Cataflam

Diclofenac (sugar-coated tab: potassium, oral drops: sodium).

Sugar-coated tablets: Reddish-brown round biconvex sugar-coated tablets.
The active substance is diclofenac potassium. In Cataflam the sodium ion of diclofenac sodium (Voltaren) has been replaced by a potassium ion.
One Cataflam sugar-coated tablet contains 50 mg of diclofenac potassium.
Oral drops: White to pale beige homogeneous oily suspension with a fruity odour.
The active substance is diclofenac resinate.
Diclofenac is bound on resinate as an ion exchanger. Resinate is a basic ion exchanger consisting of polymers of styrol and approx. 2% divinylbenzene with groups of quaternary ammonium included in the net structure.
One hundred millilitres of Cataflam suspension (oral drops) contain diclofenac resinate equivalent to 1.5 g diclofenac sodium (0.5 mg per drop or 15 mg per mL).
Excipients/Inactive Ingredients: Sugar-coated tablets: Core: Magnesium stearate; povidone; colloidal anhydrous silica; sodium starch glycollate; maize starch; calcium phosphate.
Sugar-coat: Microcrystalline cellulose; polyethylene glycol 8000; red iron oxide (E172) and titanium dioxide (E171) (dispersed Anstead); povidone; talc; sucrose.
Polish: polyethylene glycol 8000; sucrose.
Imprint with printing ink white.
Pharmaceutical formulations may vary between countries.
Oral drops: Castor oil, hydrogenated powder; paraffin liquid; saccharin sodium; copolymer of acrylic and methacrylic acid with divinylbenzene and ethylvinylbenzene (Zerolite 236 SRC 48), washed; tutti-frutti flavour.

Anti-inflammatory and anti-rheumatic product, non-steroid, acetic acid derivative.
Pharmacology: Mechanism of Action: Diclofenac, the active substance of Cataflam, 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 the concentrations reached in humans.
Sugar-coated tablets: Cataflam tablets have a rapid onset of action which makes them particularly suitable for the treatment of acute painful and inflammatory conditions.
Pharmacodynamics: 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.
Sugar-coated tablets: 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 shown to be effective in relieving the headache and in improving the accompanying symptoms nausea and vomiting.
Clinical Studies: Cataflam is a well-established product.
Pharmacokinetics: Absorption: Diclofenac is rapidly and completely absorbed from diclofenac potassium tablets or the resinate suspension. The absorption sets in immediately after administration.
Since about half of diclofenac is metabolized during its first passage through the liver ("first pass" effect), the area under the concentration curve (AUC) 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.
Sugar-coated tablets: The same amount is absorbed as from an equivalent dose of diclofenac sodium gastro-resistant tablets.
Mean peak plasma concentrations of 3.8 micromol/L are attained after 20 to 60 minutes after ingestion of one tablet of 50 mg.
Ingestion together with food has no influence on the amount of diclofenac absorbed although onset and rate of absorption may be slightly delayed.
Oral drops: After single administration of drops corresponding to 50 mg diclofenac sodium, peak plasma concentrations of about 0.5 micrograms/mL (1.63 micromol/L) are attained within 2 hours.
The plasma concentrations attained in children given equivalent doses (mg/kg body weight) are similar to those obtained in adults.
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 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/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.
Oral drops: Biotransformation of diclofenac is quick and almost complete. The metabolites are known.
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'-methoxydiclofenac, 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 in linear proportion to the size of the dose.
Special populations: Geriatric patients: No relevant age-dependent differences in the drug's absorption, metabolism, or excretion have been observed.
Renal impairment: 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.
Hepatic impairment: 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: 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.
For more information, see Use in Pregnancy & Lactation.

As an adjuvant in severe painful inflammatory infections of the throat, nose, or ears, 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.
Sugar-coated tablets: As short-term treatment for the following acute conditions in cases where particular importance is attached to a prompt onset of effect (within 30 minutes): Painful post-traumatic inflammatory states, e.g. due to sprains.
Post-operative inflammation and pain, e.g. following dental or orthopaedic surgery.
Painful and/or inflammatory conditions in gynaecology, e.g. primary dysmenorrhoea or adnexitis.
Acute migraine attacks. Cataflam should not be used for migraine prophylaxis.
Painful syndromes of the vertebral column.
Non-articular rheumatism.
Oral drops: Short-term treatment in the following acute conditions: Post-traumatic and post-operative pain, inflammation, and swelling, e.g., following dental or orthopedic surgery.

Dosage regimen: 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).
General target population: Adults: Sugar-coated tablets: The recommended initial daily dose is 100 to 150 mg. In milder cases, 75 to 100 mg daily is usually sufficient.
The total daily dose should generally be divided into 2 or 3 separate doses, as applicable.
In primary dysmenorrhea, the daily dose should be individually adjusted and is generally 50 to 150 mg. An initial dose of 50 mg is usually sufficient. If necessary, an initial dose of 100 mg 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 on the symptomatology, continued for a few days.
In migraine, an initial dose of 50 mg 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 50 mg may be taken. If needed, further doses of 50 mg may be taken at intervals of 4 to 6 hours, not exceeding a total dose of 200 mg per day.
Oral drops: Specific pharmaceutical forms (e.g. tablets, suppositories, solution for injection) are available for use in adults. The initial daily dose is 100 to 150 mg diclofenac sodium equivalent. In milder cases, 75 to 100 mg diclofenac sodium equivalent daily is usually sufficient.
The total daily dose should generally be divided into 2 to 3 separate doses.
Special populations: Renal impairment: Cataflam is contraindicated in patients with renal failure (GFR <15 mL/min/1.73 m²) (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 Cataflam to patients with renal impairment (see Precautions).
Hepatic impairment: Cataflam 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 Cataflam to patients with mild to moderate hepatic impairment (see Precautions).
Pediatric patients (below 18 years): Sugar-coated tablets: 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 25 mg could be used. For adolescents aged 14 years and over, a daily dose of 75 to 100 mg is usually sufficient. The maximum daily dose of 150 mg 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 been established in children and adolescents.
Oral drops: Cataflam oral drops are particularly suitable for pediatric use, because they enable the dose to be adapted individually to the child's body weight in accordance with the dosage schedule recommended for children (1 drop=0.5 mg).
Children aged 1 year or over and adolescents should be given the diclofenac sodium equivalent of 0.5 to 2 mg/kg body weight (1 to 4 drops) daily, depending on the severity of the disorder. For adolescents aged 14 or over, 75 to 100 mg daily is usually sufficient. The total daily dose should generally be divided into 2 to 3 separate doses.
The maximum daily dose of 150 mg diclofenac sodium equivalent should not be exceeded.
Geriatric patients (65 years of age or above): No adjustment of the starting dose is generally required for elderly patients. However, caution is indicated on basic medical grounds, especially for frail elderly patients or those with a low body weight (see Precautions).
Established cardiovascular disease or significant cardiovascular risk factors: 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 ≤100 mg daily if treated for more than 4 weeks (see Precautions).
Method of administration: Sugar-coated tablets: The tablets should be swallowed whole with liquid, preferably before meals, and must not be divided or chewed.
Oral drops: It is recommended to hold the bottle containing the suspension in the hands for at least 2 minutes to bring the suspension to room temperature. Then the bottle should be shaken well for 1 minute before opening. The required number of drops should be counted into a spoon and the content of the spoon should be swallowed, preferably during meals.

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 other 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 (GFR <15 mL/min/1.73 m²); Severe cardiac failure (see Precautions).
Like other non-steroidal anti-inflammatory drugs (NSAIDs), Cataflam is also contraindicated in patients in whom the use of acetylsalicylic acid or other NSAIDs can precipitate asthma, angioedema, urticaria, or acute rhinitis (i.e., NSAID-induced cross-reactivity reactions) (see Precautions and Adverse Reactions).

Risk of GI Ulceration, Bleeding and Perforation with NSAID: Serious GI toxicity such as bleeding, ulceration and perforation can occur at any time, with or without warning symptoms, in patients treated with NSAID therapy. Although minor upper GI problems (e.g. dyspepsia) are common, usually developing early in therapy, prescribers should remain alert for ulceration and bleeding in patients treated with NSAIDs even in the absence of previous GI tract symptoms.
Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Patients with prior history of serious adverse events and other risk factors associated with peptic ulcer disease (e.g. alcoholism, smoking and corticosteroid therapy) are at increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less than other individuals and account for most spontaneously reports for fatal GI events.

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 treatment should be discontinued.
As with all NSAIDs, including diclofenac, close medical surveillance is imperative and particular caution should be exercized 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 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 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 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 low dose acetylsalicylic acid (ASA) or other drugs 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 exercized in patients with ulcerative colitis or Crohn's disease, as their condition may be exacerbated (see Adverse Reactions).
NSAIDs, including diclofenac, may be associated with increased risk of gastrointestinal anastomotic leak. Close medical surveillance and caution are recommended when using Cataflam after gastro-intestinal surgery.
Cardiovascular effects: Treatment with NSAIDs including diclofenac, particularly at high dose and in long term, may be associated with an increased risk of 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 ≤100 mg 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 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: 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, diclofenac 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 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 caution 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 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 of NSAIDs, including Cataflam (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. 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 Contraindications). Monitoring of renal function is recommended as a precautionary measure when using Cataflam in such cases. Discontinuation of therapy is usually followed by recovery to the pre-treatment state.
Interactions with other 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 Interactions).
Masking signs of infections: Like other NSAIDs, diclofenac 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, especially in frail elderly patients or those with a low body weight.

Pregnancy: Risk summary: There are insufficient data on the use of diclofenac in pregnant women. Some epidemiological studies suggest an increased risk of miscarriage after use of a prostaglandin synthesis inhibitor (such as NSAIDs) in early pregnancy, however the overall data are inconclusive. Diclofenac has been shown to cross the placental barrier in humans. Use of NSAIDs, including diclofenac, can cause uterine inertia, premature closure of the fetal ductus arteriosus and fetal renal impairment leading to oligohydramnios. Because of these risks, 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.
In addition, Cataflam should not be used during the third trimester of pregnancy (see Contraindications).
Sugar-coated tablets: In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, or rabbits given diclofenac daily during the period of organogenesis at doses up to approximately 0.41, 0.41, and 0.81 times, respectively, the maximum recommended human dose (MRHD) of Cataflam, despite the presence of maternal and fetal toxicity (see Animal data as follows).
Oral drops: In animals, administration of a prostaglandin synthetase inhibitor has been shown to result in increased pre-implantation and post-implantation loss and embryofetal lethality. In addition, increased incidences of various malformations, including cardiovascular malformations, have been reported in animals given a prostaglandin synthetase inhibitor during organogenesis (see Animal data as follows).
Clinical considerations: Fetal Adverse Drug Reactions: Premature Closure of Fetal Ductus Arteriosus: As with other NSAIDs, use of diclofenac during the third trimester of pregnancy is contraindicated owing to the possibility of premature closure of the fetal ductus arteriosus (see Contraindications).
Oligohydramnios/Fetal Renal Impairment: Risk of fetal renal impairment with subsequent oligohydramnios has been observed when NSAIDs (including diclofenac) were used from the 20^th week of pregnancy onwards.
If an NSAID is necessary from the 20^th week gestation to the end of the 2^nd trimester, limit the use to the lowest effective dose and shortest duration possible (see Dosage & Administration). If Cataflam treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue Cataflam and follow up according to clinical practice.
Labor or Delivery: There are no studies on the effects of Cataflam during labor or delivery. As with other NSAIDs, use of diclofenac during the third trimester of pregnancy is contraindicated owing to the possibility of uterine inertia (see Contraindications).
Sugar-coated tablets: In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
Data: Human Data: Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs during the third trimester of pregnancy may cause premature closure of the fetal ductus arteriosus.
Oligohydramnios/Fetal Renal Impairment: Published studies and post-marketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal impairment leading to oligohydramnios. 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. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug.
Animal Data: Sugar-coated tablets: Reproductive and developmental studies in animals demonstrated that diclofenac administration during organogenesis did not produce teratogenicity despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (0.41 times the maximum recommended human dose [MRHD] of Cataflam, 200 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (0.41 and 0.81 times, respectively, the MRHD based on BSA comparison).
In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0.08 and 0.16 times the MRHD based on BSA) from Gestation Day 15 through Lactation Day 21, significant maternal mortality (caused by gastrointestinal ulceration and peritonitis) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, intrauterine growth retardation, and decreased fetal survival.
Administration of NSAIDs (including diclofenac) inhibited ovulation in the rabbit and implantation and placentation in the rat and led to premature closure of the fetal ductus arteriosus.
Oral drops: Additional studies indicate that, with repeated oral doses in rats (>1 mg/kg body weight), diclofenac causes effects that influence fertility (lower testosterone level, and decreased epididymal and testicular weight in association with histopathological changes). Similar effects were also observed in the F1 generation following doses of ≥1.25 mg/kg in a two-generation study. In dogs, daily subcutaneous doses of 2 mg/kg diclofenac sodium led to an increased spermatid count. Further studies describe a decreased mating frequency in female rats following a repeated dose of ≥0.5 mg/kg diclofenac. For this reason, an influence on both male and female fertility cannot be ruled out.
Diclofenac crosses the placental barrier in rodents. Administration of NSAIDs (including diclofenac) inhibited ovulation in rabbits and implantation and placentation in rats, and led to premature closure of the ductus arteriosus in pregnant rats. 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 closure of the ductus arteriosus in utero are pharmacological effects of this class of prostaglandin synthetase inhibitors (see Contraindications).
In a study in mice, teratogenicity (cleft palate) was observed at the maternally toxic dose of 4 mg/kg. In rats and rabbits, doses up to the maternally toxic level did not lead to teratogenic effects. Delayed ossification and reduced fetal weight in a study in rabbits were the only changes observed in these investigations.
At maternally toxic doses, the perinatal and post-natal development of the offspring were impaired (see fertility, also birth weight and delayed post-natal growth as previously mentioned).
Lactation: Risk Summary: 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.
Human Data: Diclofenac was detected in a low concentration (100 ng/mL) in breast milk in one nursing mother treated orally with a diclofenac salt of 150 mg/day. The estimated dose ingested by an infant consuming breast milk is equivalent to 0.03 mg/kg/day.
Females and males of reproductive potential: Female 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.
Male fertility: There is no human data on the effect of Cataflam on male fertility.
Sugar-coated tablets: Diclofenac administered to male and female rats at 4 mg/kg/day (approximately 0.16 times the MRHD based on BSA comparison) did not affect fertility.
Oral drops: In animals, based on relevant data, impairment of male fertility cannot be ruled out (see Animal data as previously mentioned). The relevance of this finding for humans is unclear.

Tabulated summary of adverse drug reactions: Adverse drug reactions from clinical trials and/or spontaneous or literature reports (table as follows) 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 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 Cataflam sugar-coated tablets, oral drops 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 an 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).
Visual effects: Visual disturbances such as visual impairment, blurred vision or diplopia appear to be NSAID class effects and are usually reversible on discontinuation. A likely mechanism for the visual disturbances is the inhibition of prostaglandin synthesis and other related compounds that alter the regulation of retinal blood flow resulting in potential changes in vision. If such symptoms occur during diclofenac treatment, an ophthalmological examination may be considered to exclude other causes.

The following interactions include those observed with Cataflam sugar-coated tablets, oral drops suspension and/or other pharmaceutical forms of diclofenac.
Observed interactions to be considered: CYP2C9 inhibitors: Caution is recommended when co-prescribing diclofenac with CYP2C9 inhibitors (such as voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to 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 Precautions).
Ciclosporin and tacrolimus: Diclofenac, like other NSAIDs may increase the nephrotoxicity of ciclosporin and tacrolimus 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 or tacrolimus.
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.
Oral drops: Due to the fact that resinate is a basic ion exchanger, generally an inhibition of absorption of other orally given medicinal products has to be taken into account.
Anticipated interactions to be considered: 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 reports of an increased risk of hemorrhage 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 hypoglycemic and hyperglycemic 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.
There have also been isolated reports of metabolic acidosis when diclofenac was coadministered with metformin, especially in patients with pre-existing renal impairment.
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.
CYP2C9 inducers: Caution is recommended when co-prescribing diclofenac with CYP2C9 inducers (such as rifampicin), which could result in a significant decrease in plasma concentration and exposure to diclofenac.

Incompatibilities: Not applicable.
Instructions for Use and Handling: Sugar-coated tablets: No special requirements.
Oral drops: Hold the bottle containing the suspension into the hands for at least 2 minutes to bring the suspension to room temperature. Then shake the bottle well for 1 minute before opening.
Turn the bottle upside down and count out the required number of drops into a spoon.

Sugar-coated tablets: Protect from moisture and store below 30°C.
Oral drops: Store between 2 to 8°C.

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.

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