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 Dicuno. 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).
Not applicable
The following adverse reactions are discussed in greater detail in other sections of the labeling:
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 Dicuno 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 Dicuno were application site skin reactions. These events were the most common reason for withdrawing from the study.
Application Site ReactionsIn 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%).
Other Common Adverse ReactionsTable 1 lists all adverse reactions occurring in > 1% of patients receiving Dicuno, where the rate in the Dicuno 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 Dicuno and More Often than in Subjects with OA Using Vehicle Control (Pooled)
| Adverse Reaction | Dicuno N=130 n (%) | Vehicle Control N=129 n (%) |
| Urinary tract infection | 4 (3%) | 1 ( < 1%) |
| Application site induration | 2 (2%) | 1 ( < 1%) |
| Contusion | 2 (2%) | 1 ( < 1%) |
| Sinus congestion | 2 (2%) | 1 ( < 1%) |
| Nausea | 2 (2%) | 0 |
The safety of Dicuno 2% is based in part, on prior experience with Dicuno 1.5%. The data described below reflect exposure to Dicuno 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 Dicuno 1.5% were application site skin reactions. These events were the most common reason for withdrawing from the studies.
Application Site ReactionsIn 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 Dicuno 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%.
Other Common Adverse ReactionsIn controlled trials, subjects treated with Dicuno 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 Dicuno 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 Dicuno 1.5%, where the rate in the Dicuno 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 Dicuno 1.5% Topical Solution in Placebo and Oral Diclofenac-Controlled Trials
| Treatment Group: | Dicuno 1.5% N=911 | Topical Placebo N=332 |
| Adverse Reaction | N (%) | N (%) |
| Dry Skin (Application Site) | 292 (32) | 17 (5) |
| Contact Dermatitis (Application Site) | 83 (9) | 6 (2) |
| Dyspepsia | 72 (8) | 13 (4) |
| Abdominal Pain | 54 (6) | 10 (3) |
| Flatulence | 35 (4) | 1 ( < 1) |
| Pruritus (Application Site) | 34 (4) | 7 (2) |
| Diarrhea | 33 (4) | 7 (2) |
| Nausea | 33 (4) | 3 (1) |
| Pharyngitis | 40 (4) | 13 (4) |
| Constipation | 29 (3) | 1 ( < 1) |
| Edema | 26 (3) | 0 |
| Rash (Non-Application Site) | 25 (3) | 5 (2) |
| Infection | 25 (3) | 8 (2) |
| Ecchymosis | 19 (2) | 1 ( < 1) |
| Dry Skin (Non-Application Site) | 19 (2) | 1 ( < 1) |
| Contact Dermatitis, vesicles (Application Site) | 18 (2) | 0 |
| Paresthesia (Non-Application Site) | 14 (2) | 3 ( < 1) |
| Accidental Injury | 22 (2) | 7 (2) |
| Pruritus (Non-Application Site) | 15 (2) | 2 ( < 1) |
| Sinusitis | 10 (1) | 2 ( < 1) |
| Halitosis | 11 (1) | 1 ( < 1) |
| Application Site Reaction (not otherwise specified) | 11 (1) | 3 ( < 1) |
In postmarketing surveillance, the following adverse reactions have been reported during post- approval use of Dicuno 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
Relevant information on the safety of Dicuno Potassium Tablets is included in previous sections of this Summary of Product Characteristics.
Relevant information on the safety of Dicunoac Potassium Tablets is included in previous sections of this Summary of Product Characteristics.
Pharmacotherapeutic group: Non-steroidal anti-inflammatory drug (NSAID).
ATC code: M01A B05
Dicuno Potassium tablets contain the potassium salt of Dicuno, a non-steroidal compound with pronounced and clinically demonstrable analgesic, anti-inflammatory and anti-pyretic properties.
Dicuno is a potent inhibitor of prostaglandin biosynthesis and a modulator of arachidonic acid release and uptake.
Dicuno 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 Dicuno Potassium tablets have been shown to be effective in relieving the headache and in improving the accompanying symptom of nausea.
Dicuno 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 Dicuno 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 Dicuno 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 Dicuno 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 Dicuno 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 Dicuno (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
Dicunoac Potassium tablets contain the potassium salt of Dicunoac, a non-steroidal compound with pronounced and clinically demonstrable analgesic, anti-inflammatory and anti-pyretic properties.
Dicunoac is a potent inhibitor of prostaglandin biosynthesis and a modulator of arachidonic acid release and uptake.
Dicunoac 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 Dicunoac Potassium tablets have been shown to be effective in relieving the headache and in improving the accompanying symptom of nausea.
Dicunoac 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 Dicunoac 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 Dicunoac 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 Dicunoac 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 Dicunoac 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 Dicunoac (daily dose 2-3 mg/kg BW, n=22) was comparable with that of indomethacin (daily dose 2-3 mg/kg BW, n=23).
After administration of Dicuno 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 Dicuno 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 Dicuno were not evaluated under the conditions of heat application, occlusive dressings overlay, or exercise following product application. Therefore, concurrent use of Dicuno under these conditions is not recommended.
DistributionDiclofenac 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.
EliminationMetabolism
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.
Not applicable.
Administrative data
