Diclovit

Overdose

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred but were rare.

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Emesis is not recommended due to a possibility of aspiration and subsequent respiratory irritation by DMSO contained in Diclovit. Consider activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

For additional information about overdosage treatment, contact a poison control center (1-800-222-1222).

Diclovit price

Incompatibilities

Not applicable

Undesirable effects

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Cardiovascular Thrombotic Events
• GI Bleeding, Ulceration and Perforation
• Hepatotoxicity
• Hypertension
• Heart Failure and Edema
• Renal Toxicity and Hyperkalemia
• Anaphylactic Reactions
• Serious Skin Reactions
• Hematologic Toxicity

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Diclovit of 130 patients treated for 4 weeks (mean duration of 28 days) in one Phase 2 controlled trial. This population's mean age was approximately 60 years, 85% of patients were Caucasian, 65% were females, and all patients had primary osteoarthritis. The most common adverse events with Diclovit were application site skin reactions. These events were the most common reason for withdrawing from the study.

In this controlled trial, application site reactions were characterized by one or more of the following: dryness (22%), exfoliation (7%), erythema (4%), pruritus (2%), pain (2%), induration (2%), rash (2%), and scabbing ( < 1%).

Table 1 lists all adverse reactions occurring in > 1% of patients receiving Diclovit, where the rate in the Diclovit group exceeded vehicle, from a controlled study conducted in patients with osteoarthritis.

Table 1: Incidence of Adverse Reactions Occurring in > 1% of Subjects with Osteoarthritis Using Diclovit and More Often than in Subjects with OA Using Vehicle Control (Pooled)

The safety of Diclovit 2% is based in part, on prior experience with Diclovit 1.5%. The data described below reflect exposure to Diclovit 1.5% of 911 patients treated between 4 and 12 weeks (mean duration of 49 days) in seven Phase 3 controlled trials, as well as exposure of 793 patients treated in an open-label study, including 463 patients treated for at least 6 months, and 144 patients treated for at least 12 months. The population mean age was approximately 60 years, 89% of patients were Caucasian, 64% were females, and all patients had primary osteoarthritis. The most common adverse events with Diclovit 1.5% were application site skin reactions. These events were the most common reason for withdrawing from the studies.

In controlled trials, application site reactions were characterized by one or more of the following: dryness, erythema, induration, vesicles, paresthesia, pruritus, vasodilation, acne, and urticaria. The most frequent of these reactions were dry skin (32%), contact dermatitis characterized by skin erythema and induration (9%), contact dermatitis with vesicles (2%) and pruritus (4%). In one controlled trial, a higher rate of contact dermatitis with vesicles (4%) was observed after treatment of 152 subjects with the combination of Diclovit 1.5% and oral diclofenac. In the open-label uncontrolled long-term safety study, contact dermatitis occurred in 13% and contact dermatitis with vesicles in 10% of patients, generally within the first 6 months of exposure, leading to a withdrawal rate for an application site event of 14%.

In controlled trials, subjects treated with Diclovit 1.5% experienced some adverse events associated with the NSAID class more frequently than subjects using placebo (constipation, diarrhea, dyspepsia, nausea, flatulence, abdominal pain, edema; see Table 2). The combination of Diclovit 1.5% and oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%), and hemoglobin (13% vs. 9%), but no difference in elevation of liver transaminases.

Table 2 lists all adverse reactions occurring in ≥ 1% of patients receiving Diclovit 1.5%, where the rate in the Diclovit 1.5% group exceeded placebo, from seven controlled studies conducted in patients with osteoarthritis. Since these trials were of different durations, these percentages do not capture cumulative rates of occurrence.

Table 2: Adverse Reactions Occurring in ≥ 1% of Patients Treated with Diclovit 1.5% Topical Solution in Placebo and Oral Diclofenac-Controlled Trials

In postmarketing surveillance, the following adverse reactions have been reported during post- approval use of Diclovit 1.5%. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: abdominal pain, accidental injury, allergic reactions, asthenia, back pain, body odor, chest pain, edema, face edema, halitosis, headache, neck rigidity, pain

Cardiovascular: palpitation, cardiovascular disorder

Gastrointestinal: diarrhea, dry mouth, dyspepsia, gastroenteritis, decreased appetite, lip swelling, mouth ulceration, nausea, rectal hemorrhage, ulcerative stomatitis, swollen tongue

Metabolic and Nutritional: creatinine increased

Musculoskeletal: leg cramps, myalgia

Nervous: depression, dizziness, drowsiness, lethargy, paresthesia at application site

Respiratory: asthma, dyspnea, laryngismus, laryngitis, pharyngitis, throat swelling

Skin and Appendages: At the Application

Site: rash, skin burning sensation;

Other Skin and Appendages Adverse Reactions: eczema, skin discoloration, urticaria

Special Senses: abnormal vision, blurred vision, cataract, ear pain, eye disorder, eye pain, taste perversion

Vascular: blood pressure increased, hypertension

Preclinical safety data

Relevant information on the safety of Diclovit Potassium Tablets is included in previous sections of this Summary of Product Characteristics.

Relevant information on the safety of Diclovitac Potassium Tablets is included in previous sections of this Summary of Product Characteristics.

Pharmacodynamic properties

Pharmacotherapeutic group: Non-steroidal anti-inflammatory drug (NSAID).

ATC code: M01A B05

Diclovit Potassium tablets contain the potassium salt of Diclovit, a non-steroidal compound with pronounced and clinically demonstrable analgesic, anti-inflammatory and anti-pyretic properties.

Diclovit is a potent inhibitor of prostaglandin biosynthesis and a modulator of arachidonic acid release and uptake.

Diclovit Potassium tablets have a rapid onset of action and are therefore suitable for the treatment of acute episodes of pain and inflammation.

In migraine attacks Diclovit Potassium tablets have been shown to be effective in relieving the headache and in improving the accompanying symptom of nausea.

Diclovit in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings.

There is limited clinical trial experience of the use of Diclovit in JRA/JIA paediatric patients. In a randomised, double-blind, 2-week, parallel group study in children aged 3-15 years with JRA/JIA, the efficacy and safety of daily 2-3 mg/kg BW Diclovit was compared with acetylsalicylic acid (ASS, 50-100 mg/kg BW/d) and placebo - 15 patients in each group. In the global evaluation, 11 of 15 Diclovit patients, 6 of 12 aspirin and 4 of 15 placebo patients showed improvement with the difference being statistically significant (p < 0.05). The number of tender joints decreased with Diclovit and ASS but increased with placebo. In a second randomised, double-blind, 6-week, parallel group study in children aged 4-15 years with JRA/JIA, the efficacy of Diclovit (daily dose 2-3 mg/kg BW, n=22) was comparable with that of indomethacin (daily dose 2-3 mg/kg BW, n=23).

Pharmacotherapeutic group: Non-steroidal anti-inflammatory drug (NSAID).

ATC code: M01A B05

Diclovitac Potassium tablets contain the potassium salt of Diclovitac, a non-steroidal compound with pronounced and clinically demonstrable analgesic, anti-inflammatory and anti-pyretic properties.

Diclovitac is a potent inhibitor of prostaglandin biosynthesis and a modulator of arachidonic acid release and uptake.

Diclovitac Potassium tablets have a rapid onset of action and are therefore suitable for the treatment of acute episodes of pain and inflammation.

In migraine attacks Diclovitac Potassium tablets have been shown to be effective in relieving the headache and in improving the accompanying symptom of nausea.

Diclovitac in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings.

There is limited clinical trial experience of the use of Diclovitac in JRA/JIA paediatric patients. In a randomised, double-blind, 2-week, parallel group study in children aged 3-15 years with JRA/JIA, the efficacy and safety of daily 2-3 mg/kg BW Diclovitac was compared with acetylsalicylic acid (ASS, 50-100 mg/kg BW/d) and placebo - 15 patients in each group. In the global evaluation, 11 of 15 Diclovitac patients, 6 of 12 aspirin and 4 of 15 placebo patients showed improvement with the difference being statistically significant (p < 0.05). The number of tender joints decreased with Diclovitac and ASS but increased with placebo. In a second randomised, double-blind, 6-week, parallel group study in children aged 4-15 years with JRA/JIA, the efficacy of Diclovitac (daily dose 2-3 mg/kg BW, n=22) was comparable with that of indomethacin (daily dose 2-3 mg/kg BW, n=23).

Pharmacokinetic properties

After administration of Diclovit topical solution (40 mg/knee every 12 h; total daily diclofenac exposure: 80 mg/knee) for 7.5 days, the mean (SD) AUC0-12 and mean (SD) Cmax were 77.27 (49.89) ng•h/mL and 12.16 (7.66) ng/mL, respectively, on Day 1; and 204.58 (111.02) ng•h/mL and 25.24 (12.95) ng/mL, respectively, at steady state on Day 8. After administration of Diclovit 1.5% topical solution (19.3 mg/knee every 6 h; total daily diclofenac exposure 77.2 mg/knee), the mean (SD) AUC0-12 and mean (SD) Cmax were 27.46 (23.97) ng•h/mL and 2.30 (2.02) ng/mL, respectively, on Day 1; and 141.49 (92.47) ng•h/mL and 17.04 (11.28) ng/mL, respectively, at steady state on Day 8.

The pharmacokinetics and effect of Diclovit were not evaluated under the conditions of heat application, occlusive dressings overlay, or exercise following product application. Therefore, concurrent use of Diclovit under these conditions is not recommended.

Diclofenac is more than 99% bound to human serum proteins, primarily to albumin.

Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac.

Metabolism

Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac. The major diclofenac metabolite, 4'hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4'-hydroxy diclofenac is primarily mediated by CYP2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxydiclofenac.

Excretion

Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites.

Little or no free unchanged diclofenac is excreted in the urine.

Special precautions for disposal and other handling

Not applicable.