As a general recommendation, the dose should be individually adjusted. Adverse effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.
Gastro-Resistant Tablet: The recommended initial daily dose is 100 to 150 mg. In milder cases, as well as for long-term therapy, 75 to 100 mg daily is usually sufficient.
The total daily dose should generally be divided into 2 to 3 doses. To suppress nocturnal pain and morning stiffness, treatment with tablets during the day can be supplemented by the administration of a suppository at bedtime (up to a total maximum daily dose of 150 mg).
In primary dysmenorrhea, the daily dose should be individually adjusted and is generally 50 to 150 mg. A dose of 50 to 100 mg should be given initially and, if necessary, increased over the course of several menstrual cycles up to a maximum of 200 mg/day. Treatment should be started on appearance of the first symptoms and, depending on the symptomatology, continued for a few days.
SR Tablet: The recommended initial daily dose is 100 mg.
In milder cases, as well as for long-term therapy, 100 mg daily is usually sufficient.
Where the symptoms are most pronounced during the night or in the morning, the tablet should preferably be taken in the evening.
Children: Gastro-Resistant Tablet: Children aged 1 year or over and adolescents should be given 0.5 to 2 mg/kg body weight daily in 2 to 3 separate doses, depending on the severity of the disorder. For treatment of juvenile rheumatoid arthritis, the daily dose can be raised up to a maximum of 3 mg/kg daily, given in separate doses.
The maximum daily dose of 150 mg should not be exceeded.
Because of their dosage strength, Difend 50 mg gastro-resistant tablets are not recommended for use in children and adolescents below 14 years of age; Difend 25 mg gastro-resistant tablets could be used in these patients.
SR Tablet: Not suitable for children and adolescents because of the dosage strength.
Elderly (Patients aged 65 or above): No adjustment of the starting dose is required for elderly patients.
Established Cardiovascular Disease or Significant Cardiovascular Risk Factors: Treatment with Difend is generally not recommended in patients with established cardiovascular disease or uncontrolled hypertension. If needed, patients with established cardiovascular disease, uncontrolled hypertension, or significant risk factors for cardiovascular disease should be treated with Difend only after careful consideration and only at doses ≤100 mg daily if treated for more than 4 weeks.
Renal Impairment: Difend is contraindicated in patients with renal failure. No specific studies have been carried out in patients with renal impairment, therefore, no specific dose adjustment recommendations can be made. Caution is advised when administering Difend to patients with mild to moderate renal impairment.
Hepatic Impairment: Difend is contraindicated in patients with hepatic failure.
No specific studies have been carried out in patients with hepatic impairment, therefore, no specific dose adjustment recommendations can be made. Caution is advised when administering Difend to patients with mild to moderate hepatic impairment.
Administration: SR Tablet: Tablets should be swallowed whole with liquid, preferably before meals and must not be divided or chewed.
Injection: Difend injection should not be given for >2 days; if necessary, treatment can be continued with Difend tablets or suppositories.
Injection: IM: The following directions for IM injection must be followed in order to avoid damage to a nerve or other tissue at the injection site.
Dosage is generally 1 75 mg ampoule daily, injected deep intragluteally into the upper outer quadrant. In severe cases (eg, colic), the daily dose can exceptionally be increased to 2 injections, separated by an interval of a few hours (1 into each buttock). Alternatively, it is possible to combine 1 ampoule with other dosage forms of Difend (eg, tablets) up to a maximum daily dosage of 150 mg.
In migraine attacks, clinical experience is limited to initial use of 1 ampoule of 75 mg administered as soon as possible, followed by suppositories up to 100 mg on the same day if required. The total dose should not exceed 175 mg on the 1st day.
IV Infusion: Difend must not be given as an IV bolus injection.
Immediately before starting an IV infusion, Difend must be diluted with saline 0.9% or glucose 5% infusion solution buffered with sodium bicarbonate according to the instructions given in Instructions for Use and Handling under Cautions for Usage.
Two (2) alternative dosage regimens of Difend are recommended.
For the treatment of moderate to severe postoperative pain, 75 mg should be infused continuously over a period of 30 min to 2 hrs. If necessary, treatment may be repeated after a few hours, but the dosage should not exceed 150 mg within any period of 24 hrs.
For the prevention of postoperative pain, a loading dose of 25-50 mg should be infused after surgery over 15 min to 1 hr, followed by a continuous infusion of about 5 mg/hr up to a maximum daily dose of 150 mg.
Ask your doctor before using Difend if you take an antidepressant such as citalopram, escitalopram, fluoxetine (Prozac), fluvoxamine, paroxetine, sertraline (Zoloft), trazodone, or vilazodone. Taking any of these medicines with an NSAID may cause you to bruise or bleed easily.
Tell your doctor about all your current medicines and any you start or stop using, especially:
a blood thinner (warfarin, Coumadin, Jantoven);
heart or blood pressure medication, including a diuretic or "water pill";
other forms of Difend (Flector, Pennsaid, Solaraze, Difend Gel);
other NSAIDs - aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib (Celebrex), indomethacin, meloxicam, and others; or
steroid medicine (prednisone and others).
This list is not complete. Other drugs may interact with Difend, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.
Table 2: Clinically Significant Drug Interactions with Difend
|Drugs That Interfere with Hemostasis|
|Clinical Impact:|| |
|Intervention:||Monitor patients with concomitant use of Difend 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.|
|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 Difend and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding. Difend is not a substitute for low dose aspirin for cardiovascular protection.|
|ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers|
|Clinical Impact:|| |
|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 Difend with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects|
|Clinical Impact:||The concomitant use of Difend with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.|
|Intervention:||During concomitant use of Difend and digoxin, monitor serum digoxin levels.|
|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 Difend and lithium, monitor patients for signs of lithium toxicity.|
|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 Difend and methotrexate, monitor patients for methotrexate toxicity.|
|Clinical Impact:||Concomitant use of Difend and cyclosporine may increase cyclosporine’s’ nephrotoxicity.|
|Intervention:||During concomitant use of Difend and cyclosporine, monitor patients for signs of worsening renal function.|
|NSAIDs and Salicylates|
|Clinical Impact:||Concomitant use of Difend 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 Difend with other NSAIDs or salicylates is not recommended.|
|Clinical Impact:||Concomitant use of Difend and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity.|
|Intervention:||During concomitant use of Difend 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., Difend, 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.
|CYP2C9 Inhibitors or Inducers:|
|Clinical Impact:||Difend is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of Difend with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of Difend whereas coadministration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of Difend.|
|Intervention:||A dosage adjustment may be warranted when Difend is administered with CYP2C9 inhibitors or inducers.|
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Information checked by Dr. Sachin Kumar, MD Pharmacology