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allopurinol (Zyloprim ®):
Allopurinol acts on purine catabolism, without disrupting the biosynthesis of purines. It reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding its formation.
Allopurinol is a structural analogue of the natural purine base, hypoxanthine. It is an inhibitor of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the end product of purine metabolism in man. Allopurinol is metabolized to the corresponding xanthine analogue, oxipurinol (alloxanthine), which also is an inhibitor of xanthine oxidase.
Gout: initially 100mg qd. Increase by 100mg/day q7days, titrate to desired uric acid level (<6 mg/dl). Usual range: (Mild gout): 200-300mg/day. Moderate-severe: 400-600mg/day. (Serum urate concentrations are often reduced more slowly with allopurinol than with uricosuric drugs and minimum concentrations may not be reached for 1-3 weeks. After serum urate concentrations are controlled, it may be possible to reduce dosage; the average adult maintenance dosage is 300 mg daily and the minimum effective dosage is 100-200 mg daily. Allopurinol therapy should be continued indefinitely)
Secondary hyperuricemia associated with chemotherapy:
Oral: 600-800 mg/day in 2-3 divided doses for prevention of acute uric acid nephropathy for 2-3 days starting 1-2 days before chemotherapy
I.V.: 200-400 mg/m2/day (maximum: 600 mg/day)
Note: Intravenous daily dose can be given as a single infusion or in equally divided doses at 6-, 8-, or 12-hour intervals. A fluid intake sufficient to yield a daily urinary output of at least 2 L in adults and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable.
Recurrent calcium oxalate stones: 200-300 mg/day in single or divided doses
Maximum dose/day: 800mg
[>50 ml/min]: No changes
[20-50]: 100-300mg q24h.
[10-20]: 100-200mg q24h.
[<10]: 100mg q24-48h.
[Hemodialysis]: 100mg q24-48h (give dose after dialysis on dialysis days.).
Mechanism of Action
The mechanism by which colchicine exerts its beneficial effect in patients with FMF has not been fully elucidated; however, evidence suggests that colchicine may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1. Additionally, colchicine disrupts cytoskeletal functions through inhibition of -tubulin polymerization into microtubules, and consequently prevents the activation, degranulation, and migration of neutrophils thought to mediate some gout symptoms.
INDICATIONS AND USAGE
1.1 Gout Flares
colchicine tablets are indicated for prophylaxis and the treatment of acute gout flares.
Prophylaxis of Gout Flares:
colchicine is indicated for prophylaxis of gout flares.
Treatment of Gout Flares:
colchicine tablets are indicated for treatment of acute gout flares when taken at the first sign of a flare.
1.2 Familial Mediterranean fever (FMF)
colchicine tablets are indicated in adults and children 4 years or older for treatment of familial Mediterranean fever (FMF).
Gouty arthritis: Adults:
Prophylaxis of acute attacks: Oral: 0.6 mg twice daily; initial and/or subsequent dosage may be decreased (ie, 0.6 mg once daily) in patients at risk of toxicity or in those who are intolerant (including weakness, loose stools, or diarrhea); range: 0.6 mg every other day to 0.6 mg 3 times/day
Oral: Initial: 0.6-1.2 mg, followed by 0.6 every 1-2 hours; some clinicians recommend a maximum of 3 doses; more aggressive approaches have recommended a maximum dose of up to 6 mg. Wait at least 3 days before initiating another course of therapy
I.V.: Initial: 1-2 mg, then 0.5 mg every 6 hours until response, not to exceed total dose of 4 mg. If pain recurs, it may be necessary to administer additional daily doses. The amount of colchicine administered intravenously in an acute treatment period (generally ~1 week) should not exceed a total dose of 4 mg. Do not administer more colchicine by any route for at least 7 days after a full course of I.V. therapy. Note: Many experts would avoid use because of potential for serious, life-threatening complications. Should not be administered to patients with renal insufficiency, hepatobiliary obstruction, patients >70 years of age, or recent oral colchicine use. Should be reserved for hospitalized patients who are under the care of a physician experienced in the use of intravenous colchicine.
Surgery: Gouty arthritis, prophylaxis of recurrent attacks: Adults: Oral: 0.6 mg/day or every other day; patients who are to undergo surgical procedures may receive 0.6 mg 3 times/day for 3 days before and 3 days after surgery
Primary biliary cirrhosis (unlabeled use): Adults: Oral: 0.6 mg twice daily
Elderly: Reduce maintenance/prophylactic dose by 50% in individuals >70 years
Dosing adjustment in renal impairment: Gouty arthritis, acute attacks: Oral: Specific dosing recommendations not available from the manufacturer:
Clcr 35-49 mL/minute: 0.6 mg once daily
Clcr 10-34 mL/minute: 0.6 mg every 2-3 days
Clcr<10 mL/minute: Avoid chronic use of colchicine. Use in serious renal impairment is contraindicated by the manufacturer.
Treatment: Clcr<10 mL/minute: Use in serious renal impairment is contraindicated by the manufacturer. If a decision is made to use colchicine, decrease dose by 75%.
Injection, solution: 0.5 mg/mL (2 mL)
Tablet: 0.6 mg
Drug UPDATES: MITIGARE ® ( colchicine ) capsules
Initial U.S. Approval: 1961
[Drug information / PDF] Dosing: Click links for more info.
U.S. Approval: 2014
Mechanism of Action: Colchicine’s effectiveness as a treatment for gout has been postulated to be due to its ability to block neutrophil-mediated inflammatory responses induced by monosodium urate crystals in synovial fluid. Colchicine disrupts the polymerization of ß-tubulin into microtubules, thereby preventing the activation, degranulation, and migration of neutrophils to sites of inflammation. Colchicine also interferes with the inflammasome complex found in neutrophils and monocytes that mediates interleukin-1ß (IL-1ß) activation.
INDICATIONS AND USAGE:
MITIGARE® is indicated for prophylaxis of gout flares in adults.
Limitations of use:
The safety and effectiveness of MITIGARE® for acute treatment of gout flares during prophylaxis has not been studied.
MITIGARE® is not an analgesic medication and should not be used to treat pain from other causes.
HOW SUPPLIED: 0.6 mg Capsules
febuxostat - ULORIC®
INDICATIONS AND USAGE
ULORIC is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout.
ULORIC is not recommended for the treatment of asymptomatic hyperuricemia.
USE IN SPECIFIC POPULATIONS
There is insufficient data in patients with severe renal impairment. No studies have been conducted in patients with severe hepatic impairment. Caution should be exercised in these patients.
No studies have been conducted in patients with secondary hyperuricemia (including patients being treated for Lesch-Nyhan syndrome or malignant disease, or in organ transplant recipients); therefore, ULORIC is not recommended for use in these patients.
DOSAGE AND ADMINISTRATION
DOSAGE AND ADMINISTRATION - SUMMARY
ULORIC is recommended at 40 mg or 80 mg once daily. The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a serum uric acid (sUA) less than 6 mg per dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended.
ULORIC can be administered without regard to food or antacid use.
No dose adjustment is necessary when administering ULORIC to patients with mild to moderate renal or hepatic impairment.
For treatment of hyperuricemia in patients with gout, ULORIC is recommended at 40 mg or 80 mg once daily.
The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a serum uric acid (sUA) less than 6 mg per dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended.
ULORIC can be taken without regard to food or antacid use.
No dose adjustment is necessary when administering ULORIC in patients with mild to moderate renal impairment. The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended.
No dose adjustment is necessary in patients with mild to moderate hepatic impairment.
Uric Acid Level
Testing for the target serum uric acid level of less than 6 mg per dL may be performed as early as 2 weeks after initiating ULORIC therapy.
Gout flares may occur after initiation of ULORIC due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended upon initiation of ULORIC. Prophylactic therapy may be beneficial for up to six months.
If a gout flare occurs during ULORIC treatment, ULORIC need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient
DOSAGE FORMS AND STRENGTHS
40 mg tablets, light green to green, round shaped, debossed with "TAP" and "40"
80 mg tablets, light green to green, teardrop shaped, debossed with "TAP" and "80"
pegloticase - KRYSTEXXA™
INDICATIONS AND USAGE
KRYSTEXXA™ (pegloticase) is a PEGylated uric acid specific enzyme indicated for the treatment of chronic gout in adult patients refractory to conventional therapy.
Gout refractory to conventional therapy occurs in patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated.
Important Limitations of Use:
KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia.
DOSAGE AND ADMINISTRATION
The recommended dose and regimen of KRYSTEXXA for adult patients is 8 mg (uricase protein) given as an intravenous infusion every two weeks.
The optimal treatment duration with KRYSTEXXA has not been established.
Visually inspect KRYSTEXXA for particulate matter and discoloration before administration, whenever solution and container permit. Do not use vials if either is present.
Use appropriate aseptic technique. Withdraw 1 mL of KRYSTEXXA from the vial into a sterile syringe. Discard any unused portion of product remaining in the 2 mL vial. Inject into a single 250 mL bag of 0.9% Sodium Chloride Injection, USP or 0.45% Sodium Chloride Injection, USP for intravenous infusion. Do not mix or dilute with other drugs.
Invert the infusion bag containing the dilute KRYSTEXXA solution a number of times to ensure thorough mixing. Do not shake.
KRYSTEXXA diluted in infusion bags is stable for 4 hours at 2° to 8°C (36° to 46°F) and at room temperature (20° to 25°C, 68° to 77°F). However it is recommended that diluted solutions be stored under refrigeration, not frozen, protected from light, and used within 4 hours of dilution. [see How Supplied/Storage and Handling]
Before administration, allow the diluted solution of KRYSTEXXA to reach room temperature. KRYSTEXXA in a vial or in an intravenous infusion fluid should never be subjected to artificial heating (e.g., hot water, microwave).
Do not administer as an intravenous push or bolus.
Monitoring Therapy: The risk of anaphylaxis and infusion reactions is higher in patients who have lost therapeutic response. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed.
The KRYSTEXXA admixture should only be administered by intravenous infusion over no less than 120 minutes via gravity feed, syringe-type pump, or infusion pump.
Patients should receive pre-infusion medications (e.g. antihistamines, corticosteroids), to minimize the risk of anaphylaxis and infusion reactions. Administer KRYSTEXXA in a healthcare setting and by healthcare providers prepared to manage anaphylaxis and infusion reactions, and observe patients for an appropriate period of time after administration.
If an infusion reaction occurs during the administration of KRYSTEXXA, the infusion may be slowed, or stopped and restarted at a slower rate, at the discretion of the physician. Since infusion reactions can occur after completion of infusion, observation of patients for approximately an hour post-infusion should be considered.
DOSAGE FORMS AND STRENGTHS
1 mL sterile concentrate for dilution containing 8 mg of pegloticase protein, expressed in uricase protein amounts.
KRYSTEXXA is supplied as a clear, colorless, sterile solution in phosphate buffered saline intended for intravenous infusion after dilution. KRYSTEXXA is supplied in a single-use 2 mL glass vial with a Teflon® coated (latex-free) rubber injection stopper to deliver KRYSTEXXA as 8 mg of uricase protein in 1 mL volume.
Storage and Handling
Before the preparation for use, KRYSTEXXA must be stored in the carton and maintained at all times under refrigeration between 2° to 8°C (36° to 46°F). Protect from light. Do not shake or freeze.
Do not use beyond the expiration date stamped.
probenecid (Benemid ®):
Probenecid is a uricosuric and renal tubular blocking agent. It inhibits the tubular reabsorption of urate, thus increasing the urinary excretion of uric acid and decreasing serum urate levels. Effective uricosuria reduces the miscible urate pool, retards urate deposition, and promotes resorption of urate deposits.
Probenecid inhibits the tubular secretion of penicillin and usually increases penicillin plasma levels by any route the antibiotic is given. A 2-fold to 4-fold elevation has been demonstrated for various penicillins.
Probenecid has also been reported to inhibit the renal transport of many other compounds including aminohippuric acid (PAH), aminosalicylic acid (PAS), indomethacin, sodium iodomethamate and related iodinated organic acids, 17-ketosteroids, pantothenic acid, phenolsulfonphthalein (PSP), sulfonamides, and sulfonylureas.
Probenecid decreases both hepatic and renal excretion of sulfobromophthalein (BSP). The tubular reabsorption of phosphorus is inhibited in hypoparathyroid but not in euparathyroid individuals.
Probenecid does not influence plasma concentrations of salicylates, nor the excretion of streptomycin, chloramphenicol, chlortetracycline, oxytetracycline, or neomycin.
INDICATIONS AND USAGE
For treatment of the hyperuricemia associated with gout and gouty arthritis.
As an adjuvant to therapy with penicillin or with ampicillin, methicillin, oxacillin, cloxacillin, or nafcillin, for elevation and prolongation of plasma levels by whatever route the antibiotic is given.
Hyperuricemia with gout: 250 mg twice daily for one week; increase to 250-500 mg/day; may increase by 500 mg/month, if needed, to maximum of 2-3 g/day (dosages may be increased by 500 mg every 6 months if serum urate concentrations are controlled)
Prolong penicillin serum levels: 500 mg 4 times/day
Gonorrhea: 1 g 30 minutes before penicillin, ampicillin, procaine, or amoxicillin
Pelvic inflammatory disease: Cefoxitin 2 g I.M. plus probenecid 1 g orally as a single dose
Neurosyphilis: Aqueous procaine penicillin 2.4 million units/day I.M. plus probenecid 500 mg 4 times/day for 10-14 days
Dosing adjustment in renal impairment: Clcr<50 mL/minute: Avoid use
Tablet: 500 mg
Mechanism of Action
In humans, uric acid is the final step in the catabolic pathway of purines. Rasburicase catalyzes enzymatic oxidation of poorly soluble uric acid into an inactive and more soluble metabolite (allantoin).
INDICATIONS AND USAGE
Elitek® is indicated for the initial management of plasma uric acid levels in pediatric and adult patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid.
Limitation of use: Elitek is indicated only for a single course of treatment
Recommended dose: 0.15 or 0.20 mg/kg as a single daily dose for 5 days. Because the safety and effectiveness of other schedules have not been established, dosing beyond 5 days or administration of more than one course is not recommended. Chemotherapy should be initiated 4 to 24 hours after the first dose of rasburicase. Rasburicase should be administered as an intravenous infusion over 30 minutes (NEVER as a bolus infusion).
Rasburicase is contraindicated in individuals deficient in glucose-6-phosphate dehydrogenase (G6PD).
Injection, powder for reconstitution: 1.5 mg [packaged with three 1 mL ampules of diluent]
sulfinpyrazone (Anturane ®)
Its pharmacologic activity is the potentiation of the urinary excretion of uric acid. It is useful for reducing the blood urate levels in patients with chronic tophaceous gout and acute intermittent gout, and for promoting the resorption of tophi.
Anturane is indicated for the treatment of:
1] Chronic gouty arthritis
2] Intermittent gouty arthritis
Patients with an active peptic ulcer or symptoms of gastrointestinal inflammation or ulceration should not receive the drug.
The drug is contraindicated in patients with a history or the presence of:
Hypersensitivity to phenylbutazone or other pyrazoles
Studies on the teratogenicity of pyrazole compounds in animals have yielded inconclusive results. Up to the present time, however, there have been no reported cases of human congenital malformation proved to be due to the use of the drug.
It is suggested that Anturane be used with caution in pregnant women, weighing the potential risks against the possible benefits.
Gout Adults: OInitially: 100-200mg orally twice daily with meals. Maintenance: 200mg orally twice daily with meals. Maximum daily dose: 800mg
Do not use if crcl<50 ml/min.
Tablet: 100 mg
Principles of treatment:
Do not treat asymptomatic hyperuricemia. Also, do not treat
hyperuricemia during acute gouty arthritis attack. Treat patients with
tophi or polyarticular gout. Probably treat patients with recurrent
attacks and serum uric acid >9 mg/dl--Start with low dose and gradually
increase (titrate to serum uric acid) over weeks to months. Monitor
serum uric acid and aim for uric acid <6.0 mg/dl (or <5.0 with tophi).
Use concomitant colchicine prophylaxis until uric acid has been at
desired level for some months and no recent gouty attacks have occurred
(6-12 months). Use uricosuric drugs (probenecid, sulfinpyrazone) when
possible because of low toxicity. Use allopurinol in patients with renal
calculi, renal insufficiency, concomitant diuretic therapy, cyclosporine
therapy, urate overproduction.
Things to Remember
1. Uric acid may be low, normal, or high during an attack.
2. Low dose colchicine should be started when initiating uric acid lowering drugs.
3. Do not initiate uric acid altering drugs during an acute attack. Wait until attack fully resolved.
4. Indications for Allopurinol use (stated above)
5. Place patient on a low purine diet (seafood, organ meats, spinach, asparagus), alcohol abstinence, weight loss if obese.
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