Duzallo is made up of two drugs, lesinurad and allopurinol. It is used by the patients who do not have maintained normal uric acid levels even after the intake of allopurinol dose. The two-drug combination inhibits the production of uric acid and also eliminate uric acid from the body.

Lesinurad and allopurinol (Duzallo) Uses:

• Gout associated hyperuricemia:

  • It helps treat the gout associated hyperuricemia in patients who fail to maintain the normal uric acid levels even after the intake of daily dose of allopurinol.
• Limitations:
  • This drug is not recommended for treating asymptomatic hyperuricemia.

Lesinurad and allopurinol (Duzallo) Dose in Adults:

Note:

• Duzallo is not recommended for patients taking allopurinol <300 mg/day.
• Patients who are not currently receiving lesinurad are recommended Prophylaxis for gout flare. 
• As per the trials conducted at clinics, patients were given colchicine or NSAID's for 5 months to treat gout flare prophylaxis. 

Lesinurad and allopurinol (Duzallo) Dose for the treatment of gout associated hyperuricemia:

• Oral:
  • One pill, either 200 mg of lesinurad and 200 mg or 300 mg of allopurinol, OD
  • Take 200 mg of Lesinurad as the maximum dose
  • Don't take more than one tablet each day.
    • Lesinurad/allopurinol tablets should be taken once daily in place of an equivalent amount of the daily allopurinol dose for patients who are unable to reach their goal blood uric acid levels while taking an allopurinol dose >300 mg.
    • Allopurinol 200 mg or 300 mg OD are both permitted in the dose formulations for duzallo.
    • Patients should begin treatment with one tablet of lesinurad 200 mg/allopurinol 300 mg once a day in place of allopurinol 300 mg if they are unable to maintain the normal levels of serum uric acid on an allopurinol 300 mg dose that is considered medically suitable.
    • Patients who are unable to reduce their serum uric acid levels while taking allopurinol 200 mg as prescribed may begin treatment with one pill of lesinurad 200 mg/allopurinol 200 mg once daily.
    • Patients who are currently taking allopurinol and lesinurad together should start their therapy by substituting one tablet of lesinurad/allopurinol for allopurinol and an equivalent amount of the daily allopurinol dose.
    • Lesinurad 200 mg along with either 200 mg or 300 mg of allopurinol once a day is permitted per the dosage forms for duzallo.

Children's use:

Not indicated

Risk in Pregnancy: N (Not defined)

• This combination is never used for reproduction studies of animals.
• For more information individual monographs can be looked upon.
• During therapy with lesinurad,  hormonal contraceptives of any kind such as oral, injectable, and topical are not as effective.
• Therapy may also include contraceptives.

Breastfeeding:

• Breast milk contains allopurinol and its active metabolite.
• It is unknown how much lesinurad is excreted.
• While deciding when to breastfeed during therapy, the risks to infants and benefits to the mother should be highly considered.
• You can view individual monographs.

Lesinurad and allopurinol (Duzallo) Dose in Kidney Disease:

Note:

• Patients who are receiving allopurinol at a dose of less than 200 mg per day and have an estimated CrCl of less than 60 mL/minute are not advised to use this combo product. 

• Prior to initiation: Preexisting impairment of renal:

  • Estimated CrCl 60 mL/min: No dosage modification is required.
  • Estimated CrCl ranges from 45 to 60 mL/min; no dosage change is required.
  • More often check on renal function.
  • Estimated CrCl 60 mL/min: No dosage modification is required.
  • Estimated CrCl flow rate: 45 to 60 mL/min
  • Estimated CrCl flow rate: 30 to 45 mL/min: Don't start a treatment; it might not be as helpful as therapy (based on limited experience).
  • CrCl estimate 30 mL/min: the use is not recommended.
  • Use is not recommended for people with ESRD or dialysis patients as well. 

• During therapy: Renal impairment:

  • Estimated CrCl persistently <45 mL/minute:
    • Discontinue treatment.
  • Serum creatinine elevated >2 times baseline:
    • Interrupt therapy.

Lesinurad and allopurinol (Duzallo) Dose in Liver disease:

• Child-Pugh classes A and B: Mild to moderate impairment: No dosage change is required.
• Child-Pugh class C severe impairment: Use is not advised.

Side effects 

• See individual agents (allopurinol and Lesinurad)

Contraindications to Lesinurad and allopurinol (Duzallo):

• Hypersensitivity to allopurinol 
• ESRD
• Severe renal impairment 
• Tumor lysis syndrome
• Dialysis
• Lesch-Nyhan syndrome

Notice:

• Although it is not a complete contraindication, the American College of Rheumatology suggests that patients with HLA-B*5801 genotype should avoid allopurinol use due to high risk of allopurinol hypersensitivity.
• HLA-B*5801 screening for patients of this genotype is recomended as per guidelines. 
• This includes people of Han Chinese and Thai heritage, regardless of renal function, as well as patients with stage 3 or worse chronic kidney disease (according to ACR recommendations).

Warnings and precautions

• Suppression of bone marrow

  • Patients who received allopurinol have reported bone marrow suppression.
  • Most of these patients also received medications that could cause hematologic toxicities.
  • After starting allopurinol, the onset can happen anywhere between 6 weeks and 6 years later.

• Cardiovascular events

  • Clinical trials revealed that major cardiac adverse events, including non-fatal MIs, cardiac deaths and strokes, were common. However, a healthy relationship is yet to be established.

• Effects related to CNS

  • Sometimes drowsiness is experienced
  • It is important to warn patients about doing something that requires being mentally alert, such as driving or operating machinery.

• Gout flare

  • Gout flare-ups may occur after beginning urate-lowering medication, such as lesinurad/allopurinol, because urate from tissue deposits may become mobilised.
  • Patients who are not taking lesinurad should be given Gout flare Prophylaxis. 
  • Lesinurad/allopurinol treatment can be continued during gout flare and its management.

• Hepatotoxicity:

  • Allopurinol has been linked to hepatotoxicity that can be reversed.
  • Serum transaminases and serum alkalinephosphatase have been elevated in asymptomatic cases.
  • If you notice any signs or symptoms of hepatotoxicity, be sure to evaluate your liver function.
  • Patients suffering from preexisting hepatic impairment are advised to get their periodic liver function tests done. 

• Hypersensitivity

  • A skin rash is correlated with allopurinol.
  • Sometimes, severe reactions may follow a skin rash, such as exfoliation, fever and lymphadenopathy.
  • The tissue response and associated vasculitis can manifest seizures, hepatitis or renal impairment, or even death.
  • Patients with kidney impairment or taking concomitant diuretics containing thiazide may need to be cautious as hypersensitivity reactions can increase.
  • Stop using the medication immediately if you notice any symptoms related to allergic reactions such as skin rash. 
  • HLA-B*5801 allele test must be done on patients prior therapy because those patients are at higher risk of developing allopurinol hypersensitivity Syndrome.

• Nephrotoxicity:

  • Xanthine-oxidase inhibitor when used with duzallo can cause an increase in serum creatinine levels (generally reversible).
  • [US Boxed Warn]: Lesinurad has caused acute renal failureIt was more common to receive lesinurad alone.
  • When used with a xanthine oxide inhibitor, several reports were recieved regarding renal failure (either acute or chronic) and nephrolithiasis.
  • Lesinurad 400 mg turned out to be more effective than the dose that was recomended. 
  • Treatment is interrupted when creatinine levels exceed 2 times than the baseline. 
  • Stop the treatment immediately if you notice symptoms of acute urinary acid nephropathy like flank pain, nausea, etc. Get the creatinine levels measured too. 
  • Discontinue therapy if you have a reason for serum creatinine abnormalities.

• Renal impairment

  • Before treatment begins, evaluate your renal function and then periodically thereafter.
  • Patients who have blood creatinine levels 1.5 to 2 times the baseline level or greater will require more frequent evaluations.
  • Patients with a CrCl of 45 milliliters per minute should not be initiated.
  • If the estimated CrCl is 45mL/minute, discontinue therapy (contradicted with CrCl30mL/minute).

• Secondary hyperuricemia

  • Patients with secondary hyperuricemia and organ transplant recipients are not Lesinurad studied.
  • Patients with Lesch-Nyhan syndrome or tumor lysis syndrome are not advised to use uric acid.

Lesinurad and allopurinol: Drug Interaction

Monitoring parameters:

• CBC, serum uric acid levels every 2 to 5 weeks while the dose is being increased or decreased until the desired level is reached, and then every 6 months after that.
• Hepatic performance (periodically in patients with preexisting hepatic disease)
• Kidney function (BUN, serum creatinine, or creatinine clearance [before starting and periodically]; more frequently in patients with estimated CrCl 60 mL/minute or with serum creatinine increases 1.5–2 times the baseline level)
• Thrombin interval (periodically in patients receiving warfarin)
• Patients who are more likely to develop allopurinol hypersensitivity syndrome may consider HLA-B*5801 testing before starting medication (see Contraindications) 
• Check for hepatotoxicity, hypersensitivity symptoms, and hydration status.

How to administer Lesinurad and allopurinol (Duzallo)?

• Take water and food early in the morning
• Drink plenty of water (eg, 2 litres of liquid per day).

Mechanism of action of Lesinurad and allopurinol (Duzallo):

• Lesinurad/allopurinol:
  • Sensitivity to uric acids is decreased by increase in excretion and decrease in production.
• Allopurinol:
  • The enzyme xanthine oxidese transforms hypoxanthine into xanthine and uric acid, is inhibited by allopurinol.
  • Oxypurinol, a product of the metabolism of allopurinol, is a xanthine oxidease inhibitor as well.
  • By lowering uric acid production while not interfering with the manufacture of essential purines, allopurinol inhibits the metabolism of purines.
• Lesinurad:
  • The renal uric acid reabsorption transporter proteins are inhibited by lesinurad.
  • In gout patients, decreased serum levels, boosts renal clearance, and raises fractional excretion.

Absorption:

In case of absorption; Lesinurad: fast elimination from the GI tract; 90% of allopurinol

Protein binding:

In case of protein binding; Lesinurad: >98%, mostly due to albumin

Metabolism:

• Allopurinol:
  • Rapidly oxidized, primarily to oxypurinol
• Lesinurad:
  • Metabolized oxidatively primarily via CYP2C9
  • Plasma exposure to metabolites is minimal
  • Metabolites are not known to contribute to the activity

Bioavailability:

• Lesinurad: ~100%

Elimination of half-life:

• Approximately 1 - 2 hours for Allopurinol
• Approximately 26 hours for Oxypurinol
• Approximately 5 hours for Lesinurad

Time to peak:

• 1.5 hours for Allopurinol
• 4.5 hours for Oxypurinol

Excretion:

• In case of Allopurinol, feces is approximately 20%
• In case of lesinurad, the urine is 63% which is approximately 30% as unchanged drug and for feces its 32%

International Brands of Lesinurad and allopurinol:

• Duzallo

Lesinurad and allopurinol (Brand Names in Pakistan):

No Brands Available in Pakistan.