Difend 1.5% Actions
Percutaneous anti-inflammatory agent.
Difend 1.5% is an anti-inflammatory and analgesic preparation for topical application. Its active substance corresponds to 1% Difend 1.5% sodium. The white, creamy, non-greasy preparation is easy to rub into the skin, and its aqueous-alcoholic base gives it a soothing and cooling effect.
Difend 1.5% has been shown in experiments to inhibit prostaglandin biosynthesis and this is regarded as an important factor in its mechanism of action.
In inflammation of traumatic or rheumatic origin, Difend 1.5% has been shown to relieve pain, reduce oedema and shorten the time to return of normal function.
Pharmacokinetics: Absorption: The amount of Difend 1.5% absorbed through the skin is proportional to the contact time and skin area covered with Difend 1.5% and depends on the total topical dose and on skin hydration. About 6% of the active substance is absorbed after topical application of Difend 1.5% 2.5 g/500 cm2, as determined by reference to total renal elimination compared with Voltaren tablets. Absorption of Difend 1.5% increases 3-fold if an occlusive dressing is applied for 10 hrs.
Distribution: Difend 1.5% can be detected in the plasma, synovial tissue and synovial fluid after topical application of Difend 1.5% to the wrists and knees. Peak plasma concentrations of Difend 1.5% are about 100 times lower after topical application of Difend 1.5% than after oral administration of Voltaren tablet. 99.7% of Difend 1.5% binds to serum proteins, mainly to albumin (99.4%).
Metabolism: Biotransformation of Difend 1.5% takes place partly by glucuronidation of the intact molecule, but mainly by single or multiple hydroxylation resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a much lesser extent than Difend 1.5%.
Elimination: Total systemic clearance of Difend 1.5% from the plasma is 263 ± 56 mL/min (mean value ± standard deviation). The terminal plasma half-life is 1-2 hrs. Four of the metabolites, including the 2 active metabolites, also have a short plasma half-life (1-3 hrs). One metabolite, 3'-hydroxy-4'-methoxy-Difend 1.5%, has a much longer half-life, but this metabolite is virtually inactive.
Difend 1.5% and its metabolites are excreted mainly in the urine.
Kinetics in Special Clinical Situations: No accumulation of Difend 1.5% and its metabolites should occur in patients with renal insufficiency.
In patients with chronic hepatitis or nondecompensated liver cirrhosis, the kinetics and metabolism of Difend 1.5% are the same as in patients without liver disease.
Keep using Difend 1.5% for the full time of treatment. However, do not use Difend 1.5% more often or for a longer time than your doctor ordered. Difend 1.5% is not for long-term use.
Difend 1.5% should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.
When used for severe or continuing arthritis, Difend 1.5% must be taken every day as ordered by your doctor in order for it to help you. Difend 1.5% usually begins to work within one week, but in severe cases up to two weeks or longer may pass before you begin to feel better. Several weeks may pass before you feel the full effects of Difend 1.5%.
You may take Difend 1.5% with or without food. However, Difend 1.5% capsules should be taken on an empty stomach.
To use the oral solution:
Use only the brand of Difend 1.5% that your doctor prescribed. Different brands may not work the same way.
The dose of Difend 1.5% will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Difend 1.5%. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of Difend 1.5%, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
If you switch brands of Difend 1.5%, your dose needs may change. Follow your doctor's instructions about how much medicine to take.
Do not crush, chew, or break an extended-release tablet. Swallow it whole. Breaking the pill may cause too much of the drug to be released at one time.
Dissolve the Difend 1.5% powder (Difend 1.5%) with 1 to 2 ounces of water. Do not use any other type of liquid. Stir this mixture and drink all of it right away. Difend 1.5% powder works best if you take it on an empty stomach.
Call your doctor if your headache does not completely go away after taking Difend 1.5%. Do not take a second dose of Difend 1.5% powder without your doctor's advice.
Do not crush, chew, or break an enteric-coated pill. Swallow the pill whole. The enteric-coated pill has a special coating to protect your stomach. Breaking the pill could damage this coating.
If you use this medication long-term, your liver function will need to be checked with frequent blood tests. Visit your doctor regularly.
Store at room temperature away from moisture and heat.
Difend 1.5% has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of Difend 1.5%, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).
Difend 1.5% is a potent inhibitor of prostaglandin synthesis in vitro. Difend 1.5% 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 Difend 1.5% is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.
The relative bioavailability of Difend 1.5% 35 mg capsules was compared to Difend 1.5% potassium immediate-release (IR) tablets 50 mg in 39 healthy subjects under fasted and fed conditions in a single-dose crossover study.
Difend 1.5% 35 mg capsules do not result in an equivalent systemic exposure to 50 mg Difend 1.5% potassium IR tablets.
When taken under fasted conditions, a 20% lower dose of Difend 1.5% in Difend 1.5% capsules resulted in a 23% lower mean systemic exposure (AUCinf) and a 26% lower mean peak concentration (Cmax) compared to Difend 1.5% potassium IR tablets. The time to reach peak concentration (Tmax) was similar for Difend 1.5% and Difend 1.5% potassium IR tablets and was ~1 hour for both.
When taken under fed conditions, a 20% lower dose of Difend 1.5% in Difend 1.5% capsules resulted in a 23% lower mean systemic exposure (AUCinf) and a 48% lower mean Cmax compared to Difend 1.5% potassium IR tablets. The Tmax for Difend 1.5% was delayed by approximately 1 hour compared to Difend 1.5% potassium IR tablets (3.32 hours vs. 2.33 hours, respectively).
When taken under fed conditions, Difend 1.5% capsules resulted in an 11% lower mean systemic exposure (AUCinf) and a 60% lower mean Cmax compared to fasted conditions. Whereas Difend 1.5% potassium IR tablets under fed conditions resulted in 8% - 10% lower mean systemic exposure (AUCinf) and 28% - 43% lower mean Cmax compared to fasted conditions, based on the results from two individual food effect studies. The Tmax for Difend 1.5% was delayed by approximately 2.32 hours under fed conditions compared to fasted conditions (3.32 hours vs. 1.00 hour, respectively), while the Tmax for Difend 1.5% potassium IR tablets was delayed by approximately 1.00 - 1.33 hours under fed conditions compared to fasted conditions (1.70 vs. 0.74 hours and 2.33 vs. 1.00 hours, respectively in two studies).
There were no differences in elimination half-life between Difend 1.5% and Difend 1.5% potassium IR tablets under fasted or fed conditions.
Difend 1.5% is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. After repeated oral administration, no accumulation of Difend 1.5% in plasma occurred.
Administration of Difend 1.5% capsules 18 mg and 35 mg was associated with dose proportional pharmacokinetics.
Taking Difend 1.5% with food causes a significant decrease in the rate but not the overall extent of systemic absorption of Difend 1.5% compared with taking Difend 1.5% on an empty stomach. Difend 1.5% capsules results in 60% lower Cmax, 11% lower AUCinf, and 2.32 hours delayed Tmax (1.0 hour during fasted versus 3.32 hours during fed) under the fed condition compared to the fasted condition. The effectiveness of Difend 1.5% when taken with food has not been studied in clinical studies. The decreased Cmax may be associated with decreased effectiveness. Taking Difend 1.5% with food may cause a reduction in effectiveness compared to taking Difend 1.5% on an empty stomach.
The apparent volume of distribution (V/F) of Difend 1.5% potassium is 1.3 L/kg. Difend 1.5% is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 mg/mL) achieved with recommended doses.
Difend 1.5% 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 Difend 1.5%.
Difend 1.5% is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. The terminal half-life of unchanged Difend 1.5% is approximately 2 hours.
Five Difend 1.5% 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 Difend 1.5%. The major Difend 1.5% metabolite, 4'-hydroxy-Difend 1.5%, has very weak pharmacologic activity. The formation of 4'-hydroxy-Difend 1.5% is primarily mediated by CYP2C9. Both Difend 1.5% and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in Difend 1.5% metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy-Difend 1.5%. In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy and 5-hydroxy-Difend 1.5% were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects.
Difend 1.5% 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 Difend 1.5% 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 Difend 1.5% plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged Difend 1.5%, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged Difend 1.5% is approximately 2 hours.
Pediatric: The pharmacokinetics of Difend 1.5% has not been investigated in pediatric patients.
Race: Pharmacokinetic differences due to race/ethnicity have not been identified.
Hepatic Impairment: No dedicated Difend 1.5% pharmacokinetics studies in patients with hepatic impairment were conducted. Hepatic metabolism accounts for almost 100% of Difend 1.5% elimination. Therefore, in patients with hepatic impairment, start with the lowest dose and if efficacy is not achieved, consider use of an alternate product.
Renal Impairment: Difend 1.5% pharmacokinetics has been investigated in subjects with renal insufficiency. No differences in the pharmacokinetics of Difend 1.5% have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60-90, 30-60, and less than 30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects.
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 4 for clinically significant drug interactions of NSAIDs with aspirin.
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Information checked by Dr. Sachin Kumar, MD Pharmacology