Voltarol 12.5 Mg Liquid Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Voltarol 12.5 mg Liquid Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One Voltarol 12.5 mg liquid capsule contains 12.5 mg of diclofenac potassium. Excipient with known effect: Sorbitol.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Soft capsules.
Oval, translucent yellow soft capsules.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Short term relief of headache, dental pain, period pain, rheumatic pain, muscular pain and backache and the symptoms of colds and flu, including fever.
4.2 Posology and method of administration
As a general recommendation, the lowest effective dose should be used for the shortest duration necessary to relieve symptoms.
Adults and children aged 14 years and over:
Initially two capsules, followed by one or two capsules every 4 to 6 hours as needed. No more than 6 capsules (75 mg) should be taken in any 24 hour period.
Voltarol 12.5mg Liquid Capsules should not be used for longer than 3 days. If symptoms persist or worsen consult your doctor.
The capsules should be swallowed whole with a drink of water.
Children and adolescents:
Voltarol 12.5mg Liquid Capsules are not are not to be used in children and adolescents under 14 years of age.
Elderly
Nonsteroidal anti-inflammatory drugs should be used with particular caution in such patients who generally are more prone to adverse reactions. In particular it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight (also see precautions).
Renal impairment
No adjustment of the starting dose is required for renally impaired patients (see section 4.4 Special warnings and precautions).
Hepatic impairment
No adjustment of the starting dose is required for hepatically impaired patients (see section 4.4 Special warnings and precautions).
4.3 Contraindications
• Known hypersensitivity to diclofenac or to any of the excipients listed in section 6.1.
• Patients in whom attacks of asthma, angioedema, urticaria, or acute rhinitis are precipitated by acetylsalicylic acid or other non-steroidal anti-inflammatory drugs such as ibuprofen.
• Active gastric or intestinal ulcer, bleeding or perforation.
• Pregnancy or breastfeeding (see section 4.6 Pregnancy and lactation).
• Severe hepatic, renal or cardiac failure (see section 4.3 Contraindications and section 4.4 Special warnings and special precautions for use).
• Concomitant use of anticoagulants and antiplatelets (see section 4.5 Interactions)
• Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors (see section 4.5 Interactions)
• History of gastrointestinal bleeding or perforation, relating to previous NSAID therapy
4.4 Special warnings and precautions for use
General
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and Gastrointestinal and Cardiovascular risks below).
The concomitant use of diclofenac with systemic NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided due to the potential for additive undesirable 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.
As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can occur in rare cases with diclofenac without earlier exposure to the drug. (see section 4.8 Undesirable effects).
Like other NSAIDs, diclofenac may mask the signs and symptoms of infection due to its pharmacodynamic properties.
Voltarol 12.5mg Liquid Capsules contain sorbitol and therefore are not recommended for patients with rare hereditary problems of fructose intolerance.
Gastrointestinal effects
Gastrointestinal bleeding, ulceration or perforation, 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 occur in patients receiving diclofenac, the medicinal product should be withdrawn.
As with all NSAIDs, including diclofenac, close medical surveillance is imperative and caution should be exercised when prescribing diclofenac 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). 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.
The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.
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 low-dose acetylsalicylic acid (ASA), 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 section 4.5).
Close medical surveillance should also be exercised in patients with ulcerative colitis or Crohn's disease, as their condition may be exacerbated (see section 4.8).
Hepatic effects
Close medical surveillance is required when prescribing diclofenac 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), diclofenac 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 edema 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). Monitoring of renal function is recommended as a precautionary measure when using diclofenac in such cases. Discontinuation of therapy is usually followed by 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 diclofenac (see section 4.8). 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. Diclofenac should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
Cardiovascular and cerebrovascular effects
Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.
Clinical trial and epidemiological data suggest that 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). Available data do not suggest an increased risk with use of low dose diclofenac (up to 75 mg/day) up to 3 days for relief of pain or fever.
Hematological effects
During prolonged treatment with diclofenac, as with other NSAIDs, monitoring of the blood count is recommended.
Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Patients with defects of hemostasis 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 to
NSAIDs such as 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 also applicable to patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.
Female fertility:
The use of Voltarol may impair female fertility and is not recommended in women attempting to conceive. In women who may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Voltarol should be considered (see section 4.6 Fertility, pregnancy and lactation).
Information concerning excipients
Voltarol 12.5 mg liquid capsules contain sorbitol and therefore patients with rare hereditary problems of fructose intolerance should not take this medicine.
The label contains the following statements:
Keep out of the sight and reach of children Do not store above 30°C
4.5 Interaction with other medicinal products and other forms of interaction
The following interactions include those observed with diclofenac gastro-resistant 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 (see section 4.4).
Other NSAIDs and corticosteroids: Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal undesirable effects (see section 4.4).
Anticoagulants and anti-platelet 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 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 section 4.4).
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.
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 potassiumsparing 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.
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.
Cardiac glycosides: Concomitant use of cardiac glycosides and NSAIDs in patients may exacerbate cardiac failure, reduce GFR and incrase plasma glycoside levels.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduct the effect of mifepristone.
Potent CYP2C9 inhibitors: Caution is recommended when co-prescribing diclofenac with potent CYP2C9 inhibitors (such as sulfinpyrazone and voriconazole), which could result in a significant increase in peak plasma concentration and exposure to diclofenac due to inhibition of diclofenac metabolism.
4.6 Fertility, pregnancy and lactation
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 in small amounts. Therefore, diclofenac should not be administered during breast feeding in order to avoid undesirable effects in the infant.
Fertility
As with other NSAIDs, the use of diclofenac 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 should be considered.
4.7 Effects on ability to drive and use machines
Patients experiencing visual disturbances, dizziness, vertigo, somnolence or other central nervous system disturbances while taking diclofenac should refrain from driving or using machines.
4.8 Undesirable effects
Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as 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); not known: cannot be estimated from the available data. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The following undesirable effects include those reported with either short-term or long-term use._
|
System Organ Class (SOC) Frequency |
Adverse Reaction |
|
Blood and lymphatic system disorders Very rare |
Thrombocytopenia, leukopenia, anaemia (including haemolytic anaemia and aplastic anaemia), agranulocytosis. |
|
Immune system disorders Rare Very rare |
Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock). Angioedema (including face oedema). |
|
Psychiatric disorders Very rare |
Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder. |
|
Nervous system disorders Common Rare Very rare |
Headache, dizziness. Somnolence. Paraesthesia, memory impairment, convulsion, anxiety, tremor, meningitis aseptic, dysgeusia, cerebrovascular accident. |
|
Eye disorders Very rare |
Visual impairment, vision blurred diplopia. |
|
Ear and labyrinth disorders Common Very rare |
Vertigo. Tinnitus, hearing impaired. |
|
Cardiac disorders Very rare |
Palpitations, chest pain, cardiac failure, myocardial infarction. |
|
Vascular disorders | |
|
System Organ Class (SOC) Frequency |
Adverse Reaction |
|
Very rare |
Hypertension, vasculitis. |
|
Respiratory, thoracic and mediastinal disorders Rare Very rare |
Asthma (including dyspnoea). Pneumonitis. |
|
Gastrointestinal disorders Common |
Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, decreased appetite. |
|
Rare |
Gastritis, gastrointestinal haemorrhage, Haematemesis, diarrhoea hemorrhagic, 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 Rare Very rare |
Transaminases increased. Hepatitis, jaundice, liver disorder. Hepatitis fulminant, hepatic necrosis, hepatic failure. |
|
Skin and subcutaneous tissue disorders Common Rare Very rare |
Rash. Urticaria. Dermatitis bullous, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), dermatitis exfoliative, alopecia, photosensitivity reaction, purpura, Henoch-Schonlein purpura, pruritus. |
|
Renal and urinary disorders Very rare |
Renal failure acute, haematuria, proteinuria, nephrotic syndrome, tubulointerstitial nephritis, renal papillary necrosis. |
|
General disorders and administration site conditions Rare |
Oedema. |
Clinical trial and epidemiological data suggest that 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) (see section 4.4).
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 internet at www.mhra.gov.uk/yellowcard.
4.9 Overdose
Symptoms
There is no typical clinical picture resulting from diclofenac overdosage. Overdose 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. These 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 in case of a potentially toxic overdose, and gastric decontamination (e.g. vomiting, gastric lavage) in case of a potentially life-threatening overdose.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, nonsteroids, acetic acid derivatives and related substances (ATC code M01A B05).
Voltarol 12.5mg Liquid Capsules contain diclofenac potassium, a non-steroidal antiinflammatory drug (NSAID) with pronounced analgesic, anti-inflammatory and antipyretic properties. Inhibition of prostaglandin biosynthesis is considered fundamental to its mechanism of action. Prostaglandins play a major role in causing inflammation, pain and fever.
Voltarol 12.5mg Liquid Capsules have a rapid onset of action and therefore suitable for the treatment of acute episodes of pain, fever and inflammation.
Diclofenac potassium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to those reached in humans.
5.2 Pharmacokinetic properties Absorption
Diclofenac is rapidly and completely absorbed. Following ingestion of two 12.5 mg capsules, mean peak plasma concentrations of 3.68 micromol/L are attained after approximately 25 minutes (median Tmax). The amount absorbed is in linear proportion to the size of the dose.
Clinical pharmacokinetic data has demonstrated that extent of absorption (AUC) is equivalent for Voltarol 12.5mg Liquid Capsules and Voltarol 12.5mg tablets. Early exposure is greater for the soft capsule compared to the tablet, and Cmax for the soft capsule is higher than that of the tablet with a faster Tmax.
Since about half of diclofenac is metabolised during its first passage through the liver (“first pass” effect), the area under the concentration curve is about half as large following oral administration as it is following a parenteral dose of equal size.
Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
Distribution
99.7% of diclofenac binds to serum proteins, mainly to albumin (99.4%). The apparent volume of distribution 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 reached. The apparent half-life for elimination from the synovial fluid is 3 to 6 hours. Two hours after reaching peak plasma levels, 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, most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.
Elimination
Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min. 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. A fifth metabolite, 3’-hydroxy-4’-methoxy-diclofenac, has a much longer plasma half-life. 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 less than 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.
5.3 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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule fill content: polyethylene glycol 600, glycerol (E 422).
Capsule shell: gelatin, glycerol (E422), Polysorb 85/70/00 (sorbitol, sorbitans), quinoline yellow (E104).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 30°C.
6.5 Nature and contents of container
PVC/PVDC/Aluminium opaque blisters. Pack size: 10 or 18 capsules.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Novartis Consumer Health Limited
Park View, Riverside Way, Watchmoor Park
Camberley, Surrey, GU15 3YL
8 MARKETING AUTHORISATION NUMBER(S)
PL 00030/0439
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
09/07/2014
10 DATE OF REVISION OF THE TEXT
09/07/2014