WARNINGS
Included as part ofPRECAUTIONSSection.
PRECAUTIONS
Cardiovascular thrombotic events
Clinical trials of up to three years of duration with several COX-2 selective and non-selective NSAIDs have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on the available data, it is unclear whether the risk of cardiovascular thrombotic events is similar for all NSAIDs. The relative increase from baseline in major cardiovascular thrombotic events induced by NSAID use appears to be similar in patients with and without known cardiovascular disease or risk factors for cardiovascular disease. However, patients with known cardiovascular disease or risk factors had a higher absolute incidence of excessive major cardiovascular thrombotic events due to their increased baseline rate. Some observational studies have shown that this increased risk of serious cardiovascular thrombotic events started within the first few weeks of treatment. The increase in cardiovascular thrombosis risk was observed most consistently at higher doses.
To minimize the potential risk of an adverse cardiovascular event in NSAID-treated patients, use the lowest effective dose for the shortest possible duration. Physicians and patients should be vigilant for the development of such events throughout the course of treatment, even in the absence of prior cardiovascular symptoms. Patients should be informed of the symptoms of serious cardiovascular events and the actions to be taken if they occur.
There is no consistent evidence that concomitant aspirin use reduces the increased risk of major cardiovascular thrombotic events associated with NSAID use. Concomitant use of aspirin and an NSAID such as diclofenac increases the risk of serious gastrointestinal (GI) events.
Status after coronary artery bypass graft surgery (CABG).
Two large, controlled clinical trials using a COX-2 selective NSAID to treat pain in the first 10-14 days after CABG surgery have shown an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in CABG.
Post-MI Patients
Observational studies conducted in the Danish National Registry have shown that patients treated with NSAIDs in the post-myocardial infarction period had an increased risk of reinfarction, cardiovascular death and all-cause mortality from the first week of treatment. In the same cohort, the incidence of deaths in the first year after 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 death rate decreased somewhat after the first year after myocardial infarction, the increased relative risk of death in NSAID users persisted for at least the next four years of follow-up.
Avoid using Alcazar in patients who have recently had a heart attack unless the benefit is expected to outweigh the risk of recurrent cardiovascular thrombotic events. When Alcazar is used in patients with recent MI, patients should be monitored for signs of cardiac ischaemia.
Gastrointestinal bleeding, ulceration and perforation
NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events, including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or colon, 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 gastrointestinal adverse event while on NSAID therapy is symptomatic. Upper gastrointestinal ulcers, excessive bleeding or perforation caused by NSAIDs occurred in about 1% of patients treated for 3 to 6 months and in about 2% to 4% of patients treated for 1 year. However, even short-term NSAID therapy is not without risk.
Risk factors for GI bleeding, ulceration and perforation
Patients with a history of peptic ulcer disease and/or gastrointestinal bleeding who were taking NSAIDs had a more than 10-fold increased risk of developing gastrointestinal bleeding 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; alcohol consumption; older age; and poor general health. Most post-marketing reports of fatal gastrointestinal events have occurred in elderly or debilitated patients. In addition, there is an increased risk of gastrointestinal bleeding in patients with advanced liver disease and/or coagulopathy.
Strategies to minimize GI risks in NSAID-treated patients:
- Use the lowest effective dose for the shortest possible duration.
- Avoid administering more than one NSAID at the same time.
- Use in patients at increased risk should be avoided unless the benefit is expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, therapies other than NSAIDs should be considered.
- Watch out for signs and symptoms of gastrointestinal ulceration and bleeding during NSAID therapy.
- If a serious gastrointestinal adverse event is suspected, promptly initiate evaluation and treatment and discontinue Alcazar until a serious gastrointestinal adverse event is ruled out.
- Patients should be monitored more closely for signs of gastrointestinal bleeding when concomitant use of low-dose aspirin for cardiac prophylaxis.
hepatotoxicity
In clinical trials of oral diclofenac-containing products, significant elevations (i.e., greater than three times the ULN) in AST (SGOT) (ALT was not measured in all trials) occurred in approximately 2% of approximately 5,700 patients at any time during diclofenac treatment measured). .
In a large, open-label, controlled study of 3,700 patients treated with oral diclofenac for 2 to 6 months, patients were first re-monitored at 8 weeks and 1,200 patients at 24 weeks. Significant elevations in ALT and/or AST occurred in approximately 4% of 3,700 patients and included marked elevations (greater than 8 times the ULN) in approximately 1% of 3,700 patients. In this open-label study, patients had 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 in ALT or AST observed intake of diclofenac compared to other NSAIDs. Elevations in transaminases have been observed more frequently in patients with osteoarthritis than in patients with rheumatoid arthritis.
Almost all significant elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of oral diclofenac therapy in 42 of the 51 patients in all studies who developed marked transaminase elevations.
Cases of drug-induced hepatotoxicity have been reported in post-marketing reports in the first month and in some cases in the first 2 months of NSAID therapy, but can occur at any time during treatment with diclofenac.
Post-marketing surveillance has reported cases of severe hepatic reactions, including hepatic necrosis, jaundice, fulminant hepatitis with and without jaundice, and hepatic failure. Some of these reported cases have resulted in death or liver transplants.
In a European retrospective population-based, case-controlled study, 10 cases of oral diclofenac-related drug-induced liver injury were associated with a statistically significant 4-fold adjusted odds ratio of liver injury with current use compared to no use of diclofenac. In this particular study, based on a total of 10 cases of diclofenac-related liver injury, the adjusted odds ratio continued to increase for female gender, doses of 150 mg or more, and duration of use greater than 90 days.
Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, since severe hepatotoxicity can develop without a prodrome of various symptoms. The optimal times for performing the first and subsequent transaminase measurements are not known. Based on data from clinical trials and post-marketing experience, transaminases should be monitored within 4 to 8 weeks of starting diclofenac treatment. However, severe hepatic reactions can occur at any time during treatment with diclofenac.
If abnormal liver function 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.), should Alcazar to be dropped off immediately.
Educate patients about the warning signs and symptoms of hepatotoxicity (eg, nausea, fatigue, lethargy, diarrhea, itching, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop or if systemic manifestations appear (e.g., eosinophilia, rash, etc.), discontinue Alcazar immediately and conduct a clinical evaluation of the patient.
To minimize the potential risk of a liver-related adverse event in patients treated with Alcazar, use the lowest effective dose for the shortest duration possible. Be cautious when prescribing Alcazar concomitantly with drugs known to be potentially hepatotoxic (e.g. paracetamol, antibiotics, antiepileptics).
hypertension
NSAIDs, including Alcazar, can cause high blood pressure to come back or make pre-existing high blood pressure worse, both of which may contribute to an increased incidence of cardiovascular events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have an impaired response to these therapies when taking NSAIDs.
Monitor blood pressure (BP) at the start of NSAID treatment and throughout the course of therapy.
heart failure and edema
The Coxib and Traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials showed an approximately two-fold increase in heart failure hospitalizations in COX-2-selectively treated patients and nonselectively NSAID-treated patients compared to placebo-treated patients. In a Danish National Register study of heart failure patients, NSAID use increased the risk of heart attack, heart failure hospitalization and death.
In addition, fluid retention and edema have been observed in some patients treated with NSAIDs. Administration of diclofenac may attenuate the cardiovascular effects of several therapeutic agents used to treat these conditions (eg, diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]).
Avoid using Alcazar in patients with severe heart failure unless the benefit is expected to outweigh the risk of worsening heart failure. When Alcazar is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
renal toxicity and hyperkalemia
kidney toxicity
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other kidney damage.
Renal toxicity has also been observed in patients in whom renal prostaglandins play a compensatory role in maintaining renal blood flow. In these patients, administration of an NSAID can cause a dose-dependent reduction in prostaglandin production and, secondarily, in renal blood flow, which can trigger overt renal decompensation. Patients at greatest risk of this reaction are those with renal impairment, dehydration, hypovolaemia, congestive heart failure, hepatic impairment, patients taking diuretics and ACE inhibitors or ARBs, and elderly patients. Discontinuation of NSAID therapy is usually followed by recovery to pre-treatment status.
There is no information from controlled clinical trials on the use of Alcazar in patients with advanced kidney disease. The renal effects of Alcazar may accelerate the progression of renal dysfunction in patients with pre-existing kidney disease.
Correct volume status in dehydrated or hypovolaemic patients prior to initiating treatment with Alcazar. Monitor renal function in patients with renal or hepatic impairment, congestive heart failure, dehydration, or hypovolemia while using Alcazar. Avoid using Alcazar in patients with advanced kidney disease unless the benefit is expected to outweigh the risk of worsening kidney function. When Alcazar is used in patients with advanced kidney disease, patients should be monitored for signs of deterioration in kidney function.
Hyperkalemia
Elevations in serum potassium, including hyperkalemia, have been reported with the use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic hypoaldosteronistic state.
Anaphylactic reactions
Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma.
Get emergency help if an anaphylactic reaction occurs.
Worsening of asthma associated with 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, Alcazar is contraindicated in patients with this form of aspirin sensitivity. When Alcazar is used in patients with pre-existing asthma (without known sensitivity to aspirin), patients must be monitored for changes in asthma signs and symptoms.
Serious skin reactions
NSAIDs, including diclofenac, can cause serious skin side effects such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events can happen without warning. Educate patients about the signs and symptoms of serious skin reactions and discontinue use of Alcazar at the first appearance of a rash or other sign of hypersensitivity. Alcazar is contraindicated in patients with a history of serious skin reactions to NSAIDs.
Do not apply Alcazar to open skin wounds, infection, inflammation or exfoliative dermatitis as this may affect the absorption and tolerability of the drug.
Premature closure of the fetal ductus arteriosus
Diclofenac can cause premature closure of the fetal ductus arteriosus. Avoid using NSAIDs, including Alcazar, in pregnant women after 30 weeks of pregnancy (third trimester).
Hematological 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 signs or symptoms of anemia develop in a patient treated with Alcazar, hemoglobin or hematocrit should be monitored.
NSAIDs, including Alcazar, can increase the risk of bleeding events. Co-morbidities such as coagulopathy or concomitant use of warfarin, other anticoagulants, antiplatelet agents (eg, aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding.
Masking inflammation and fever
The pharmacological activity of Alcazar in reducing inflammation and possibly fever may reduce the usefulness of diagnostic signs in detecting infection.
laboratory monitoring
Because severe gastrointestinal bleeding, hepatotoxicity, and kidney damage can occur without warning symptoms or signs, patients taking long-term NSAID treatment should be regularly monitored with a full blood count and chemical profile.
sun exposure
Advise patients to avoid exposure to natural or artificial sunlight on treated knees, as studies in animals suggested that topical treatment with diclofenac resulted in an earlier occurrence of UV light-induced skin tumors. The potential effects of Alcazar on the skin response to UV damage in humans are unknown.
eye contact
Avoid contact of Alcazar with eyes and mucous membranes. Advise patients to immediately flush eyes with water or saline solution if eye contact occurs and to seek medical attention if irritation persists for more than an hour.
Oral nonsteroidal anti-inflammatory drugs
Concomitant use of oral NSAIDs with Alcazar 1.5% resulted in a higher rate of rectal bleeding and more frequent abnormal creatinine, urea and hemoglobin levels. Therefore, do not use combination therapy with Alcazar and an oral NSAID unless the benefit outweighs the risk, and do regular laboratory testing.
Patient Counseling Information
Instruct the patient to use the FDA-approved patient identifier (Medication guide) accompanying each prescription issued. Provide patients, families, or their caregivers with the following information before starting therapy with Alcazar and regularly during ongoing therapy.
Cardiovascular thrombotic events
Advise patients to be alert for symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurred speech, and to promptly report any such symptoms to their physician.
Gastrointestinal bleeding, ulceration and perforation
Advise patients to report symptoms of ulceration and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis, to their physician. Educate patients about the increased risk of, signs and symptoms of gastrointestinal bleeding when concomitantly using low-dose aspirin for cardiac prophylaxis.
hepatotoxicity
Educate patients about the warning signs and symptoms of hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, advise patients to discontinue Alcazar and seek medical attention immediately.
heart failure and edema
Advise patients to be alert to symptoms of congestive heart failure, including shortness of breath, unexplained weight gain, or edema, and to contact their doctor if such symptoms occur.
Anaphylactic reactions
Educate patients about the signs of an anaphylactic reaction (eg, difficulty breathing, swelling of the face or throat). Advise patients to seek emergency help immediately if these occur.
Serious skin reactions
Advise patients to stop taking Alcazar immediately if they develop any type of rash and to contact their doctor as soon as possible.
female fertility
Advise women of childbearing potential who wish to conceive that NSAIDs, including Alcazar, may be associated with reversible ovulation delay
Fetal Toxicity
Inform pregnant women that they should avoid the use of Alcazar and other NSAIDs after 30 weeks of pregnancy because of the risk of premature closure of the fetal ductus arteriosus.
Avoid concomitant use of NSAIDs
Inform patients that the concomitant use of Alcazar 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. Advise patients that NSAIDs can be found in "over-the-counter" medications used to treat the common cold, fever, or insomnia.
Use of NSAIDs and low-dose aspirin
Inform patients not to take low-dose aspirin at the same time as Alcazar until they have spoken to their doctor.
eye contact
Instruct patients to avoid contact of Alcazar with eyes and mucous membranes. Advise patients to immediately flush eyes with water or saline solution if eye contact occurs and to seek medical attention if irritation persists for more than an hour.
Avoidance of secondary exposure
Advise patients to avoid skin contact between others and the knee(s) where Alcazar has been applied until the knee(s) are completely dry.
Special application instructions
Advise patients not to apply Alcazar to open skin wounds, infection, inflammation, or exfoliative dermatitis, as this may interfere with absorption and reduce drug tolerability.
Instruct patients to wait until the Alcazar-treated area is completely dry before applying sunscreen, insect repellent, lotion, moisturizer, cosmetic, or other topical medication.
Advise patients to minimize or avoid exposure of the treated knee(s) to natural or artificial sunlight.
Nonclinical Toxicology
Carcinogenesis, mutagenesis, impairment of fertility
carcinogenesis
Carcinogenicity studies in mice and rats administered diclofenac sodium as a diet for 2 years revealed no significant increase in tumor incidence at doses up to 2 mg/kg/day, approximately 0.85- and 1.7-fold, respectively maximum recommended topical dose of Alcazar in humans (based on apparent bioavailability and body surface area comparison).
In a dermal carcinogenicity study performed in albino mice, daily topical application of diclofenac sodium for two years at concentrations up to 0.035% diclofenac sodium (a diclofenac sodium concentration 57 times lower than that present in Alcazar) did not result in an increased incidence of neoplasms .
In a photococarcinogenicity study performed in hairless mice, topical application of diclofenac sodium at doses up to 0.035% diclofenac sodium (diclofenac sodium concentration 57 times lower than that present in Alcazar) resulted in an earlier median time of onset of tumors .
Mutagenese
Diclofenac was not mutagenic or clastogenic in a battery of genotoxicity assays that included the bacterial reverse mutation assay.in-vitroMouse lymphoma point mutation assay, chromosomal aberration studies in Chinese hamster ovary cellsin-vitro, AndliveRat Chromosome Aberration Assay of Bone Marrow Cells.
impairment of fertility
Fertility studies have not been conducted with Alcazar. Administration of diclofenac sodium to male and female rats at doses up to 4 mg/kg/day (approximately 3.4 times the MRHD of Alcazar based on apparent bioavailability and body surface area comparison) had no effect on the fertility. Studies conducted in rats found no effect of dermally applied DMSO on fertility, reproductive performance, or offspring performance.
Use in certain population groups
pregnancy
pregnancy category Cbefore the 30th week of pregnancy; Category D from the 30th week of pregnancy
Summary of Risks
Use of NSAIDs, including Alcazar, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid using NSAIDs, including Alcazar, in pregnant women after 30 weeks of pregnancy (third trimester).
There are no adequate and well-controlled studies of Alcazar in pregnant women. Data from observational studies on potential embryofoetal risks from NSAID use in women in the first or second trimester of pregnancy are inconclusive. In the general US population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations and 15-20% for miscarriage. Published reproductive and developmental studies on dimethyl sulfoxide (DMSO, the solvent used in Alcazar) are inconclusive as to possible teratogenicity. In animal reproductive studies, no evidence of teratogenicity was observed in mice, rats or rabbits given diclofenac during organogenesis at doses up to approximately 0.6, 0.6 and 1.3 times the maximum recommended human dose (MRHD), respectively. by Alcazar, despite the presence of maternal and fetal toxicity at these doses. Based on animal data, prostaglandins have been shown to play an important role in endometrial vascular permeability, blastocyst implantation and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac resulted in increased pre- and post-implantation loss.
Clinical Considerations
labor or delivery
There are no studies on the effects of Alcazar during labor or delivery. In animal studies, NSAIDs, including diclofenac, inhibit prostaglandin synthesis, cause delayed labor, and increase the incidence of stillbirth.
Data
animal data
Reproductive and developmental studies in animals showed that administration of diclofenac sodium during organogenesis, despite 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 Alcazar, 162 mg/day, based on body surface area (BSA) comparison, and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately the 0.6 and 1 3 times the MRHD, based on BSA comparison). Published reproductive and developmental studies on dimethyl sulfoxide (DMSO, the solvent used in Alcazar) are inconclusive on possible teratogenicity. In rats, maternal toxic doses of diclofenac were associated with dystocia, prolonged gestation, reduced fetal weight and growth, and reduced fetal survival.
lactation
Summary of Risks
Based on available data, diclofenac may be present in breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CATAFLAM and possible adverse effects of CATAFLAM or the mother's underlying medical condition on the breastfed infant.
Data
A woman treated orally with diclofenac salt, 150 mg/day had a milk diclofenac level of 100 mcg/l, corresponding to an infant dose of approximately 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women taking diclofenac (either after a 100 mg/day oral dose for 7 days or a single 50 mg intramuscular dose immediately after delivery).
Females and males with reproductive potential
infertility
Women
Based on the mechanism of action, use of prostaglandin-mediated NSAIDs, including Alcazar, may delay or prevent ovarian follicle rupture, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt the prostaglandin-mediated follicle rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider stopping NSAIDs, including Alcazar, in women who are having trouble conceiving or who are undergoing screening for infertility.
Pediatric use
Safety and efficacy in pediatric patients have not been established.
geriatric use
Elderly patients are at greater risk of NSAID-associated serious cardiovascular, gastrointestinal and/or renal adverse reactions compared to younger patients. If the expected benefits to the elderly patient outweigh these potential risks, start dosing at the lower end of the dosing range and monitor patients for side effects.
Of the 911 patients treated with Alcazar in seven controlled phase 3 clinical trials, 1.5% were 444 patients aged 65 years and older. There was no age-related difference in the frequency of side effects. Of the 793 patients treated with Alcazar 1.5% in an open-label safety study, 334 patients were aged 65 and over, including 107 patients aged 75 and over. There was no difference in the incidence of adverse events with long-term use of Alcazar 1.5% in this elderly patient population.