Data Sheet
VOLTAREN® D
Diclofenac Free Acid
50 mg Dispersible Tablets.
Qualitative and quantitative composition
The active substance is [o[(2,6-dichlorophenyl)-amino]-phenyl]-acetate (= diclofenac free acid).
One Voltaren® D dispersible tablet contains 46.5 mg of diclofenac free acid, which is equivalent to 50 mg of diclofenac sodium.
For a full list of excipients, see List of excipients.
Pharmaceutical form
Dispersible tablets.
Clinical particulars
Therapeutic indications
Short-term treatment of the following acute conditions:
- Post-operative inflammation and pain, e.g. following dental or orthopaedic surgery.
- Painful post-traumatic inflammatory states, e.g. due to sprains.
- Flare-up of osteoarthritis.
- Acute attacks of gout.
- Non-articular rheumatism.
- Painful syndromes of the vertebral column.
- Painful and/or inflammatory conditions in gynaecology, e.g. primary dysmenorrhoea or adnexitis.
- As an adjuvant in severe painful inflammatory infections of the ear, nose or throat, e.g. pharyngotonsillitis, otitis. In keeping with general therapeutic principles, the underlying disease should be treated with basic therapy, as appropriate. Fever alone is not an indication.
Dosage and method of administration
After assessing the risk/benefit ratio in each individual patient, the lowest effective dose for the shortest possible duration should be used.
Adults
The recommended initial daily dose is 2 to 3 Voltaren D dispersible tablets. In milder cases, 2 Voltaren D dispersible tablets daily are usually sufficient. The total daily dose should generally be divided into 2 to 3 separate doses.
In primary dysmenorrhoea, the daily dose should be individually adjusted and is generally 1 to 3 Voltaren D dispersible tablets. A dose of 1 to 2 tablets should be given initially and, if necessary, increased over the course of several menstrual cycles up to a maximum of 4 tablets daily. Treatment should be started on appearance of the first symptoms and, depending on the symptomatology, continued for a few days.
Children and adolescents
Because of their dosage strength, Voltaren D dispersible tablets are not recommended for use in children and adolescents below 14 years of age. For adolescents aged 14 or over, 2 Voltaren D dispersible tablets daily are usually sufficient, taken in separate doses.
The maximum daily dose of 150 mg should not be exceeded.
Administration
Voltaren D dispersible tablets should preferably be taken before meals. Voltaren D dispersible tablets should be dropped into a glass of water and the liquid stirred to aid dispersion before swallowing. Since a proportion of the active substance may remain in the glass after swallowing, it is advisable to rinse the glass with a small amount of water and swallow again. The dispersible tablets must not be divided or chewed.
Contraindications
- Known hypersensitivity to the active substance or to any of the excipients.
- Active gastric or intestinal ulcer, bleeding or perforation.
- Last trimester of pregnancy (see Pregnancy and lactation).
- Severe hepatic renal or cardiac failure (see Special warnings and precautions for use).
- Like other non-steroidal anti-inflammatory drugs (NSAIDs), Voltaren D is also contraindicated in patients in whom attacks of asthma, urticaria, or acute rhinitis are precipitated by acetylsalicylic acid or other NSAIDs.
Special warnings and precautions for use
Warnings
Cardiovascular thrombotic events:
Observational studies have indicated that non-selective NSAIDs may be associated with an increased risk of serious cardiovascular events including myocardial infarction and stroke, which may increase with dose or duration of use. Patients with cardiovascular disease or cardiovascular risk factors may also be at greater risk. To minimise 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 (see 'Dosage and administration').
There is no consistent evidence that the concurrent use of aspirin mitigates the possible increased risk of serious cardiovascular thrombotic events associated with NSAID use.
Hypertension:
NSAIDs may lead to the onset of new hypertension or worsening of pre-existing hypertension and patients taking anti-hypertensives with NSAIDs may have an impaired anti-hypertensive response. Caution is advised when prescribing NSAIDs to patients with hypertension. Blood pressure should be monitored closely during initiation of NSAID treatment and at regular intervals thereafter.
Heart failure
Fluid retention and oedema have been observed in some patients taking NSAIDs, therefore caution is advised in patients with fluid retention or heart failure.
Gastrointestinal effects:
Gastrointestinal bleeding, ulceration or perforation, which may increase with dose or duration of use and which can be fatal, have 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. They generally have more serious consequences in the elderly. If gastrointestinal bleeding or ulceration occurs in patients receiving Voltaren D, the medicinal product should be withdrawn.
Upper GI ulcers, gross bleeding or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
Caution is advised in patients with risk factors for gastrointestinal events who may be at greater risk of developing serious gastrointestinal events, e.g. the elderly, those with a history of serious gastrointestinal events, smoking and alcoholism.
The concurrent use of aspirin and NSAIDs also increases the risk of serious gastrointestinal adverse events.
Doctors should warn patients about the signs and symptoms of serious gastrointestinal toxicity.
Severe skin reactions
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported very rarely in association with the use of NSAIDs, including Voltaren D (see Adverse effects). These serious adverse events are idiosyncratic and are independent of dose or duration of use. 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. Patients should be advised of the signs and symptoms of serious skin reactions and to consult their doctor at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity, and Voltaren D should be discontinued.
As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur in rare cases with diclofenac, without earlier exposure to the drug.
Like other NSAIDs, Voltaren D may mask the signs and symptoms of infection due to its pharmacodynamic properties.
Precautions
General
The concomitant use of Voltaren D 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 adverse effects.
Caution is indicated in the elderly on basic medical grounds. In particular, it is recommended that the lowest effective dose be used in frail elderly patients or those with a low body weight.
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.
Gastrointestinal effects
As with all NSAIDs, including diclofenac, close medical surveillance is imperative and particular caution should be exercised when prescribing Voltaren D in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see Adverse effects). The risk of GI bleeding is higher with increasing NSAID doses and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation and in the elderly.
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.
Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding). Caution is recommended 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 (see Interaction with other medicinal products and other forms 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 Adverse effects).
Hepatic effects
Close medical surveillance is required when prescribing Voltaren D 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 Voltaren D, 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), Voltaren D should be discontinued. Hepatitis may occur with use of diclofenac without prodromal symptoms.
Caution is called for when using Voltaren D 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 Contraindications). Monitoring of renal function is recommended as a precautionary measure when using Voltaren D in such cases. Discontinuation of therapy is usually followed by recovery to the pre-treatment state.
Haematological effects
Use of Voltaren D is recommended only for short-term treatment. If however, Voltaren D is used for a prolonged period, monitoring of the blood count is recommended, as with other NSAIDs.
Like other NSAIDs, Voltaren D may temporarily inhibit platelet aggregation. Patients with defects of haemostasis should be carefully monitored.
Interaction with other medicinal products and other forms of interaction
The following interactions include those observed with Voltaren D dispersible tablets and/or other pharmaceutical forms of diclofenac.
Lithium: If used concomitantly, diclofenac may raise plasma concentrations of lithium. Monitoring of the serum lithium level is recommended.
Digoxin: If used concomitantly, diclofenac may raise plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.
Diuretics and antihypertensive agents: Like other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensive agents (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 have their blood pressure 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. Concomitant treatment with potassium-sparing drugs may be associated with increased serum potassium levels, which should therefore be monitored frequently (see Special warnings and precautions for use.
Other NSAIDs and corticosteroids: Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal adverse effects (see Special warnings and precautions for use.
Anticoagulants and anti-platelet agents: Caution is recommended since concomitant administration could increase the risk of bleeding (see Special warnings and precautions for use). Although clinical investigations do not appear to indicate that diclofenac affects the action of anticoagulants, there are isolated 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 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: 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 may be increased.
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.
Quinolone antibacterials: There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.
Pregnancy and lactation
Pregnancy
The use of diclofenac in pregnant women has not been studied. Therefore, Voltaren D should not be used during the first two trimesters of pregnancy unless the potential benefit to the mother outweighs the risk to the foetus. As with other NSAIDs, use of diclofenac during the third trimester of pregnancy is contraindicated owing to the possibility of uterine inertia and/or premature closure of the ductus arteriosus (see Contraindications). Animal studies have not shown any directly or indirectly harmful effects on pregnancy, embryonal/foetal development, parturition or postnatal development (see Preclinical safety data).
Lactation
Like other NSAIDs, diclofenac passes into the breast milk in small amounts. Therefore, Voltaren D should not be administered during breast feeding in order to avoid adverse effects in the infant.
Fertility
As with other NSAIDs, the use of Voltaren D 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 Voltaren D should be considered.
Effects on ability to drive and use machines
Patients experiencing visual disturbances, dizziness, vertigo, somnolence or other central nervous system disturbances while taking Voltaren D should refrain from driving or using machines.
Adverse effects
Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports.
The following adverse effects include those reported with Voltaren D dispersible tablets and/or other pharmaceutical forms of diclofenac, with either short-term or long-term use.
Table 1
| 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: | Angioneurotic oedema (including face oedema). |
| Psychiatric disorders | |
| Very rare: | Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder. |
| Nervous system disorders | |
| Common: | Headache, dizziness. |
| Rare: | Somnolence. |
| Very rare: | Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident. |
| Eye disorders | |
| Very rare: | Visual disturbance, vision blurred, diplopia. |
| Ear and labyrinth disorders | |
| Common: | Vertigo. |
| Very rare: | Tinnitus, hearing impaired. |
| Cardiac disorders | |
| Very rare: | Palpitations, chest pain, cardiac failure, myocardial infarction. |
| Vascular disorders | |
| Very rare: | Hypertension, vasculitis |
| Respiratory, thoracic and mediastinal disorders | |
| Rare: | Asthma (including dyspnoea). |
| Very rare: | Pneumonitis. |
| Gastrointestinal disorders | |
| Common: | Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia. |
| Rare: | Gastritis, gastrointestinal haemorrhage,Haematemesis, diarrhoea haemorrhagic, 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, diaphragm-like intestinal strictures, 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 eruptions, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), dermatitis exfoliative, loss of hair, photosensitivity reaction, purpura, allergic purpura, pruritus. |
| Renal and urinary disorders | |
| Very rare: | Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis. |
| General disorders and administration site conditions | |
| Rare: | Oedema. |
Overdose
Symptoms
There is no typical clinical picture resulting from diclofenac overdosage. Overdosage can cause symptoms such as vomiting, gastrointestinal haemorrhage, diarrhoea, dizziness, tinnitus or convulsions. In the event of significant poisoning, acute renal failure and liver damage are possible.
Therapeutic measures
Management of acute poisoning 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 disorder, and respiratory depression.
Special measures such as forced diuresis, dialysis or haemoperfusion are probably of no help in eliminating NSAIDs, including diclofenac, due to the high protein binding and extensive metabolism.
Activated charcoal may be considered after ingestion of a potentially toxic overdose, and gastric decontamination (e.g. vomiting, gastric lavage) after ingestion of a potentially life-threatening overdose.
Pharmacological properties
Pharmacodynamic properties
Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, non-steroids, acetic acid derivatives and related substances (ATC code: M01A B05).
Mechanism of action
Diclofenac, the active substance of Voltaren D, is a non-steroidal compound with pronounced antirheumatic, anti-inflammatory, analgesic and antipyretic properties. Inhibition of prostaglandin biosynthesis, which has been demonstrated in experiments, is considered fundamental to its mechanism of action. Prostaglandins play a major role in causing inflammation, pain and fever.
Diclofenac in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to those reached in humans.
Pharmacodynamic effects
Voltaren D dispersible tablets have a rapid onset of action, which makes them particularly suitable for the treatment of acute painful and inflammatory conditions, and for those patients who have difficulty in swallowing conventional tablets.
In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac elicit a clinical response characterised by marked relief from signs and symptoms such as pain at rest, pain on movement, morning stiffness, and swelling of the joints, as well as by an improvement in function.
In post-traumatic and post-operative inflammatory conditions, diclofenac rapidly relieves both spontaneous pain and pain on movement and reduces inflammatory swelling and wound oedema.
In addition, the active substance is capable of relieving the pain and reducing the extent of bleeding in primary dysmenorrhoea. Voltaren D has also been found to exert a pronounced analgesic effect in other moderately and severely painful states.
Pharmacokinetic properties
Absorption
Absorption of diclofenac from Voltaren D dispersible tablets sets in immediately after administration, the bioavailability of diclofenac being 82% of that achieved with gastro-resistant tablets.
Mean peak plasma concentrations of about 1 micrograms/mL (3 micromol/L) are attained on average 1 hour after ingestion of one Voltaren D dose on an empty stomach. The amount absorbed is linearly related to the size of the dose.
Ingestion of dispersible tablets together with or immediately after a meal does not delay the onset of absorption but reduces the amount absorbed by an average of about 16% and the maximum concentrations by about 50%.
Since about half of diclofenac is metabolised during its first passage through the liver ("first pass" effect), the area under the concentration curve (AUC) following oral or rectal administration is about half that following an equivalent parenteral dose.
Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
Distribution
99.7% diclofenac is bound to serum proteins, mainly to albumin (99.4%). The apparent volume of distribution calculated is 0.12 to 0.17 L/kg.
Diclofenac enters the synovial fluid, where maximum concentrations are measured 2 to 4 hours after peak plasma values have been attained. The apparent half-life for elimination from the synovial fluid is 3 to 6 hours. Two hours after reaching peak plasma values, concentrations of the active substance are already higher in the synovial fluid than in the plasma, and they remain higher for up to 12 hours.
Biotransformation
Biotransformation of diclofenac takes place partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites (3'-hydroxy-,4'-hydroxy-,5-hydroxy-,4',5-dihydroxy- and 3'-hydroxy-4'-methoxy-diclofenac), most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a much smaller extent than diclofenac.
Elimination
Total systemic clearance of diclofenac from plasma is 263 56 mL/min (mean value SD). The terminal half-life in plasma is 1 to 2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1 to 3 hours. One metabolite, 3'-hydroxy-4'-methoxy-diclofenac has a much longer plasma half-life. However, this metabolite is virtually inactive.
About 60% of the administered dose is excreted in the urine as the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.
Characteristics in patients
No relevant age-dependent differences in the drug's absorption, metabolism or excretion have been observed.
In patients suffering from renal impairment, no accumulation of the unchanged active substance can be inferred from the single-dose kinetics when applying the usual dosage schedule. At a creatinine clearance of <10 mL/min, the calculated steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.
In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.
Preclinical safety data
Preclinical data from acute and repeated dose toxicity studies, as well as from genotoxicity, mutagenicity, and carcinogenicity studies with diclofenac revealed no specific hazard for humans at the intended therapeutic doses. There was no evidence that diclofenac had a teratogenic potential in mice, rats or rabbits.
Diclofenac had no influence on the fertility of parent animals in rats. The prenatal, perinatal and postnatal development of the offspring was not affected.
Pharmaceutical particulars
List of excipients
Microcrystalline cellulose; sodium starch glycollate; croscarmellose sodium; silica, colloidal anhydrous; castor oil, hydrogenated; talc.
Incompatibilities
Not applicable.
Shelf life
2 years.
Special precautions for storage
Do not store above 25°C.
Store in original package in order to protect from moisture.
Voltaren D dispersible tablets must be kept out of the reach and sight of children.
Nature and contents of container
Blister packs containing 20 dispersible tablets
Instructions for use/handling
No special requirements.
Medicine classification
Prescription Medicine
Name and address
Novartis New Zealand Limited
Private Bag 65904
Mairangi Bay
Auckland 0754
Building G, 5 Orbit Drive
Rosedale
Auckland 0632
Telephone: 09 361 8100
Date of preparation
8 June 2009
(Ref: BPI 25 September 2008 + Medsafe requirements 5/6/07)