Cataflam Sugar Coated Tablet

Cataflam®

Pharmaceutical term, Active substance, Active moiety, Excipients, Indications, Dosage, General target population, Special population, Mode of administration, Contraindications, Gastrointestinal effects, Cardiovascular effects, Hematologic effects, Respiratory effects, Hepatobiliary effect, Skin reactions, Renal effects, Interactions with NSAIDs, Masking signs of infections, Adverse drug reactions, Interactions, Anticipated interactions, Pregnancy effects, Breastfeeding effects, Fertility effects, Overdosage, Mechanism of action, Absorption, Distribution, Biotransformation/ metabolism, Elimination, Linearity/non-linearity, Clinical studies, Non-clinical safety data, Incompatibility, Storage, Instructions for use/handling and Manufacturer of Cataflam Tablet Medicine for Arthritis.

Anti-inflammatory and anti-rheumatic product, non-steroid, acetic acid derivative and related substance.
DESCRIPTION AND COMPOSITION

Pharmaceutical term

Sugar-coated tablets.

 

Active substance
The active substance is potassium-[o-[(2,6-dichlorophenyl)- amino]-phenyl]-acetate (= diclofenac potassium). In Cataflam the sodium ion of diclofenac sodium (Voltaren®) has been replaced by a potassium ion.

One Cataflam sugar-coated tablet contains 25mg or 50mg of diclofenac potassium.

Certain dosage strengths may not be available in all countries.

 

Active moiety

Diclofenac.

 

Excipients

Core

Magnesium stearate; povidone; silica colloidal anhydrous; sodium starch glycollate; maize starch; calcium phosphate.

 

Sugar-coat

Microcrystalline cellulose; polyethylette glycol 8000; red iron oxide (E172) and titanium dioxide (E171) (dispersed Anstead); pevidone; talc; sucrose.

 

Polish

Polyethylene glycol 8000; sucroso.

Imprint with printing ink brown for 25mg and white for 50mg

Pharmaceutical formulations may vary between countries.

 

INDICATIONS

Short-term treatment in the following acute-conditions:

• Post-traumatic pain, inflammation and smelling; e.g. due to sprains.

• Post-operative pain inflammation and swelling, e.g. following dental or orthopedic surgery.

• Painful and or inflammatory conditions in gynecology, e.g primary dysmenorrhea or adnexitis.

• Migraine attacks.

• Painful syndromes of the vertebral column.

• Non-articular rheumatism.

• As an adjuvant in severe painful inflammatory infections of the ear, nose or throat, e.g. pharyngotonsillitis, otitis. Is keeping with general therapeutic principles, the underlying disease should be treated with basic therapy, as appropriate. Fever alone is not an indication.
DOSAGE AND ADMINISTRATION

Dosage

As a general recommendation, the dose should be individually  adjusted. Adverse effects maybe minimized by using the lowest effective dose for the shortest duration neccesary to control symptoms (see section WARNINGS AND PRECAUTIONS).

 

General target Population

The recommended initial daily dose is 100 to 150mg. In milder cases, 75 to 100mg daily is usually sufficient.

The total daily dose should generally be divided into 2 or 3 separate doses, as applicable.

In primary dysmonerrhea, the daily dose should be individually adjusted and is generally 50 to 150mg. An initial dose of 50mg is usually sufficient. If necessary, an initial dose of 100mg can be prescribed with a maximum of 200 mg/day reached over the course of several menstrual cycles. Treatment should be started on appearance of the first symptoms and, depending of the symptomatology, continued for a few days.

In migraine, as initial dose of 50mg should be taken at the first signs of an impending attack. In cases where pain relief within 2 hours after the first dose is not sufficient, a further dose of 50mg may be taken. If needed, further doses of 50mg may be taken at intervals ef 4 to 6 hours, not exceeding a total dose of 200 mg per day.

 

Special populations

Pediatrics

Cataflam tablets are not recommended for use in children and adolescents below 14 years of age. For treatment in children and adolescents below 14 years of age, oral drops or suppositories of diclofenac 12.5 mg and 25mg could be used. For adolescents aged 14 years and over, a daily dose at 75 to 100mg is usually sufficient.

The maximum daily dose of 150mg should not be exceeded. The total daily dose should generally be divided into 2 to 3 separate doses, as applicable.
The use of Cataflam (all forms) in migraine attacks has not born established in children and adolescents.

 

Geriatrics (Patients aged 65 or above)

No adjustment of the starting dose is required for elderly patients (see section WARNINGS AND PRECAUTIONS).

 

Established cardiovascular disease or significant cardiovascular risk factors
Treatment wth Cataflam is generally not recommended in patients with established cardiovascular disease or uncontrolled hypertension. If needed, patients with established cardiovascular, uncontrolled hypertension or significant risk factors for cardiovascular disease should be treated with Cataflam only after careful consideration and only at doses <100 mg daily if treated for more than 4 weeks (see section WARNINGS AND PRECAUTIONS).

 

Renal impairment

Cataflam is contraindicated in patients with renal failure (see section 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 Cataflam to patients with mild to moderate renal impairment patients (see section WARNINGS AND PRECAUTIONS).

 

Hepatic impairment

Cataflam is contraindicated in patients with hepatic failure (see section 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 Cataflam to patients with mild to moderate hepatic impairment (see section WARNINGS AND PRECAUTIONS).

 

Mode of administration

The tablets should be swallowed whole with liquid, preferably before meals, and must not be divided or chewed.

 

CONTRAINDICATIONS

* Known hypersensitivity to the active substance or any of the other excipients.

* Active gastric or intestinal ulcer, bleeding or perforation (see section WARNINGS AND PRECAUTIONS and also section ADVERSE DRUG REACTIONS).

* Last trimester of pregnancy (see section WOMEN OF CHILD-BEARING POTENTIAL, PREGNANCY, BREAST-FEEDING AND FERTILITY).

* Hepatic failure.

* Renal failure.

* Severe cardiac failure (see section WARNINGS AND PRECAUTIONS).

* Like other non-steroidal anti-inflammatory drugs (NSAIDs), Cataflam is also contraindicated in patients in whom attacks of asthma, urticaria, or acute rhinitis are precipitated by acetylsalicylic acid or other NSAIDs (see section WARNINGS AND PRECAUTIONS and also section ADVERSE DRUG REACTIONS).

 

WARNINGS AND PRECAUTIONS

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 Cataflam, 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 Cataflam in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see section ADVERSE DRUG REACTIONS). The risk of GI bleeding is higher with increasing NSAID doses and is patients with a history of ulcer, particularly if complicated with hemorrhage or perforation and in the elderly.

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

Combination therapy with protective agents (e.g proton pump inhibitors or misoprostol) should he 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 an systemic corticosteroids, anticoagulants, anti-platelet agents or selective serotonin-reuptake inhibitors (see section 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 (sea section ADVERSE DRUG REACTIONS).

 

Cardiovascular effects

Treatment with NSAIDs including diclofenac, particularly at high dose and in long term, maybe associated with a small increased risk at serious cardiovascular thrombotic events (including myocardial infarction and stroke).

Treatment with Cataflam is generally not recommended in patients with established cardiovascular disease (congestive heart failure, established ischemic heart disease, peripheral arterial disease) or uncontrolled hypertension. If needed, patients with established cardiovascular disease, uncontrolled hypertension or significant risk factors for cardiovascular disease (e.g. hypertension, hyperlipidemia, diabetes mellitus and smoking) should be treated with Cataflam only after careful consideration and only at doses < 100mg daily when treatment continues for more than 4 weeks.

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. 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 remain alert for the signs and symptoms of serious arteriothrombotic events (e.g. chest pain, shortness at 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

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

Like other NSAIDs, Cataflam may temporarily inhibit platelet aggregation. Patients with defects of hemostasis 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 as 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 effect

Close medical surveillance is required when prescribing Cataflam 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 Cataflam, 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), Cataflam should be discontinued. Hepatitis may occur with use of diclofenac without prodromal symptoms. Caution is called for when using Cataflam 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 at NSAIDs, including Cataflam (see section ADVERSE DRUG REACTIONS). Patients appear to be at highest risk of these reactions early in the course at therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Cataflam 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 from any cause, e.g. before or after major surgery (see section CONTRAINDICATIONS). Monitoring of renal function in recommended as a precautionary measure when using Cataflam in such cases. Discontinuation of therapy is usually followed by recovery to the pre-treatment state.

 

Geriatric patient

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

 

Interactions with NSAIDs

The concomitant use of Cataflam with systemic NSAIDs including cyclooxygenase-2 selective inhibitors, should be avoided due to the potential for additive undesirable effects (see section INTERACTIONS).

 

Masking signs of infections

Like other NSAIDs, Cataflam may mask the signs and symptoms of intectiso due to its pharmacodynomic properties.

 

ADVERSE DRUG REACTIONS

Adverse drug reactions from clinical trials and/or spontaneous or literature reports (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order at 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 (<1/1000 to <1/100); rare(>1/10000 to <1/1000); very rare (<1/10000).

The following undesirable effects include those reported with Cataflam sugar-coated tablets and/or other pharmaceutical forms of diclofenac, with either short-term or long-term use.

 

Tablet 1 Adverse drug reactions

Blood and lymphatic system disorders

Very rare

Thrombocytopenia, leukopenia, anemia (including hemolytic and aplastic anemia), agranulocytosis.

 

Immune system disorders

Rare

Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock).

 

Very rare

Angioedema (including face edema).

 

Psychiatric disorders

Very rare

Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.

 

Nervous system disorders

Common

Headache, dizziness

 

Rare

Somnolence

 

Very rare

Paresthesia, memory impairment, convulsion, anxiety, tremor, meningitis aseptic, dysgeusia, cerebrovascular accident.

 

Eye disorders

Very rare

Visual impairment, vision blurred, diplopia.

 

Ear and labyrinth disorders

Common

Vertigo

 

Very rare

Tinnitus, hearing impaired.

 

Cardiac disorders

Uncommon*

Myocardial infarction, cardiac failure, palpitations, chest pain.

 

Vascular disorders

Very rare

Hypertension, vasculitis

 

Respiratory, thoracic and mediastinal disorders

Rare

Asthma (including dyspnea)

 

Very rare

Pneumonitis

 

Gastrointestinal disorders

Common

Nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, decreased appetite.

 

Rare

Gastritis, gastrointestinal hemorrhage, hematemesis, diarrhea hemorrhagic, melena, gastrointestinal ulcer (with as without bleeding or perforation).

 

Very rare

Colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis, glossitis, esophageal disorder, intestinal diaphragm disease, pancreatitis.

 

Hepatobiliary disorders

Common

Transaminases increased

 

Rare

Hepatitis, jaundice, liver disorder

 

Very rare

Hepatitis fulminant, hepatic necrosis, hepatic failure

 

Skin and subcutaneous tissue disorders

Common

Rash

 

Rare

Urticaria

 

Very rare

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, hematuria, proteinuria, nephrotic syndrome, tubulointestitial nephritis, renal papillary necrosis.

 

General disorders and administration site conditions

Rare

Edema

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

 

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 (150mg daily) and during long-term treatment (see section WARNINGS AND PRECAUTIONS).

 

INTERACTIONS

The following interactions include those observed with Cataflam sugar-coated tablets and/or other pharmaceutical forms of diclofenac.

Observed interactions to be considered

Potent CYP2CS inhibitor

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 dueto inhibition of diclofenac metabolism.

 

Lithium

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

 

Digoxin

It used concomitantly, diclofenac may raise plasma concentrations of lithium. Monitoring of the serum digoxin level is recommended.

 

Dioretica 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 WARNINGS AND 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 potassiumlevels, which should therefore be monitored frequently (see section WARNINGS AND PRECAUTIONS).

 

Quinolone antibacterials

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

 

Anticipated interactions to be considered

Other NSAIDs and corticosteriods

Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal undesirable effects (see section WARNINGS AND PRECAUTIONS).

 

Anticoagulants and anti-platelet agents

Caution is recommended since concomitant administration could increase the risk of bleeding (see section WARNINGS AND 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 hemorrhage in patients receiving diclofenac and anticoagulants concomitantly. Close monitoring at such patients is therefore recommended.

 

Selective serotonin reuptake inhibitors (SSRIs)

Concomitant administration of systemic NSAIDs, including diclofenac, and SSRls may increase the risk of gastrointestinal bleeding (see section WARNINGS AND 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 hypoglycemic and hyperglycemic effects necessitating changes in the dosage of the antidiatetic 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 at methotrexate may rise and the toxicity at this substance be increased.

 

WOMEN OF CHILD-BEARING POTENTIAL, PREGNANCY BREAST-FEEDING AND FERTILITY

Women of child-bearing potential

There are no data to suggest any recommendations to women of child-fearing potential.

 

Pregnancy

There are insufficient data on the use of diclofenac in pregnant women. Therefore, Cataflam should not be used during the first two trimesters of pregnancy unless the expected benefits to the mother outweigh the risks to the fetus. 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 section CONTRAINDICATIONS and also section NON-CLINICAL SAFETY DATA).

 

Breast-feeding

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

 

Fertility

As with other NSAIDs, the use of Cataflam 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 Cataflam should be considered.

 

OVERDOSAGE

Symptoms

There is no typical clinical picture resulting from diclofenac overdosage. Overdosage can cause symptoms such as vomiting, gastrointestinal hemorrhage, diarrhea, dizziness, tinnitus on 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 hypertension, 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.

Actuated 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.

 

CLINICAL PHARMACOLOGY

Mechanism of action (MOA)

Cataflam contains potassium salt of diclofenac, a non-steroidal compound with pronounced antirheumatic, analgesic, anti-inflammatory and antipyretic properties. lnhibition of prostaglandin biosynthesis, which has been demonstrated in experiments, is considered fundamental to its mechanism of action. BietraasfenraatlaWaretabaliea, Administrative el NSAIDs (including diclefenuci inhibited
of action. Prostaglandins play an important role in causing inflammation, pain and fever.

Cataflam tablets have a rapid onset of action which makes them particularly suitable for the treatment of acute painful and inflammatory conditions.

Diclofenac in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in humans.

 

Pharmacodynamics (PD)

Cataflam has been found to exert a pronounced analgesic effect in moderate and severe pain. In the presence of inflammation e.g. due to trauma or following surgical interventions, it rapidly relieves both spontaneous pain and pain on movement and diminishes inflammatory swelling and wound edema.

Clinical studies have also revealed that in primary dysmenorrhea the active substance is capable of relieving the pain and reducing the extent of bleeding.

In migraine attacks Cataflam has been effective in relieving headache and in improving the accompanying symptoms nausea and vomiting.

 

Pharmacokinetics (PK)

Absorption

Diclofenac is rapidly and cempletety absorbed from diclofenac potassium tablets. The absorption sets in immediately after administration and the same amount is absorbed as from an equivalent dose of diclofenac sodium gastro-resistant tablets.

Mean peak plasma concentrations of 3.8 micro mol/L are attained after 20 to 60 minutes after ingestion of one tablet of 50mg. Ingestion together with food has no influence on the amount at diclofenac absorbed although onset and rate of absorption may be slightly delayed.

Since about half of diclofenac is metabolized during its first passage through the liver (“first pass” effect), the area under concentration curve (AOC) is about half as large following oral or rectal 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 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 reached. The apparent half-life for eliminating 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.

Diclofenac was detected in a low concentration (100ng/mL) in breast milk in one nursing mother. The estimated amount ingested by an infant consuming breast milk is equivalent to a 0,.03mg/kg/day dose.

 

Biotransformation/metabolism

Biotransformation of diclofenac takes place partly by glucurronidation 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±56mL/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’-hydrocy-4’-methoxy-diclofenac, has a much longer plasma half-life. However, this metabolite is virtually inactive.

About 60% of the administered dose is executed 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 executed as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.

 

Linearity/non-linearity

The amount adsorbed is in linear proportion to the size of the dose.

 

Special populations

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 kinetic when applying the usual dosage schedule. At a creatinine clearance of less than 10mL/min, the calculated steady-state plasma levels of the hydroxyl 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 abd metabolism of diclofenac are the same as in patients without liver disease.

 

CLINICAL STUDIES

Cataflam is a well established product.

 

NON-CLINICAL 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. In standard preclinical nimal studies, 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. Except for minimal fetal effects at maternally toxic doses, the prenatal, perinatal and postnatal development of the offspring was not affected.

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 arteriosis in utero are pharmacological consequences of this class of prostaglandin synthensis inhibitors (see section CONTRAINDICATIONS and also section WOMEN OF CHILD-BEARING POTENTIAL, PREGNANCY, BREAST-FEEDING AND FERTILITY).

 

INCOMPATIBILITIES

Not applicable.

 

STORAGE

See folding box.

 

Cataflam tablets should not be used after the date marked “EXP” on the pack.

 

Cataflam tablets must be kept out of the reach and sight of children.

 

INSTRUCTIONS FOR USE AND HANDLING

No special requirements.

 

Manufacturer

See folding box.

 

International Package Leaflet

Information issued: September 2013.

 

® =registered trademark.

 

Norvatis Pharma AG, Basel, Switzerland.