DRUGS & SUPPLEMENTS
Active ingredient: Diclofenac Potassium
Diclofenac Potassium uses
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS
Cardiovascular Thrombotic Events
Gastrointestinal Bleeding, Ulceration, and Perforation
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS
See full prescribing information for complete boxed warning.
RECENT MAJOR CHANGES
Boxed Warning 5/2016
Warnings and Precautions, Cardiovascular Thrombotic Events (5.1) 5/2016
Warnings and Precautions, Heart Failure and Edema (5.5) 5/2016
1 INDICATIONS AND USAGE
Diclofenac Potassium sodium topical solution is indicated for the treatment of signs and symptoms of osteoarthritis of the knee(s).
Diclofenac Potassium sodium topical solution is a nonsteroidal anti-inflammatory drug indicated for the treatment of signs and symptoms of osteoarthritis of the knee(s). (1)
2 DOSAGE AND ADMINISTRATION
2.1 General Dosing Instructions
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals
For the relief of the signs and symptoms of osteoarthritis of the knee(s), the recommended dose is 40 drops per knee, 4 times a day.
Apply Diclofenac Potassium sodium topical solution to clean, dry skin.
To avoid spillage, dispense Diclofenac Potassium sodium topical solution 10 drops at a time either directly onto the knee or first into the hand and then onto the knee. Spread Diclofenac Potassium sodium topical solution evenly around front, back and sides of the knee. Repeat this procedure until 40 drops have been applied and the knee is completely covered with solution.
To treat the other knee, if symptomatic, repeat the procedure.
Application of Diclofenac Potassium sodium topical solution in an amount exceeding or less than the recommended dose has not been studied and is therefore not recommended.
2.2 Special Precautions
3 DOSAGE FORMS AND STRENGTHS
Diclofenac Potassium sodium topical solution: 1.5% w/w
Diclofenac Potassium sodium topical solution 1.5% w/w (3)
Diclofenac Potassium sodium topical solution is contraindicated in the following patients:
5 WARNINGS AND PRECAUTIONS
5.1 Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as Diclofenac Potassium, increases the risk of serious gastrointestinal (GI) events .
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke .
Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of Diclofenac Potassium sodium topical solution in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Diclofenac Potassium sodium topical solution is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs, including Diclofenac Potassium, cause serious gastrointestinal adverse events including inflammation bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2 % to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated patients:
In clinical trials, of oral diclofenac-containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) were observed in about 2% of approximately 5,700 patients at some time during Diclofenac Potassium treatment (ALT was not measured in all studies).
In a large, open-label, controlled trial of 3,700 patients treated with oral Diclofenac Potassium for 2 to 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of 3,700 patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving Diclofenac Potassium when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.
Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with Diclofenac Potassium in 42 of the 51 patients in all trials who developed marked transaminase elevations.
In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with Diclofenac Potassium. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.
In a European retrospective population-based, case-controlled study, 10 cases of Diclofenac Potassium associated drug-induced liver injury with current use compared with non-use of Diclofenac Potassium were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with Diclofenac Potassium, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days.
Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with Diclofenac Potassium, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with Diclofenac Potassium. However, severe hepatic reactions can occur at any time during treatment with Diclofenac Potassium.
If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), Diclofenac Potassium sodium topical solution should be discontinued immediately.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue Diclofenac Potassium sodium topical solution immediately, and perform a clinical evaluation of the patient.
To minimize the potential risk for an adverse liver-related event in patients treated with Diclofenac Potassium sodium topical solution, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing Diclofenac Potassium sodium topical solution with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, antiepileptics).
NSAIDs, including Diclofenac Potassium sodium topical solution, can lead to new onset of hypertension, or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs .
Monitor blood pressure (BP) closely during the initiation of NSAID treatment and throughout the course of therapy.
5.5 Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs.
Use of Diclofenac Potassium may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) .
Avoid the use of Diclofenac Potassium sodium topical solution in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Diclofenac Potassium sodium topical solution is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
5.6 Renal Toxicity and Hyperkalemia
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of Diclofenac Potassium sodium topical solution in patients with advanced renal disease. The renal effects of Diclofenac Potassium sodium topical solution may hasten the progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating Diclofenac Potassium sodium topical solution. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Diclofenac Potassium sodium topical solution . Avoid the use of Diclofenac Potassium sodium topical solution in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Diclofenac Potassium sodium topical solution is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
5.7 Anaphylactic Reactions
Diclofenac Potassium has been associated with anaphylactic reactions in patients with and without known hypersensitivity to Diclofenac Potassium and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)].
Seek emergency help if an anaphylactic reaction occurs.
5.8 Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Diclofenac Potassium sodium topical solution is contraindicated in patients with this form of aspirin sensitivity . When Diclofenac Potassium sodium topical solution is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
5.9 Serious Skin Reactions
NSAIDs, including Diclofenac Potassium, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Diclofenac Potassium sodium topical solution at the first appearance of skin rash or any other sign of hypersensitivity. Diclofenac Potassium sodium topical solution is contraindicated in patients with previous serious skin reactions to NSAIDs . Do not apply Diclofenac Potassium sodium topical solution to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug.
5.10 Premature Closure of Fetal Ductus Arteriosus
Diclofenac Potassium may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Diclofenac Potassium sodium topical solution, in pregnant women starting at 30 weeks of gestation .
5.11 Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with Diclofenac Potassium sodium topical solution has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including Diclofenac Potassium sodium topical solution, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding .
The effects of Diclofenac Potassium sodium topical solution on platelet function were studied in 10 healthy subjects administered 80 drops four times a day for 7 days. There was no significant change in platelet aggregation following one week of treatment .
5.12 Masking of Inflammation and Fever
The pharmacological activity of Diclofenac Potassium sodium topical solution in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
5.13 Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically .
5.14 Sun Exposure
Instruct patients to avoid exposure to natural or artificial sunlight on treated knee(s) because studies in animals indicated topical Diclofenac Potassium treatment resulted in an earlier onset of ultraviolet light-induced skin tumors. The potential effects of Diclofenac Potassium sodium topical solution on skin response to ultraviolet damage in humans are not known.
5.15 Eye Exposure
Avoid contact of Diclofenac Potassium sodium topical solution with eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour.
5.16 Oral Nonsteroidal Anti-Inflammatory Drugs
Concomitant use of oral NSAIDs with Diclofenac Potassium sodium topical solution resulted in a higher rate of rectal hemorrhage, more frequent abnormal creatinine, urea and hemoglobin. Therefore, do not use combination therapy with Diclofenac Potassium sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Most common adverse reactions with Diclofenac Potassium sodium topical solution are application site reactions. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience
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 Diclofenac Potassium sodium topical solution 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 Caucasians, 64% were females, and all patients had primary osteoarthritis. The most common adverse events with Diclofenac Potassium sodium topical solution were application site skin reactions. These events were the most common reason for withdrawing from the studies.
Application Site Reactions
In controlled trials, the most common treatment-related adverse events in patients receiving Diclofenac Potassium sodium topical solution were application site skin reactions. 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 Diclofenac Potassium sodium topical solution and oral Diclofenac Potassium. 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%.
Adverse Events Common to the NSAID Class
In controlled trials, subjects treated with Diclofenac Potassium sodium topical solution 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 1). The combination of Diclofenac Potassium sodium topical solution and oral Diclofenac Potassium, compared to oral Diclofenac Potassium 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 1 lists all adverse reactions occurring in ≥1% of patients receiving Diclofenac Potassium sodium topical solution, where the rate in the Diclofenac Potassium sodium topical solution 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 1: Adverse Reactions occurring in ≥1% of patients treated with Diclofenac Potassium sodium topical solution in placebo and oral diclofenac-controlled trials.
†Preferred Term according to COSTART
6.2 Postmarketing Experience
In non-U.S. postmarketing surveillance, the following adverse reactions have been reported during post-approval use of Diclofenac Potassium sodium topical solution. 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 reaction, asthenia, back pain, body odor, chest pain, edema, face edema, halitosis, headache, lack of drug effect, neck rigidity, pain
Cardiovascular: palpitation, cardiovascular disorder
Digestive: diarrhea, dry mouth, dyspepsia, gastroenteritis, decreased appetite, mouth ulceration, nausea, rectal hemorrhage, ulcerative stomatitis
Metabolic and Nutritional: creatinine increased
Musculoskeletal: leg cramps, myalgia
Nervous: depression, dizziness, drowsiness, lethargy, paresthesia, paresthesia at application site
Respiratory: asthma, dyspnea, laryngismus, laryngitis, pharyngitis
Skin and Appendages: At the Application Site: Adverse Reactions: contact dermatitis, contact dermatitis with vesicles, dry skin, pruritus, rash; Other Skin and Appendages eczema, rash, pruritus, skin discoloration, urticaria
Special Senses: abnormal vision, blurred vision, cataract, ear pain, eye disorder, eye pain, taste perversion
7 DRUG INTERACTIONS
See Table 2 for clinically significant drug interactions with Diclofenac Potassium.
Table 2: Clinically Significant Drug Interactions with Diclofenac Potassium
8 USE IN SPECIFIC POPULATIONS
Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation
Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of Diclofenac Potassium sodium topical solution in women who have difficulties conceiving (8.3)
Pregnancy Category C prior to 30 weeks gestation; Category D starting 30 weeks gestation
Use of NSAIDs, including Diclofenac Potassium sodium topical solution, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Diclofenac Potassium sodium topical solution, in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of Diclofenac Potassium sodium topical solution in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. Published reproductive and developmental studies of dimethyl sulfoxide (DMSO, the solvent used in Diclofenac Potassium sodium topical solution) are equivocal as to potential teratogenicity. In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, or rabbits given Diclofenac Potassium daily during the period of organogenesis at doses up to approximately 0.6, 0.6, and 1.3 times, respectively, the maximum recommended human dose (MRHD) of Diclofenac Potassium sodium topical solution, despite the presence of maternal and fetal toxicity at these doses. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as Diclofenac Potassium, resulted in increased pre- and post-implantation loss.
Labor or Delivery
There are no studies on the effects of Diclofenac Potassium sodium topical solution during labor or delivery. In animal studies, NSAIDS, including Diclofenac Potassium, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
Reproductive and developmental studies in animals demonstrated that Diclofenac Potassium sodium 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 (approximately 0.6 times the maximum recommended human dose [MRHD] of Diclofenac Potassium sodium topical solution, 154 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0.6 and 1.3 times, respectively, the MRHD based on BSA comparison). Published reproductive and developmental studies of dimethyl sulfoxide (DMSO, the solvent used in Diclofenac Potassium sodium topical solution) are equivocal as to potential teratogenicity.
In rats, maternally toxic doses of Diclofenac Potassium were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival.
Based on available data, Diclofenac Potassium may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CATAFLAM and any potential adverse effects on the breastfed infant from the CATAFLAM or from the underlying maternal condition.
One woman treated orally with a Diclofenac Potassium salt, 150 mg/day, had a milk Diclofenac Potassium level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac Potassium was not detectable in breast milk in 12 women using Diclofenac Potassium.
8.3 Females and Males of Reproductive Potential
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDS, including Diclofenac Potassium sodium topical solution, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including Diclofenac Potassium sodium topical solution, in women who have difficulties conceiving or who are undergoing investigation of infertility.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
Elderly patients, compared to younger patients, are a greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)].
Of the 911 patients treated with Diclofenac Potassium sodium topical solution in seven controlled, Phase 3 clinical trials, 444 subjects were 65 years of age and over. There was no age-related difference in the incidence of adverse events. Of the 793 patients treated with Diclofenac Potassium sodium topical solution in one open-labeled safety trial, 334 subjects were 65 years of age and over including 107 subjects 75 and over. There was no difference in the incidence of adverse events with long-term exposure to Diclofenac Potassium sodium topical solution for this elderly population.
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 [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)].
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 Diclofenac Potassium sodium topical solution. 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 overdose treatment, contact a poison control center (1-800-222-1222).
Diclofenac Potassium sodium topical solution 1.5% is a nonsteroidal anti-inflammatory drug, available as a clear, colorless to faintly pink-orange solution for topical application.
Diclofenac Potassium sodium topical solution contains 1.5% w/w Diclofenac Potassium sodium, USP, a benzeneacetic acid derivative that is a nonsteroidal anti-inflammatory drug (NSAID), designated chemically as 2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid, monosodium salt. It is a white to off-white crystalline powder, hygroscopic, and odorless that is freely soluble in methanol, soluble in alcohol, and sparingly soluble in water. The molecular weight is 318.13. Its molecular formula is C14H10Cl2NNaO2 and it has the following structural formula:
Each 1 mL of solution contains 16.05 mg of Diclofenac Potassium sodium, USP. The inactive ingredients in Diclofenac Potassium sodium topical solution include: alcohol, dimethyl sulfoxide USP (DMSO, 45.5% w/w), glycerin, propylene glycol, and purified water.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Diclofenac Potassium has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of Diclofenac Potassium sodium topical solution, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase.
Diclofenac Potassium is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac Potassium concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because Diclofenac Potassium is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.
After topical administration to healthy human volunteers of single and multiple maximum doses of diclofenac sodium topical solution, 40 drops (approximately 1.2 mL) to each knee (80 drops total dose), the following Diclofenac Potassium pharmacokinetic parameters were obtained: (see Table 3).
Table 3: Single-Dose (80 drops) and Multiple Dose (80 drops four times daily for 7 days) D iclofenac Sodium Topical Solution Pharmacokinetic Parameters
1Apparent total body clearance
Diclofenac Potassium systemic exposure from Diclofenac Potassium sodium topical solution application (4 times daily for 1 week) was approximately 1/3 of the Diclofenac Potassium systemic exposure from the Solaraze (diclofenac topical gel) application (twice daily for 4 weeks).
Diclofenac Potassium is more than 99% bound to human serum proteins, primarily to albumin.
Diclofenac Potassium 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 Potassium.
Five Diclofenac Potassium metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy Diclofenac Potassium. The major Diclofenac Potassium metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4'-hydroxy Diclofenac Potassium is primarily mediated by CPY2C9. Both Diclofenac Potassium and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in Diclofenac Potassium metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy-diclofenac.
Diclofenac Potassium 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 Potassium is excreted in the urine.
Pediatric: The pharmacokinetics of Diclofenac Potassium sodium topical solution has not been investigated in pediatric patients.
Race: Pharmacokinetic differences due to race have not been studied.
Drug Interaction Studies
Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin .
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies in mice and rats administered Diclofenac Potassium sodium as a dietary constituent for 2 years resulted in no significant increases in tumor incidence at doses up to 2 mg/kg/day corresponding to approximately 0.35- and 0.7-fold of the maximum recommended human topical dose (MRHD) of Diclofenac Potassium sodium topical solution (based on apparent bioavailability and body surface area comparison).
In a dermal carcinogenicity study conducted in albino mice, daily topical applications of Diclofenac Potassium sodium for two years at concentrations up to 0.035% Diclofenac Potassium sodium (a 43-fold lower Diclofenac Potassium sodium concentration than present in Diclofenac Potassium sodium topical solution) did not increase neoplasm incidence.
In a photococarcinogenicity study conducted in hairless mice, topical application of Diclofenac Potassium sodium at doses up to 0.035% Diclofenac Potassium sodium (a 43-fold lower Diclofenac Potassium sodium concentration than present in Diclofenac Potassium sodium topical solution) resulted in an earlier median time of onset of tumors.
Diclofenac Potassium was not mutagenic or clastogenic in a battery of genotoxicity tests that included the bacterial reverse mutation assay, in vitro mouse lymphoma point mutation assay, chromosomal aberration studies in Chinese hamster ovarian cells in vitro, and in vivo rat chromosomal aberration assay of bone marrow cells.
Impairment of Fertility
Fertility studies have not been conducted with Diclofenac Potassium sodium topical solution. Diclofenac Potassium sodium administered to male and female rats at doses up to 4 mg/kg/day (1.4-fold of the MRHD of Diclofenac Potassium sodium topical solution based on apparent bioavailability and body surface area comparison) did not affect fertility. Studies have not been conducted to determine the safety of DMSO on fertility.
13.2 Animal Toxicology and/or Pharmacology
No adverse effects were observed using indirect ophthalmoscopy after multiple-daily dermal application to rats for 26 weeks and minipigs for 52 weeks of DMSO at twice the concentration found in Diclofenac Potassium sodium topical solution. Published studies of dermal or oral administration of DMSO to rabbits, dogs and pigs described refractive changes of lens curvature and cortical fibers indicative of myopic changes and/or incidences of lens opacity or discoloration when evaluated using slit-lamp biomicroscopy examination, although no ocular abnormalities were observed in rhesus monkeys during daily oral or dermal treatment with DMSO for 9 to 18 months.
14 CLINICAL STUDIES
14.1 Studies in Osteoarthritis of the Knee
The use of Diclofenac Potassium sodium topical solution for the treatment of the signs and symptoms of osteoarthritis of the knee was evaluated in two double-blind controlled trials conducted in the US and Canada, involving patients treated with Diclofenac Potassium sodium topical solution at a dose of 40 drops four times a day for 12 weeks. Diclofenac Potassium sodium topical solution was compared to topical placebo (2.3% DMSO with other excipients) and/or topical vehicle solution (45.5% w/w DMSO with other excipients), applied directly to the study knee. In both trials, Diclofenac Potassium sodium topical solution treatment resulted in statistically significant clinical improvement compared to placebo and/or vehicle, in all three primary efficacy variables―pain, physical function (Western Ontario and McMaster Universities LK3.1 OA Index (WOMAC) pain and physical function dimensions) and Patient Overall Health Assessment (POHA)/Patient Global Assessment (PGA). Numerical results are summarized in Tables 4 and 5.
Table 4: Change in treatment outcomes after 12 weeks of treatment in one study of efficacy of d iclofenac sodium topical solution
Table 5: Change in treatment outcomes after 12 weeks of treatment in one study of efficacy of Diclofenac Potassium sodium topical solution
16 HOW SUPPLIED/STORAGE AND HANDLING
Diclofenac Potassium sodium topical solution 1.5% w/w is supplied as a clear, colorless to faintly pink-orange solution containing 16.05 mg of Diclofenac Potassium sodium per 1 mL of solution, in a white high density polyethylene bottle with a white low-density dropper cap. It is available as follows:
150 mL bottle NDC 65162-911-74
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide) and Instructions for Use that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with Diclofenac Potassium sodium topical solution and periodically during the course of ongoing therapy.
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately .
Gastrointestinal Bleeding, Ulceration, and Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding .
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop Diclofenac Potassium sodium topical solution and seek immediate medical therapy .
Heart Failure and Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur .
Inform patients of the signs of an anaphylactic reaction (e.g. difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)].
Serious Skin Reactions
Advise patients to stop Diclofenac Potassium sodium topical solution immediately if they develop any type of generalized rash and contact their physicians as soon as possible.
Advise females of reproductive potential who desire pregnancy that NSAIDs, including Diclofenac Potassium sodium topical solution, may be associated with a reversible delay in ovulation
Inform pregnant women to avoid use of Diclofenac Potassium sodium topical solution and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)].
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of Diclofenac Potassium sodium topical solution with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.
Use of NSAIDS and Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with Diclofenac Potassium sodium topical solution until they talk to their healthcare provider [see Drug Interactions (7) ].
Instruct patients to avoid contact of Diclofenac Potassium sodium topical solution with the eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour.
Prevention of Secondary Exposure
Instruct patients to avoid skin-to-skin contact between other people and the knee(s) to which Diclofenac Potassium sodium topical solution was applied until the knee(s) is completely dry.
Application Site Reactions
Diclofenac Potassium sodium topical solution can cause a localized skin reaction at the application site. Advise patients to contact their physicians as soon as possible if they develop any type of localized application site rash.
Special Application Instructions
Bridgewater, NJ 08807
Medication Guide for Nonsteroidal Anti-inflammatory Drugs
This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued or Revised 11/2016
Instructions for Use
Diclofenac Potassium (dye-KLOE-fen-ak) Sodium Topical Solution 1.5%
Read the Medication Guide that comes with Diclofenac Potassium sodium topical solution first. Be sure that you read, understand and follow these Instructions for Use before you use Diclofenac Potassium sodium topical solution for the first time.
Important: For use on the skin only (topical). Do not get Diclofenac Potassium sodium topical solution in your eyes, nose or mouth.
Before you use Diclofenac Potassium sodium topical solution:
Steps for using Diclofenac Potassium sodium topical solution:
Step 1. Wash your hands with soap and water before applying Diclofenac Potassium sodium topical solution.
Step 2. Put 10 drops of Diclofenac Potassium sodium topical solution either on your hand or directly on your knee (see Figure A).
Step 3. Spread Diclofenac Potassium sodium topical solution evenly on the front, back and sides of your knee (see Figures B and C). Repeat steps 2 and 3, three times so that your knee is completely covered with a total of 40 drops of Diclofenac Potassium sodium topical solution.
Step 4. If your healthcare provider has prescribed Diclofenac Potassium sodium topical solution for both knees, repeat steps 2 and 3 for the other knee.
After you use Diclofenac Potassium sodium topical solution:
How should I store Diclofenac Potassium sodium topical solution?
Keep Diclofenac Potassium sodium topical solution and all medicines out of the reach of children.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
*Trademarks are the property of their respective owners.
Bridgewater, NJ 08807
Figure A1 Figure A2 Figure B Figure C
Diclofenac Potassium available forms, composition, doses:
Indications and Usages:
Diclofenac Potassium destination | category:
Drugs with same active ingredients (Pharmaceutical companies):
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Diclofenac Potassium?
Depending on the reaction of the Diclofenac Potassium after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Diclofenac Potassium not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Diclofenac Potassium addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
Reviewsdrugs.com conducted a study on Diclofenac Potassium, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Diclofenac Potassium consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
Visitor reported usefulNo survey data has been collected yet
Visitor reported side effectsNo survey data has been collected yet
One visitor reported price estimatesWhat is your opinion about drug cost? Did you feel the cost is apt, or did you feel it is expensive?
The report given by the sdrugs.com website users shows the following figures about several people who felt the medicine Diclofenac Potassium is expensive, and the medicine is not expensive. The results are mixed. The perception of the cost of the medicine to be expensive or not depends on the brand name of the medicine, country, and place where it is sold, and the affordability of the patient. You can choose a generic drug in the place of the branded drug to save the cost. The efficiency of the medicine will not vary if it is generic or a branded one.
One visitor reported frequency of useHow often in a day do you take the medicine?
Are you taking the Diclofenac Potassium drug as prescribed by the doctor?
Few medications can be taken Once in a day more than prescribed when the doctor's advice mentions the medicine can be taken according to frequency or severity of symptoms. Most times, be very careful and clear about the number of times you are taking the medication. The report of sdrugs.com website users about the frequency of taking the drug Diclofenac Potassium is mentioned below.
Two visitors reported dosesWhat is the dose of Diclofenac Potassium drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 51-100mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitor reported time for resultsNo survey data has been collected yet
Visitor reported administrationNo survey data has been collected yet
Two visitors reported age
The information was verified by Dr. Arunabha Ray, MD Pharmacology