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. 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).
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 ratesobserved in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In controlled trials during the premarketing development of FLECTOR PATCH, approximately 600 patients with minor sprains, strains, and contusions were treated with FLECTOR PATCH for up to two weeks.
Adverse Events Leading To Discontinuation Of TreatmentIn the controlled trials, 3% of patients in both the FLECTOR PATCH and placebo patch groups discontinued treatment due to an adverse event. The most common adverse events leading to discontinuation were application site reactions, occurring in 2% of both the FLECTOR PATCH and placebo patch groups. Application site reactions leading to dropout included pruritus, dermatitis, and burning.
Common Adverse EventsLocalized Reactions
Overall, the most common adverse events associated with FLECTOR PATCH treatment were skin reactions at the site of treatment. Table 1 lists all adverse events, regardless of causality, occurring in ≥ 1% of patients in controlled trials of FLECTOR PATCH. A majority of patients treated with FLECTOR PATCH had adverse events with a maximum intensity of “mild” or “moderate.”
Table 1: Common Adverse Events (by body system and
preferred term) in ≥ 1% of Patients treated with FLECTOR PATCH or Placebo
Patch
| Category | Diclofenac N=572 |
Placebo N=564 |
||
| N | Percent | N | Percent | |
| Application Site Conditions | 64 | 11 | 70 | 12 |
| Pruritus | 31 | 5 | 44 | 8 |
| Dermatitis | 9 | 2 | 3 | < 1 |
| Burning | 2 | < 1 | 8 | 1 |
| Other2 | 22 | 4 | 15 | 3 |
| Gastrointestinal Disorders | 49 | 9 | 33 | 6 |
| Nausea | 17 | 3 | 11 | 2 |
| Dysgeusia | 10 | 2 | 3 | < 1 |
| Dyspepsia | 7 | 1 | 8 | 1 |
| Other3 | 15 | 3 | 11 | 2 |
| Nervous System Disorders | 13 | 2 | 18 | 3 |
| Headache | 7 | 1 | 10 | 2 |
| Paresthesia | 6 | 1 | 8 | 1 |
| Somnolence | 4 | 1 | 6 | 1 |
| Other 4 | 4 | 1 | 3 | < 1 |
| 1 The table lists adverse events occurring in
placebo-treated patients because the placebo-patch was comprised of the same
ingredients as FLECTOR PATCH except for diclofenac. Adverse events in the
placebo group may therefore reflect effects of the non-active ingredients. 2 Includes: application site dryness, irritation, erythema, atrophy, discoloration, hyperhidriosis, and vesicles. 3 Includes: gastritis, vomiting, diarrhea, constipation, upper abdominal pain, and dry mouth. 4 Includes: hypoesthesia, dizziness, and hyperkinesias. |
Foreign labeling describes that dermal allergic reactions may occur with FLECTOR PATCH treatment. Additionally, the treated area may become irritated or develop itching, erythema, edema, vesicles, or abnormal sensation.
Following a single application of the FLECTOR PATCH on the upper inner arm, peak plasma concentrations of diclofenac (range 0.7 – 6 ng/mL) were noted between 10 – 20 hours of application. Plasma concentrations of diclofenac in the range of 1.3 – 8.8 ng/mL were noted after five days with twice-a-day FLECTOR PATCH application.
Systemic exposure (AUC) and maximum plasma concentrations of diclofenac, after repeated dosing for four days with FLECTOR PATCH, were lower ( < 1%) than after a single oral 50mg diclofenac sodium tablet.
The pharmacokinetics of FLECTOR PATCH has been tested in healthy volunteers at rest or undergoing moderate exercise (cycling 20 min/h for 12 h at a mean HR of 100.3 bpm). No clinically relevant differences in systemic absorption were observed, with peak plasma concentrations in the range of 2.2 – 8.1 ng/mL while resting, and 2.7 – 7.2 ng/mL during exercise.
DistributionDiclofenac has a very high affinity ( > 99%) for human serum 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-, 5-hydroxy-, 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 CPY2C9. Both diclofenac 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 metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy- diclofenac.
Excretion
The plasma elimination half-life of diclofenac after application of FLECTOR PATCH is approximately 12 hours. 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. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites.
Pregnancy Category C prior to 30 weeks gestation; Category D starting 30 weeks gestation.
Risk SummaryUse of NSAIDs, including FLECTOR PATCH, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including FLECTOR PATCH, in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of FLECTOR PATCH 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 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies, diclofenac epolamine administered orally to pregnant rats and rabbits during the period of organogenesis produced embryotoxicity at approximately 3 and 7 times, respectively, the topical exposure from the maximum recommended human dose (MRHD) of FLECTOR PATCH. In rats, increased incidences of skeletal anomalies and maternal toxicity were also observed at this dose. Diclofenac epolamine administered orally to both male and female rats prior to mating and throughout the mating period, and during gestation and lactation in females produced embryotoxicity at doses approximately 3 and 7 times, respectively, the topical exposure from the MRHD.
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, resulted in increased pre- and post-implantation loss.
Clinical ConsiderationsLabor or Delivery
There are no studies on the effects of FLECTOR PATCH during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
DataAnimal data
Pregnant Sprague Dawley rats were administered 1, 3, or 6 mg/kg diclofenac epolamine via oral gavage daily from gestation days 6 to 15. Maternal toxicity, embryotoxicity, and increased incidence of skeletal anomalies were noted with 6 mg/kg/day diclofenac epolamine, which corresponds to 3 times the maximum recommended daily exposure in humans based on a body surface area comparison. Pregnant New Zealand White rabbits were administered 1, 3, or 6 mg/kg diclofenac epolamine via oral gavage daily from gestation days 6 to 18. No maternal toxicity was noted; however, embryotoxicity was evident at 6 mg/kg/day group which corresponds to 7 times the maximum recommended daily exposure in humans based on a body surface area comparison.
Male rats were orally administered diclofenac epolamine (1, 3, 6 mg/kg) for 60 days prior to mating and throughout the mating period, and females were given the same doses 14 days prior to mating and through mating, gestation, and lactation. Embryotoxicity was observed at 6 mg/kg diclofenac epolamine (3 times the maximum recommended daily exposure in humans based on a body surface area comparison), and was manifested as an increase in early resorptions, post-implantation losses, and a decrease in live fetuses. The number of live born and total born were also reduced as was F1 postnatal survival, but the physical and behavioral development of surviving F1 pups in all groups was the same as the deionized water control, nor was reproductive performance adversely affected despite a slight treatment-related reduction in body weight.
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 ratesobserved in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In controlled trials during the premarketing development of FLECTOR PATCH, approximately 600 patients with minor sprains, strains, and contusions were treated with FLECTOR PATCH for up to two weeks.
Adverse Events Leading To Discontinuation Of TreatmentIn the controlled trials, 3% of patients in both the FLECTOR PATCH and placebo patch groups discontinued treatment due to an adverse event. The most common adverse events leading to discontinuation were application site reactions, occurring in 2% of both the FLECTOR PATCH and placebo patch groups. Application site reactions leading to dropout included pruritus, dermatitis, and burning.
Common Adverse EventsLocalized Reactions
Overall, the most common adverse events associated with FLECTOR PATCH treatment were skin reactions at the site of treatment. Table 1 lists all adverse events, regardless of causality, occurring in ≥ 1% of patients in controlled trials of FLECTOR PATCH. A majority of patients treated with FLECTOR PATCH had adverse events with a maximum intensity of “mild” or “moderate.”
Table 1: Common Adverse Events (by body system and
preferred term) in ≥ 1% of Patients treated with FLECTOR PATCH or Placebo
Patch
| Category | Diclofenac N=572 |
Placebo N=564 |
||
| N | Percent | N | Percent | |
| Application Site Conditions | 64 | 11 | 70 | 12 |
| Pruritus | 31 | 5 | 44 | 8 |
| Dermatitis | 9 | 2 | 3 | < 1 |
| Burning | 2 | < 1 | 8 | 1 |
| Other2 | 22 | 4 | 15 | 3 |
| Gastrointestinal Disorders | 49 | 9 | 33 | 6 |
| Nausea | 17 | 3 | 11 | 2 |
| Dysgeusia | 10 | 2 | 3 | < 1 |
| Dyspepsia | 7 | 1 | 8 | 1 |
| Other3 | 15 | 3 | 11 | 2 |
| Nervous System Disorders | 13 | 2 | 18 | 3 |
| Headache | 7 | 1 | 10 | 2 |
| Paresthesia | 6 | 1 | 8 | 1 |
| Somnolence | 4 | 1 | 6 | 1 |
| Other 4 | 4 | 1 | 3 | < 1 |
| 1 The table lists adverse events occurring in
placebo-treated patients because the placebo-patch was comprised of the same
ingredients as FLECTOR PATCH except for diclofenac. Adverse events in the
placebo group may therefore reflect effects of the non-active ingredients. 2 Includes: application site dryness, irritation, erythema, atrophy, discoloration, hyperhidriosis, and vesicles. 3 Includes: gastritis, vomiting, diarrhea, constipation, upper abdominal pain, and dry mouth. 4 Includes: hypoesthesia, dizziness, and hyperkinesias. |
Foreign labeling describes that dermal allergic reactions may occur with FLECTOR PATCH treatment. Additionally, the treated area may become irritated or develop itching, erythema, edema, vesicles, or abnormal sensation.
DRUG INTERACTIONSSee Table 2 for clinically significant drug interactions with diclofenac.
Table 2: Clinically
Significant Drug Interactions with Diclofenac
| Drugs That Interfere with Hemostasis | |
| Clinical Impact: |
|
| Intervention: | Monitor patients with concomitant use of FLECTOR PATCH with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding. |
| Aspirin | |
| Clinical Impact: | Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. |
| Intervention: | Concomitant use of FLECTOR PATCH and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding. FLECTOR PATCH is not a substitute for low dose aspirin for cardiovascular protection. |
| Diuretics | |
| Clinical Impact: | Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
| Intervention: | During concomitant use of FLECTOR PATCH with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. |
| Digoxin | |
| Clinical Impact: | The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
| Intervention: | During concomitant use of FLECTOR PATCH and digoxin, monitor serum digoxin levels. |
| Lithium | |
| Clinical Impact: | NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
| Intervention: | During concomitant use of FLECTOR PATCH and lithium, monitor patients for signs of lithium toxicity. |
| Methotrexate | |
| Clinical Impact: | Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
| Intervention: | During concomitant use of FLECTOR PATCH and methotrexate, monitor patients for methotrexate toxicity. |
| Cyclosporine | |
| Clinical Impact: | Concomitant use of FLECTOR PATCH and cyclosporine may increase cyclosporine’s nephrotoxicity. |
| Intervention: | During concomitant use of FLECTOR PATCH and cyclosporine, monitor patients for signs of worsening renal function. |
| NSAIDs and Salicylates | |
| Clinical Impact: | Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy. |
| Intervention: | The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. |
| Pemetrexed | |
| Clinical Impact: | Concomitant use of FLECTOR PATCH and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
| Intervention: | During concomitant use of FLECTOR PATCH and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
