrhagic diarrhoea, melaena, gastrointestinal ulcer (with or without bleeding or perforation).

Very rare: Colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’ s disease), constipation, stomatitis, glossitis, oesophageal disorder, intestinal diaphragm disease, Pancreatitis.

Hepatobiliary disorders

Common: Transaminases increased.

Rare: Hepatitis, jaundice, liver disorder.

Very rare: Fulminant hepatitis, hepatic necrosis, hepatic failure.

Skin and subcutaneous tissue disorders

Common: Rash.

Rare: Urticaria.

Very rare: Bullous dermatitis, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), exfoliative dermatitis, alopecia, photosensitivity, purpura, Henoch-Schoenlein purpura, pruritus.

Renal and urinary disorders

Common: Fluid retention, oedema, hypertension.

Very rare: Acute renal failure, haematuria, proteinuria, tubulointerstitial nephritis, nephrotic syndrome, renal papillary necrosis.

Clinical and epidemiological data suggest that diclofenac, particularly at high doses (150 mg daily) and with prolonged use, may be associated with an elevated risk of arterial thromboembolic events (e.g. myocardial infarction or stroke).

WARNINGS AND PRECAUTIONS:

General warning for the use of systemic non-steroidal anti-inflammatory drugs:

Gastrointestinal ulceration, bleeding or perforation may occur at any time during treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), whether COX-2 selective or not, even in the absence of warning symptoms or a predisposing history. To minimize this risk, the lowest effective dose should be given for the shortest possible duration of treatment.

Patients with gastrointestinal disorders, hepatic dysfunction or a history suggestive of gastric or intestinal ulceration should not use this medicinal product unless it is strictly indicated, and require close medical supervision during treatment.

An increased risk of thrombotic cardiovascular and cerebrovascular complications with certain COX-2 selective inhibitors have been seen. It is not yet known whether this risk correlates directly with the COX-1/COX-2 selectivity of individual NSAIDs. As no comparable clinical study data are available at present for long-term treatment with the maximum dosage of diclofenac, the possibility of a similarly elevated risk cannot be ruled out. Until such data become available,

The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID. The risk may increase with longer use of the NSAID. The risk appears greater at higher doses, the risk for heart attack or stroke is similar with all NSAIDs. NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease. A large number of studies support this finding, with varying estimates of how much the risk is increased, depending on the drug and the doses studied.

A careful risk-benefit assessment must be carried out prior to using diclofenac in patients with clinically confirmed coronary heart disease, cerebrovascular disorders, peripheral arterial occlusive disease or considerable risk factors (e.g. hypertension, hyperlipidemia, and diabetes mellitus, smoking). Due to this risk, too, the lowest effective dose should be given for the shortest possible duration of treatment.

The renal effects of NSAIDs include fluid retention with oedema and/or arterial hypertension. For this reason, diclofenac should be used with caution in patients with cardiac dysfunction and other conditions that predispose to fluid retention. Caution is also indicated in patients who take concomitant diuretics or ACE inhibitors, or who are at increased risk of hypovolaemia.

The consequences are generally more serious in the elderly. If gastrointestinal bleeding or ulceration occurs in patients undergoing treatment with Diclofast, the medicinal product should be withdrawn.

Cutaneous reactions

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 diclofenac. Patients appear to be at highest risk at the start of treatment, with the onset of the reaction usually occurring within the first month of treatment.

Diclofast should be discontinued at the first sign of rash, mucosal lesions or any other sign of hypersensitivity. As with other NSAIDs, allergic reactions – including anaphylactic/anaphylactoid reactions may occur in rare cases, even without prior exposure to diclofenac.

Masking signs of infection

Its pharmacodynamic properties mean that, like other NSAIDs, Diclofast may mask the signs and symptoms of infection.

Precautions

General

The concomitant use of Diclofast with systemic NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to the potential for additive adverse effects.

Caution is required in elderly patients on basic medical ground s. In particular, it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight.

Pre-existing asthma

In patients with asthma, seasonal allergic rhinitis, chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions to NSAIDs such as asthma exacerbations (analgesic intolerance or analgesic-induced asthma), Quincke’s oedema or urticaria are more frequent than in other patients. Therefore, particular caution is required in such patients (emergency readiness). This also applies to patients with allergic reactions e.g. rash, pruritus or urticaria – to other substances.

Gastrointestinal effects

As with all NSAIDs, including diclofenac, close medical surveillance is required and particular caution should be exercised when prescribing Diclofast in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation. The risk of GI bleeding is greater with higher NSAID doses and in patients with a history of ulcer (particularly if complicated by bleeding or perforation) and in elderly patients.

Treatment should be initiated and maintained at the lowest effective dose in order to reduce the risk of GI toxicity in patients with a history of ulcer (particularly if complicated by bleeding or perforation) and in elderly patients.

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 that may increase gastrointestinal risk.

Patients with a history of GI toxicity, particularly elderly patients, should report any unusual abdominal symptoms (especially GI bleeding). Caution is required in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants, anti-platelet agents or selective serotonin reuptake inhibitors.

Hepatic effects

Close medical surveillance is required when giving Diclofast to patients with hepatic impairment, as their condition might be exacerbated.

As with all NSAIDs, including diclofenac, levels of one or more liver enzymes may rise during treatment with Diclofast. This has been observed very frequently with diclofenac, but is very rarely accompanied by clinical symptoms. Most of these cases involve borderline increases. Frequently the increases observed were moderate (≥ 3 to < 8 times the upper limit of normal), while the incidence of marked increases (≥ 8 times the upper limit of normal) remained around 1%. Raised liver enzyme levels accompanied by clinically manifest liver damage are uncommon, elevated enzyme levels were generally reversible after discontinuation of the drug. It should be noted, however, that Diclofast^® is recommended for short-term treatment only (not more than 3 days).

Diclofast^® should be discontinued if abnormal liver function tests persist or worsen, if clinical signs or symptoms suggestive of liver disease develop, or if other manifestations occur (e .g. eosinophilia, rash) .

In addition to elevated liver enzymes, there have been rare reports of severe hepatic reactions including jaundice and, very rarely, fulminant hepatitis, hepatic necrosis and hepatic failure which, in isolated cases, had a fatal outcome.

Hepatitis may develop without prodromal symptoms in patients using diclofenac. Caution is required when using Diclofast^® in patients with hepatic porphyria, since it may trigger an attack.

Renal effects

Owing to the importance of prostaglandins in maintaining renal blood flow, prolonged treatment with high doses of NSAIDs, including diclofenac, frequently (1- 10%) results in oedema and hypertension.

Particular caution is required in patients with impaired cardiac or renal function, in patients with a history of hypertension, in elderly patients, in patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and in patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery. Monitoring of renal function is recommended as a precautionary measure when using Diclofast^® in such cases. Patients usually recover to their pre-treatment state following discontinuation of therapy.

Cardiovascular effects

Treatment with NSAIDs including diclofenac, particularly at high doses and for prolonged periods, may be associated with a slightly increased risk of serious cardiovascular thrombotic events (including myocardial infarction and stroke). To minimize the potential risk of an adverse cardiovascular event in patients taking an NSAID, especially in those with cardiovascular risk factors, the lowest effective dose should be used for the shortest possible duration.

Haematological effects

Diclofast^® is recommended for short-term use only. As with other NSAIDs, regular blood counts are recommended if Diclofast^® is nonetheless used for prolonged periods .

Like other NSAIDs, Diclofast^® may temporarily inhibit platelet aggregation. Patients with coagulation disorders should be closely monitored.

Pregnancy: and breast-feeding:

Fertility

Diclofenac may impair female fertility and is therefore not recommended in women attempting to conceive. Consideration should be given to withdrawing diclofenac in women who are having difficulty conceiving, or in those being tested for infertility.

In animals, based on relevant data, impairment of male fertility cannot be ruled out. The relevance of this finding for humans is unclear.

Pregnancy

Inhibition of prostaglandin synthesis may have a negative impact on pregnancy and or embryofetal development. An elevated risk of miscarriage and of cardiac malformation and gastroschisis following use of a prostaglandin synthetase inhibitor during early pregnancy was noticed. The risk is assumed to rise with the dose and the duration of therapy.

In animals, administration of a prostaglandin synthetase inhibitor has been shown to result in increased pre-implantation and post-implantation loss and embryofetal lethality. In addition, increased incidences of various malformations, including cardiovascular malformations, have been reported in animals given a prostaglandin synthetase inhibitor during organogenesis.

During the first and second trimesters of pregnancy, diclofenac should not be given unless absolutely necessary. If diclofenac is used by a woman attempting to conceive, or during the first or second trimesters of pregnancy, the dose should be kept as low – and the duration of treatment as short – as possible.

Diclofenac is contraindicated during the third trimester of pregnancy.

All prostaglandin synthetase inhibitors may:

• expose the fetus to the following risks:

Cardiopulmonary toxicity (with premature closure of the ductus arteriosus, and pulmonary hypertension);

Renal dysfunction, which may progress to renal failure with oligohydramnios.

• expose the mother and child to the following risks:

Possible prolongation of bleeding time, an effect of inhibition of platelet aggregation even at very low doses;

Inhibition of uterine contractions, resulting in delayed or prolonged labour.

Lactation

As with other NSAIDs, small amounts of diclofenac pass into the breast milk. As a precaution, diclofenac should therefore not be used by women who are breast-feeding. If treatment is essential, the infant should be switched to bottle feeding.

Effects on ability to drive and use machines

Patients experiencing visual disturbance s, light-headedness, dizziness, drowsiness or other central nervous system disturbances while taking Diclofast^® should refrain from driving or using machines.

DRUG INTERACTIONS:

The following interactions were observed with diclofenac.

Observed interactions to be considered

• Potent CYP2C9 inhibitors

Caution is recommended when co-administering diclofenac with potent CYP2C9 inhibitors (such as voriconazole), which may result in a significant increase in peak plasma concentrations and total exposure to diclofenac due to inhibition of diclofenac metabolism.

• Lithium

Diclofenac may increase plasma concentrations of concomitantly administered lithium. Monitoring of serum lithium levels is recommended.

• Digoxin

Diclofenac may increase plasma concentrations of concomitantly administered digoxin. Monitoring of serum digoxin levels is recommended.

• Diuretics and antihypertensive agents

As with other NSAIDs, concomitant use of diclofenac may reduce the antihypertensive effects of diuretics or antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme [ACE] inhibitors). The combination should therefore be administered with caution, and patients – especially elderly patients – should have their blood pressure monitored regularly. Patients should be adequately hydrated, and attention should be paid to monitoring renal function on initiating combination therapy, and regularly thereafter, particularly with diuretics and ACE inhibitors due to the increased risk of nephrotoxicity.

• Ciclosporin

Diclofenac, like other NSAIDs, may increase the nephrotoxicity of ciclosporin due to its effects on renal prostaglandins. It should therefore be given at doses lower than those that would be used in patients not receiving ciclosporin.

• Drugs known to cause hyperkalaemia:

Concomitant treatment with potassium-sparing diuretics, ciclosporin, tacrolimus or trimethoprim may be associated with increased serum potassium levels, which should therefore be monitored frequently

• Quinolone antibiotics

There have been isolated reports of convulsions that may have been due to concomitant use of quinolones and NSAIDs.

Anticipated interactions to be considered

• Other NSAIDs and corticosteroids

Concomitant administration of diclofenac with other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal adverse effects.

• Anticoagulants and antiplatelet agents

Caution is required since concomitant administration could increase the risk of bleeding

Although clinical investigations do not appear to indicate that diclofenac affects the action of anticoagulants, there have been isolated reports of an increased risk of bleeding 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 “Warnings and precautions”) .

• Antidiabetic agents

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 reactions following administration of diclofenac, necessitating adjustment of the dosage of the antidiabetic agent. For this reason, monitoring of blood glucose levels is recommended as a precautionary measure during combination therapy.

• Methotrexate

Caution is required when NSAIDs, including diclofenac, are administered less than 24 hours before or after treatment with methotrexate because blood levels of methotrexate may rise, and methotrexate toxicity may increase.

• Phenytoin

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

DOSAGE AND ADMINISTRATION:

As a general recommendation, the dose should be individually adjusted and the lowest effective dose given for the shortest possible duration.

Adults      

The usual daily dose is 2-3 sachets of Diclofast^® (100- 150 mg per day). In milder cases as well as for adolescents over 14 years of age. 2 sachets of Diclofast^® daily (50-100 mg) are usually sufficient. The total daily amount should generally be given in 2-3 divided doses.

In primary dysmenorrhoea the daily dosage should be individually adjusted and is generally 1-3 sachets. A dose of 1-2 sachets should be prescribed initially.

Migraine: An initial dose of 50 mg is recommended at the first signs of an impending attack. If pain relief is inadequate approximately 2 hours after the first dose, a further 50mg dose may be taken. If needed, further 50 mg doses may be taken at intervals of 6-8 hours, not exceeding the maximum dose of 150 mg within 24 hours.

Special dosage instructions

Children

Because of its dosage strength, Diclofast^®is not recommended for use in children below 14 years of age. Diclogesic^® 12.5 mg suppositories are available for use in children.

No data are currently available on the use of Diclofast^® in migraine attacks in children.

Elderly patients (aged 65 or above)

No adjustment of the starting dose is required for elderly patients.

Renal impairment

No adjustment of the starting dose is required for renally impaired patients.

Hepatic impairment

No adjustment of the starting dose is required for hepatically impaired patients.

Administration

Dissolve the contents of a sachet by stirring into a glass of (non-carbonated) water, then drink. The solution may remain slightly cloudy, but this has no effect on the efficacy of the medicinal product.

The solution should preferably be taken before meals.

OVERDOSE

Signs and symptoms

There is no typical clinical picture following diclofenac overdosage. Overdosage may cause symptoms such as vomiting, gastrointestinal bleeding, diarrhoea, dizziness, tinnitus or convulsions.

Acute renal failure and liver damage are possible in the event of severe intoxication.

Therapeutic measures

Management of acute intoxication with NSAIDs, including diclofenac, essentially consists of supportive measures and symptomatic treatment. Supportive measures and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal disorders and respiratory depression.

Specific measures such as forced diuresis, dialysis or haemoperfusion are unlikely to be helpful in eliminating NSAIDs, including diclofenac, due to their high protein binding and extensive metabolism.

Activated charcoal may be considered after ingestion of a potentially toxic overdose, and gastric decontamination (e.g, vomiting, gastri c lavage) after ingestion of a potentially life-threatening overdose.

Presentations:

Diclofast^® Powder for Oral Solution: Each pack contains 9 sachets. Each sachet contains 50 mg diclofenac potassium in powder for oral solution.

Storage Conditions:

Do not store above 30°C.