Almiral

Diclofenac sodium.

Active substance: The active substance is sodium-[o[(2, 6-dichlorophenyl)-amino]-phenyl]-acetate (= Diclofenac Sodium).
One tablet contains 25 mg or 50 mg of diclofenac sodium.

Pharmacotherapeutic Group: Anti-inflammatory and anti-rheumatic product, non-steroid, acetic acid derivative and related substance.
Pharmacology: Mechanism of Action (MOA): Almiral contains diclofenac sodium, 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 an important role in causing inflammation, pain and fever.
Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in humans.
Pharmacodynamics: In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac elicit a clinical response characterized 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 edema.
In clinical trials diclofenac has also been found to exert a pronounced analgesic effect in moderate and severe pain of non-rheumatic origin. Clinical studies have also revealed that, in primary dysmenorrhoea, diclofenac is capable of relieving the pain and reducing the extent of bleeding.
Pharmacokinetics: Absorption: Diclofenac is completely absorbed from the tablets after their passage through the stomach.
Mean peak plasma concentrations of 1.5 micrograms/mL (5 micromol/L) are attained on average 2 hours after ingestion of one tablet of 50 mg. The passage of a tablet through the stomach is slower when ingested with or after a meal than when it is taken before a meal, but the amount of diclofenac absorbed remains the same.
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.
The plasma concentrations attained in children given equivalent doses (mg/kg body weight) are similar to those obtained in adults.
Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
Distribution: 99.7% of 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.
Diclofenac was detected in a low concentration (100 ng/mL) in breast milk in one nursing mother. The estimated amount ingested by an infant consuming breast milk is equivalent to a 0.03 mg/kg/day dose.
Biotransformation/metabolism: 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 lesser 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.
Linearity/non-linearity: The amount absorbed is linearly related to the size of the dose.
Special populations: No relevant age-dependent differences in the drug's absorption, metabolism or excretion have been observed. However, in a few elderly patients a 15-minute intravenous infusion resulted in 50% higher plasma concentrations than expected from the data on young healthy subjects.
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.
Toxicology: Non-clinical Safety Data: Diclofenac did not influence fertility of parent animals (rats). Except for minimal fetal effects at maternally toxic doses, the pre, peri- and postnatal development of the offspring was not affected. In standard preclinical animal studies, no teratogenic effects were detected in mice, rats and rabbits. No mutagenic effects could be demonstrated in various in vitro and in vivo experiments, and no carcinogenic potential was detected in long term studies in rats and mice.
Administration of NSAIDs (including diclofenac) inhibited ovulation in the rabbit and implantation and placentation in the rat, and led to premature closure of the ductus arteriosus in the pregnant rat. Maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, decreased fetal survival, and intrauterine growth retardation in rats. The slight effects of diclofenac on reproduction parameters and delivery as well as constriction of the ductus arteriosus in utero are pharmacologic consequences of this class of prostaglandin synthesis inhibitors (see CONTRAINDICATION and USE IN PREGNANCY & LACTATION).

Treatment of: Inflammatory and degenerative forms of rheumatism: Rheumatoid arthritis, juvenile rheumatoid arthritis ankylosing spondylitis, osteoarthritis and spondylarthritis, painful syndromes of the vertebral column, non-articular rheumatism.
Acute attacks of gout.
Post-traumatic and post-operative pain, inflammation and swelling, e.g. following dental or orthopaedic surgery.
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: As a general recommendation, the dose should be individually adjusted. Adverse effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see PRECAUTIONS).
Adults: The recommended initial daily dose is 100 to 150 mg. In milder cases, as well as for long term therapy, 75 to 100 mg daily is usually sufficient. The total daily dose should generally be divided into 2 to 3 doses. To suppress nocturnal pain and morning stiffness, treatment with tablets during the day can be supplemented by the administration of a suppository at bedtime (up to a total maximum daily dose of 150 mg).
In primary dysmenorrhoea, the daily dose should be individually adjusted and is generally 50 to 150 mg. A dose of 50 to 100 mg should be given initially and, if necessary, increased over the course of several menstrual cycles up to a maximum of 200 mg/day. Treatment should be started on appearance of the first symptoms and, depending on the symptomatology, continued for a few days.
Special populations: Pediatrics: Children aged 1 year or over and adolescents should be given 0.5 to 2 mg/kg body weight daily in 2 to 3 separate doses, depending on the severity of the disorder. For treatment of juvenile rheumatoid arthritis, the daily dose can be raised up to a maximum of 3 mg/kg daily, given in separate doses. Generally, because of the dosage strength, only the 25 mg tablet should be used in children and adolescents.
Geriatrics (Patients aged 65 or above): Although the pharmacokinetics of Almiral are not impaired to any clinically relevant extent in elderly patients, Almiral should be used with particular caution in such patients who generally are more prone to adverse reactions (see PRECAUTIONS).
Established cardiovascular disease or significant cardiovascular risk factors: The use of high dose diclofenac (150 mg/day) for more than 4 weeks is contraindicated in patients with established cardiovascular disease (congestive heart failure, established ischemic heart disease, peripheral arterial disease) or uncontrolled hypertension. If diclofenac treatment is needed, patients with established cardiovascular disease, uncontrolled hypertension or significant cardiovascular risk factors (e.g. hypertension, hyperlipidaemia, diabetes mellitus and smoking) should be treated only after careful consideration and at doses ≤100 mg daily if the treatment is for more than 4 weeks. As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, diclofenac should always be prescribed at the lowest effective daily dose and for the shortest duration possible (see CARDIOVASCULAR EFFECTS under PRECAUTIONS).
Renal impairment: Almiral is contraindicated in patients with renal failure (see CONTRAINDICATIONS).
No specific studies have been carried out in patients with renal impairment, therefore, no specific dose adjustment recommendations can be made. Caution is advised when administering Almiral to patients with mild to moderate renal impairment (see PRECAUTIONS).
Hepatic impairment: Almiral is contraindicated in patients with hepatic failure (see CONTRAINDICATIONS).
No specific studies have been carried out in patients with hepatic impairment, therefore, no specific dose adjustment recommendations can be made. Caution is advised when administering Almiral to patients with mild to moderate hepatic impairment (see PRECAUTIONS).
Method of administration: The tablets should be swallowed whole with liquid, preferably before meals, and must not be divided or chewed.

Symptoms: There is no typical clinical picture resulting from diclofenac overdosage. Overdosage can cause symptoms such as vomiting, gastrointestinal hemorrhage, diarrhea, 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 hemoperfusion 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.

Known hypersensitivity to the active substance or to any of the excipients.
Active gastric or intestinal ulcer, bleeding or perforation (see PRECAUTIONS and ADVERSE REACTIONS).
Last trimester of pregnancy (see USE IN PREGNANCY & LACTATION).
Hepatic failure.
Renal failure.
Severe cardiac failure (see PRECAUTIONS).
Patients in whom attacks of asthma, urticaria, or acute rhinitis are precipitated by acetylsalicylic acid and/or other drugs with prostaglandin-synthetase inhibitory activity (see PRECAUTIONS and ADVERSE REACTIONS).
Treatment of peri-operative pain in setting of coronary artery bypass graft (CABG) surgery.
The use of high dose diclofenac (150 mg/day) for more than 4 weeks is contraindicated in patients with established cardiovascular disease (congestive heart failure, established ischemic heart disease, peripheral arterial disease) or uncontrolled hypertension (see SPECIAL POPULATIONS under DOSAGE & ADMINISTRATION and CARDIOVASCULAR EFFECTS under PRECAUTIONS).

General: Almiral tablets contain lactose and therefore are not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
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 occurs in patients receiving Almiral, 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 Almiral in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see ADVERSE REACTIONS). 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) 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 INTERACTIONS).
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 REACTIONS).
Cardiovascular effects: Treatment with NSAIDs including diclofenac, particularly at high dose and in long term, may be associated with a small increased risk of serious cardiovascular thrombotic events (including myocardial infarction and stroke).
As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the lowest effective daily dose should be used for the shortest duration possible (see SPECIAL POPULATIONS under DOSAGE & ADMINISTRATION). The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially when treatment continues for more than 4 weeks. Patients should be advised to 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.
Hematologic effects: During prolonged treatment with Almiral, as with other NSAIDs, monitoring of the blood count is recommended.
Like other NSAIDs, Almiral may temporarily inhibit platelet aggregation. Patients with defects of haemostasis should be carefully monitored.
Respiratory effects (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 edema 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.
Hepatobiliary effects: Close medical surveillance is required when prescribing Almiral 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 Almiral (e.g. in the form of tablets or suppositories), 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), Almiral should be discontinued. Hepatitis may occur with use of diclofenac without prodromal symptoms. Caution is called for when using Almiral in patients with hepatic porphyria, since it may trigger an attack.
Skin 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 Almiral (see ADVERSE REACTIONS).
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. Almiral should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur in rare cases with diclofenac without earlier exposure to the drug.
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 of any cause, e.g. before or after major surgery (see CONTRAINDICATIONS). Monitoring of renal function is recommended as a precautionary measure when using Almiral in such cases. Discontinuation of therapy is usually followed by recovery to the pre-treatment state.
Interactions with NSAIDs: The concomitant use of Almiral with systemic NSAIDs including cyclooxygenase-2 selective inhibitors, should be avoided due to undesirable effects (see INTERACTIONS).
Masking signs of infections: Like other NSAIDs, Almiral may mask the signs and symptoms of infection due to its pharmacodynamic properties.
Use in the Elderly: 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.

Pregnancy: There are insufficient data on the use of diclofenac in pregnant women. Therefore, Almiral should not be used during the first two trimesters of pregnancy unless the expected benefits to the mother outweigh the risks to the fetus. Use of NSAIDs at about 20 weeks gestation or later in pregnancy may cause foetal renal dysfunction leading to oligohydramnios and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. 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 and PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).
Breast-feeding: Diclofenac passes into the breast milk in small amounts. Therefore, Almiral should not be administered during breast feeding in order to avoid undesirable effects in the infant.
Fertility: The use of Almiral 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 Almiral should be considered.

Adverse drug reactions from clinical trials and/or spontaneous or literature cases (table) are listed by MedDRA system organ class.
Within each system organ class, the adverse drug reactions 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 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).
The following undesirable effects include those reported with Almiral tablets and/or other pharmaceutical forms of diclofenac, with either short-term or long-term use. (See table.)

Click on icon to see table/diagram/image

Description of selected adverse drug reactions: Arteriothrombotic events: Meta-analysis and pharmacoepidemiological data point towards a small increased risk of arteriothrombotic events (for example myocardial infarction) associated with the use of diclofenac, particularly at a high dose (150 mg daily) and during long-term treatment (see PRECAUTIONS).

The following interactions include those observed with Almiral tablets and/or other pharmaceutical forms of diclofenac.
Potent CYP2C9 inhibitors: Caution is recommended when co-prescribing diclofenac with potent CYP2C9 inhibitors (such as voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism.
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 PRECAUTIONS.)
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 PRECAUTIONS).
Quinolone antibacterials: There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.
Other NSAIDs and corticosteroids: Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal undesirable effects (see PRECAUTIONS).
Anticoagulants and anti-platelet agents: Caution is recommended since concomitant administration could increase the risk of bleeding (see PRECAUTIONS). 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 PRECAUTIONS).
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.
Phenytoin: When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.
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 be increased.

Incompatibilities: Not applicable.
Instructions for Use and Handling: No special requirements.

Store in a cool and dry place away from light.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M01AB05 - diclofenac ; Belongs to the class of acetic acid derivatives and related substances of non-steroidal antiinflammatory and antirheumatic products.

POM