Pharmacological Treatment Options for Gout and Hyperuricemia

Pharmacological Treatment Options for _Gout and Hyperuricemia_

Thomas Tran, PharmD Candidate 2007

NSAIDs / Colchicine / Uricosuric Agents / Xanthine Oxidase Inhibitor / Corticosteroids
Product Availability
Generic (Brand) / ·Indomethacin(Indocin)
·Naproxen( Naprosyn)
·Ibuprofen(Motrin)
·Sulindac(Clinoril)
·Ketoprofen(Orudis) / ·Colchicine(Colsalide) / ·Probenecid(Benemid)
·Sulfinpyrazone((Anturane) / ·Allopurinol(Zyloprim) / ·Prednisone(Deltasone)
·Triamcinolone
Acetonide(Aristocort A)
· ACTH(Corticotropin)
Mechanism
of Action / ·Inhibits prostaglandin synthesis by decreasing the activity of the enzyme, cyclooxygenase, which results in decreased formation of prostaglandin precursors / ·Exact mechanism of action unknown
·Decreases leukocyte lactic acid production and phagocytosis of urate crystals resulting in decreased uric acid deposition and decreased inflammatory response / Competitively inhibits the reabsorption of uric acid at the proximal convoluted tubule, thereby promoting its excretion and reducing serum uric acid levels / ·Inhibits xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine to uric acid
·Allopurinol is metabolized to oxypurinol which is also an inhibitor of xanthine oxidase
·Allopurinol acts on purine catabolism, reducing the production of uric acid without disrupting the biosynthesis of vital purines / Decreases inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability.
EFFICACY
(Indication/Use, Clinical Data Support) / Helps relieve inflammation related to gout
Harris MD, Siegel LB, Alloway JA. Gout and hyperuricemia. American Family Physician. 1999; 59:925-34 / Used in the treatment of acute gouty arthritis attacks and prevention of recurrences of such attacks / ·Used for the prevention of gouty arthritis and hyperuricemia.
·In recurrent gout may be combined with allopurinol in resistant hyperuricemia.
·For probenecid efficacy, serum uric acid levels may begin to fall in 1-2 days. / ·When given orally it prevents the attack of gouty arthritis and nephropathy
·Treatment of secondary hyperuricemia which may occur during treatment of tumors or leukemia
·Prevention of recurrent calcium oxalate calculi.
·Serum uric acids can begin to fall in 1-2 days and maximum serum uric acid suppression occurs in 7-14 days
·Frequency of attacks begin to decrease in 3-6 months and tophi begin to decrease in 6 months. / ·Corticosteroids may be used to treat acute attacks of gouty arthritis
·They are reserved primarily for resistant cases or for
patients with a contraindication to colchicine and NSAID therapy
SAFETY
(Major Drug Interactions,
Pre-cautions, Contra-indications,
Adverse Effects,
Pregnancy Risk Category) / Adverse Effects:
·GI bleeding, GI ulceration/perforation, MI, stroke, thromboembolism, nephrotoxicity and bronchospasm.
Precautions:
·Increased risk of serious cardiovascular thrombotic events, MI, and stroke; risk may increase with duration of use and in patients at risk for CV disease.
·There is also an increased risk of serious GI adverse events (bleeding, ulceration, perforation) that can occur at any time
·Precaution should also be advised in asthmatics and in women during late pregnancy.
Contraindications:
·Hypersensitivity to any of the drugs, aspirin, or other NSAIDs
·Patients in whom asthma, urticaria or rhinitis are precipitated
·Those with active GI bleeding or ulcer disease
Drug Interactions:
·Ketorolac
·Tacrolimus
·Methotrexate
·Enoxaparin
·Ciprofloxacin
Pregnancy Category:
·C/D in the 3rd trimester / Adverse Effects:
·N/V/D and abdominal pain (>10%)
Precautions:
·Use with caution in debilitated/elderly patients, those with mild/moderate cardiac, GI or renal disease.
Contraindications:
·Hypersensitivity to colchicines or any component of the formulation
·Severe renal, GI, liver or cardiac disorders, and pregnancy (parenteral)
Drug Interactions: ·Clarithromycin ·Erythromycin
·Interferon Alfa-2a
·Cyclosporine
Pregnancy Category:
C(Oral); D( Parenteral) / Adverse Effects:
·Flushing, dizziness, fever, alopecia, rash, n/v.
Precautions:
·Use with caution in patients with peptic ulcer.
·Salicylates may diminish the therapeutic effect of probenecid ·Use with caution in patients with impaired renal function
·May cause exacerbation of acute gouty attack
·For Sulfinpyrazone, safety and efficacy are not established in children < 18 years of age.
Contraindications:
·High dose aspirin therapy
·Blood dyscrasias
·Active peptic ulcer
·Moderate to severe renal
impairment
·Children < 2 years of age (probenecid)
·Pregnancy- near term(for sulfinpyrazone)
Drug Interactions:
·Probenecid is antagonized by concurrent administration of ASA
·Low dose ASA causes uric acid retention
·High dose ASA causes uricosuric effect
·Sulfinpyrazone
1) CYP2C9 inducers may decrease levels of sulfinpyrazone (phenytoin, rifampin)
2)Risk of acetaminophen hepatotoxicity increased
3)May increase levels of CYP2C9 substrates (fluoxetine,dapsone,losartan)
Pregnancy Category:
·B (Probenecid)
·C/D (Sulfinpyrazone) / Adverse Effects:
· >1%: skin rash, n/v, renal impairment
Precautions:
·Do not use to treat asymptomatic hyperuricemia. ·Discontinue at first signs of rash
·Caution in renal impairment, those taking concurrent diuretic therapy
·Must decrease azathioprine dose by 1/4th to 1/3rd of normal dose
·Increased incidence of rash occurs with ampicillin/amox/augmentin
Contraindications:
·Hypersensitivity to allopurinol or any component of the formulation
Drug interactions:
·Ampicillin, amoxicillin, azathioprine, mercaptopurine
Pregnancy Category: C / Adverse Effects:
·Insomnia
·Increased appetite ·Glucose intolerance,
hyperglycemia ·Indigestion
·Nervousness
Contraindications:
·Hypersensitivity to drug or its components, serious infections, systemic fungal infections
Precautions:
·Withdraw therapy with gradual tapering
·May retard bone growth
·Caution in patients with hypothyroidism, cirrhosis, CHF, ulcerative colitis, thromboembolic disorders.
Drug Interactions:
·Bupropion
·Rotavirus Vaccine Live
·Aldesleukin
·Quetiapine
Pregnancy Category:
·Prednisone (C)
·Triamcinolone
Acetonide (C)
·ACTH (C)
NSAIDs / Colchicine / Uricosuric Agents / Xanthine Oxidase Inhibitor / Corticosteroids
Dosage & Administration
(Include renal and/or hepatic adjustments) / ·For treatment of acute gouty arthritis, indomethacin may be begun with a relatively large dose for the first 24 to 48 hours and then
tapered over 3 to 4 days to minimize the risk of recurrent attacks.
·For example, 75 mg of indomethacin should be given initially, followed
by 50 mg every 6 hours for 2 days and then 50 mg every 8 hours for
1 or 2 days.
·No renal dosing adjustment necessary for Indomethacin
·Hepatic dosing adjustment not defined for Indomethacin / ·1 mg STAT then 0.5 mg q2-3hours until relief or GI symptoms occur, or total dose of 4-6 mg
·Once effective dose is known, at subsequent attacks give:
1) 50% of that total dose STAT followed by remainder in 0.5mg increments qhr
2) Or as a single dose 4-5 hours after initial dose (max dose 4-6 mg)
3) Less effective if started more than 24 hours after onset of acute attack.
·Renal dosing:
CrCl 10-50ml/min: decrease dose 50%.
CrCl<10ml/min: use is contraindicated.
·Hepatic Dosing:
Caution advised in mild/moderate impairment. Contraindicated in severe impairment. / Probenecid:
·250mg po bid for first week, then 500mg po bid for 2 months
·Ineffective if CrCl<30ml/min
·Level is increased if CrCl 40-50 ml/min
Sulfinpyrazone:
·Chronic Gout/Hyperuricemia: 100-200 mg twice daily; max daily dose 800 mg.
·Renal dosing (both probenecid and sulfinpyrazone):
- CrCl<50ml/min: Avoid use
·Hepatic dosing (both probenecid and sulfinpyrazone):
- Not defined / ·300mg po qd in normal renal function
·200mg po qd in renal insufficiency. Initiate at 100mg po qd and titrate up.
·Concomitant colchicine therapy: 0.6 mg po bid for first month of therapy
·Renal dosing:
(Oral)
-CrCl 40-60ml/min: max 200 mg/day
-CrCl 20-40: max 150 mg/day
-CrCl 10-20: max 100 mg QD-QOD
-CrCl <10: 100 mg 3x/week
-HD: give 50% usual dose as supplement
(IV)
-CrCl 10-20: max 200 mg/day
-CrCl 3-10: max 100 mg/day
-CrCl < 3: 100 mg/day at extended intervals
·Hepatic dosing adjustment not defined for allopurinol / ·Doses of 40 to 80 USP units of ACTH gel are
given IM every 6 to 8 hours for 2 to 3 days, and then the doses are reduced in stepwise fashion and discontinued
·Intra-articular administration of triamcinolone hexacetonide in a dose of 20 to 40 mg may be useful in treating acute gout limited to one or
two joints
·Prednisone:
-Administered orally in doses of 30- 60 mg for 3 to 5 days in patients with multiple-joint involvement
-Rebound attacks may occur on steroid withdrawal, the dose should be tapered gradually by 5-mg decreases over 10 to 14 days and discontinued
·Renal dosing (all 3
agents): no adjustment necessary
·Hepatic dosing (all 3 agents): not defined
Monitoring
(Efficacy and Toxicity Parameters) / Efficacy:
- Decreased pain, inflammation, and swelling of affected joints.
Toxicity:
·BUN/Cr
·BP
·Cr if advanced renal
disease or >65 years of age
·CBC, Chemistry profile
·Eye exam if long term treatment / Efficacy:
·Relief of pain and frequency of gout attacks.
Toxicity:
·Diarrhea
·Creatinine at baseline ·CBC q4-6 months;
more frequently in
patients with renal or
hepatic impairment. / Efficacy:
·Monitor the frequency and intensity/duration of gout attacks and the serum and urinary uric acid levels
Toxicity:
·CBC and SCr at baseline / Efficacy:
·Serum uric acid levels 6mg/dl or less
·Plasma oxypurinol levels of 30-100mmol/L
·In patients with normal renal function, elevations in plasma xanthine levels(6-9 mmol/L) indicate sufficient inhibition of xanthine oxidase to cause normouricemia in most patients
Toxicity:
·Liver and renal function tests, Scr
·Plasma Oxypurinol levels
·CBC
·Eye exam annually / Efficacy:
·Relief of pain and frequency of gout attacks
Toxicity:
·Blood glucose, BP,
electrolytes.
Patient Education / ·You should not use this medicine if you have had an allergic reaction to these agents, aspirin, or other pain and arthritis medicines such as ibuprofen, naproxen, advil
·Make sure your doctor knows if you are also using aspirin, a blood thinner such as warfarin, or a steroid
·Also, make sure your doctor knows if you are using a blood pressure medicine / ·Colchicine should not be taken if you have serious heart, liver, kidney disease, a severe stomach disorder, or a blood disorder.
·Avoid drinking alcohol while taking colchicine.
·Make sure your doctor knows if you are taking any cancer medicine, medicine to treat an overactive thyroid, chloramphenicol, cytoxan, interferon / ·You should not use these medications if you have had an allergic reaction to these agents.
·Children under 2 years of age should not take probenecid.
·Pregnant women (near term) should not use sulfinpyrazone
·To help prevent gout attacks, avoid beer, wine, liquor, and purine-rich foods, such as liver, anchovies, sardines, kidney, and lentils
·Make sure your doctor knows if you are taking cancer medicines, heparin, aspirin, indomethacin, methotrexate, or zidovudine / ·It is important to keep taking allopurinol, even if you are taking other medicines for gout attacks
·The attacks should become shorter and less severe after you take allopurinol for several months
·Drink 10 to 12 full glasses of liquids each day
·You may take the medicine after meals to avoid stomach upset
·Make sure your doctor knows if you are taking blood thinners, diuretics, ampicillin, amoxicillin, cyclosporine, or azathioprine
·Stop use and call your doctor immediately if you notice a skin rash, pain when you urinate, or blood in your urine / ·Take as directed
·Monitor blood pressure daily
·Do not stop taking this medicine without first talking with your doctor
·You may need to take smaller and smaller doses before completely stopping this medicine
·Avoid being around people with viral infections such as measles or chickenpox
·If you are exposed to these infections, check with your doctor as soon as possible
Cost
(1-month) / ·Indomethacin
1) Capsule 25 mg (30 ea): $7.99
2) Extended release capsule 75 mg (30 ea): $48.99
·Naproxen: cost varies with dosing
·Ibuprofen
1) 400 mg tablet (30 ea): $7.99
2) 600 mg tablet (30 ea): $7.99
3) 800 mg tablet (30 ea): $8.99
·Sulindac
1) 150 mg tablet (60 ea): $18.99
2) 200 mg tablet (60 ea): $21.99
·Ketoprofen: cost varies with dosing / Colchicine 0.6 mg tablet (60 ea): $14.35 / Probenecid 500 mg tablet (60 ea): $34.99
This information is currently not available for Sulfinpyrazone / ·Allopurinol
1)100 mg tablet (100 ea): $12.99
2) 300 mg tablet (100 ea): $22.99 / ·Prednisone: cost varies with dosing
·Triamcinolone
Acetonide: cost varies with dosing and package size
·ACTH: cost is unknown
References
(Guidelines, Drug Info Sources) / See below

** Hawkins DW, Rahn DW. Gout and Hyperuricemia. In: DiPiro JT, Talbert RL, Yee GC et al., eds. Pharmacotherapy: A pathophysiological approach. 6th ed. New York: Mcgraw-Hill Companies, Inc; Chap 91.

** Klasco RK (Ed): DRUGDEX® System (electronic version). Thomson Micromedex, Greenwood Village,

Colorado, USA. Available at: http://www.thomsonhc.com (cited: 09/22/06).

** Lexi-Comp, Inc. (Lexi-Drugs EssentialsÔ). Lexi-Comp, Inc.; September 22nd, 2006

Thomas Tran, PharmD Candidate 2007 Pharmacotherapy Presentation – Pharmaceutical Care Rotation

University of Maryland School of Pharmacy Happy Harry’s Pharmacy Patient Care Center, Perryville, MD