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Hisrack Actions |
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Similar to other NSAIDs, the anti-inflammatory effects of Hisrack result from inhibition of the enzyme cycooxygenase (COX). This decreases the synthesis of peripheral prostaglandins involved in mediating inflammation. Hisrack binds to the upper portion of the COX enzyme active site and prevents its substrate, arachidonic acid, from entering the active site. Hisrack was previously thought to be a non-selective COX inhibitor, but it is now known to be 5 – 50 times more selective for COX-2 than COX-1. Antipyresis may occur by central action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat loss.
For safe and effective use of Hisrack, do not take more of it, do not take it more often, and do not take it for a longer time than ordered by your doctor. Taking too much of Hisrack may increase the chance of unwanted effects, especially in elderly patients.
When used for severe or continuing arthritis, Hisrack must be taken regularly as ordered by your doctor in order for it to help you. Hisrack usually begins to work within one week, but in severe cases up to two weeks or even longer may pass before you begin to feel better. Also, several weeks may pass before you feel the full effects of Hisrack.
Swallow the extended-release tablet whole. Do not crush, break, or chew it.
The dose of Hisrack 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 Hisrack. 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 Hisrack, 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.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label.
Do not crush, chew, or break an extended-release tablet. Swallow the pill whole. It is specially made to release medicine slowly in the body. Breaking the pill would cause too much of the drug to be released at one time.
It may take up to 2 weeks of using this medicine before your symptoms improve. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve.
If you take Hisrack for a long period of time, your doctor may want to check you on a regular basis to make sure this medication is not causing harmful effects. Do not miss any scheduled visits to your doctor.
This medication can cause you to have unusual results with certain medical tests. Tell any doctor who treats you that you are using Hisrack.
Store Hisrack at room temperature away from moisture and heat.
Hisrack Extended-Release Tablets are a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Hisrack Extended-Release Tablets, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition.
Hisrack Extended-Release Tablets and Hisrack tablets both contain Hisrack, but differ in their release characteristics. The systemic availability of Hisrack from Hisrack Extended-Release Tablets is generally greater than 80%. Hisrack does not undergo significant first-pass metabolism following oral administration. After oral administration of Hisrack Extended-Release Tablets in doses up to 800 mg once daily, peak concentrations occur approximately 6 hours after dosing and are dose proportional for both total and free Hisrack.
Table 1 shows the comparison of Hisrack pharmacokinetic parameters after the administration of Hisrack tablets and Hisrack Extended-Release Tablets.
Table 2 shows the Hisrack pharmacokinetic parameters in various populations. The data from patients with renal and hepatic impairment were obtained following administration of (immediate-release) Hisrack tablets.
Mean (CV)%* | ||
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Pharmacokinetic Parameters | Hisrack Tablets | Hisrack Extended-Release Tablets |
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Extent ofOral Absorption (Bioavailability) [F] | ≥ 80% | ≥ 80% |
Time to Peak Concentration (Tmax), h | 1.4 (61%) | 6.7 (47%) |
Oral Clearance (CL/F), mL/h/kg | 49.1 (33%) | 46.8 (37%) |
Apparent Volume of Distribution (Vd/F), mL/kg | 393 (29%) | 566 (26%) |
Terminal Half-Life (t½), h | 6.4 (22%) | 8.4 (30%) |
Hisrack Extended-Release Tablets | Hisrack Tablets | |||||||
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PK Parameters | Normal Healthy Adults (18 to 44)† (n=116) | Healthy Males (18 to 43) (n=102) | Healthy Females (25 to 44) (n=14) | Elderly (>65 yr) (66 to 88) (n=24) | Hemodialysis‡ (24 to 65) (n=9) | Renal Impairment‡ (46 to 73) (n=10) | Hepatic Impairment‡(34 to 60) (n=9) | |
Dialysis On | Dialysis Off | |||||||
NA = not available | ||||||||
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Tmax, h | 6.7 (47%)* | 6.8 (45%) | 4.5 (56%) | 6.2 (51%) | 1.7 (88%) | 0.9 (67%) | 2.1 (46%) | 1.1 (15%) |
Oral Clearance, mL/h/kg (CL/F) | 46.8 (37%) | 46.8 (37%) | 47.2 (38%) | 51.6 (40%) | NA | NA | 58.3 (19%) | 42.0 (43%) |
Apparent Volume of Distribution, mL/kg (Vd/F) | 566 (26%) | 580 (26%) | 459 (28%) | 552 (34%) | NA | NA | NA | NA |
Terminal Half-Life, h | 8.4 (30%) | 8.4 (29%) | 7.6 (45%) | 7.8 (26%) | 5.1 (22%) | 7.5 (34%) | NA | 5.7 (24%) |
Food has no significant effect on the extent of Hisrack Extended-Release Tablets absorption, however, food significantly increased Cmax (54%) following a 600 mg dose.
The extent of absorption of Hisrack is not affected when Hisrack is administered with antacid. Coadministration, with an antacid, decreases the peak concentration reached by about 15 to 20% with no measurable effect on time-to-peak.
Distribution
The mean apparent volume of distribution (Vd/F) of Hisrack following administration of Hisrack Extended-Release Tablets is 566 mL/kg. Hisrack is more than 99% bound to plasma proteins, primarily to albumin, and is independent of Hisrack concentration over the dose range studied. It is not known whether Hisrack is excreted in human milk. However, based on its physical-chemical properties, excretion into breast milk is expected.
Metabolism
Hisrack metabolites do not contribute significantly to the pharmacological activity of Hisrack Extended-Release Tablets.
Following administration of immediate-release Hisrack, several metabolites have been identified in human plasma and urine. Other metabolites remain to be identified. The metabolites include 6-, 7-, and 8- hydroxylated Hisrack and Hisrack glucuronide. After a single dose of 14C-Hisrack, hydroxylated metabolites accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated-Hisrack metabolites do not accumulate in the plasma of patients with normal renal function. The extent of accumulation of hydroxylated-Hisrack metabolites in patients with renal dysfunction has not been studied. The role, if any, of a specific cytochrome P450 system in the metabolism of Hisrack is unknown. The hydroxylated-Hisrack metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces.
Excretion
The mean oral clearance of Hisrack following oral Hisrack Extended-Release Tablets dosing is 47 (±17) mL/h/kg. The terminal half-life (t½) of Hisrack after Hisrack Extended-Release Tablets administration is 8.4 hours compared to 6.4 hours for Hisrack tablets. Approximately 1% of an Hisrack tablet dose is excreted unchanged in the urine, with 72% of the dose excreted into the urine as parent drug plus metabolites:
-Hisrack, unchanged | 1% |
-Hisrack glucuronide | 13% |
-hydroxylated metabolites (6-, 7-, and 8-OH) | 5% |
-hydroxylated metabolite glucuronides | 20% |
-unidentified metabolites | 33% |
Fecal excretion accounted for 16% of the dose.
Special Populations
In clinical studies, age was not shown to have any effect on half-life or protein binding, and demonstrated no change in expected drug accumulation. No dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics. The elderly may need dosage adjustment, however, as they may be more sensitive to antiprostaglandin effects than younger patients.
The pharmacokinetics of Hisrack Extended-Release Tablets were assessed in an open-label, 12-week clinical trial which included plasma sampling for population pharmacokinetics. Seventy-two (72) patients, 6 to 16 years of age, with juvenile rheumatoid arthritis, received Hisrack Extended-Release Tablets in doses of 13.3 to 21.3 mg/kg given as 400 to 1000 mg once daily. The results from a population pharmacokinetic analysis based on the 59 subjects who completed the trial are as follows:
Parameter | JRA* (Age: 6 to 16)† n = 59 |
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Oral Clearance (CL/F), mL/h/kg | 47.8 (38%) |
Apparent Volume of Distribution (Vd/F), mL/kg | 78.9 (61%) |
Half-life (t½), h | 12.1 (75%) |
While similar, the pharmacokinetic parameters for children with juvenile rheumatoid arthritis did not directly correlate with adult pharmacokinetic data in rheumatoid arthritis. In the population pharmacokinetic analysis, body weights below 50 kg were found to correlate with CL/F.
Pharmacokinetic differences due to race have not been identified. Clinical studies included patients of many races, all of whom responded in a similar fashion.
The pharmacokinetics of Hisrack following administration of Hisrack Extended-Release Tablets have not been investigated in subjects with hepatic insufficiency. Following administration of Hisrack tablets, the plasma protein binding and disposition of total and free Hisrack were unchanged in the presence of compensated hepatic cirrhosis. Although no dosage adjustment is generally required in patients with chronic hepatic diseases, Hisrack clearance is dependent on liver function and could be reduced in patients with severe hepatic failure.
The pharmacokinetics of Hisrack following administration of Hisrack Extended-Release Tablets have not been investigated in subjects with renal insufficiency. Hisrack renal clearance following administration of Hisrack tablets was unchanged in the presence of mild-to-moderate renal failure (creatinine clearance, 37 to 88 mL/min). Although renal elimination is a significant pathway of excretion for Hisrack metabolites, no dosing adjustment in patients with mild-to-moderate renal dysfunction is generally necessary. Hisrack plasma protein binding decreases in patients with severe renal deficiency. Hisrack should be used with caution in such patients because, as with other NSAIDs, it may further decrease renal function in some patients. Hisrack is not significantly removed from the blood in patients undergoing hemodialysis.
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Information checked by Dr. Sachin Kumar, MD Pharmacology
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