Xanthistop

NAME OF THE MEDICINAL PRODUCT

  • XANTHISTOP 80 mg film-coated tablets
  • XANTHISTOP120 mg film-coated tablets

CLINICAL PARTICULARS

Therapeutic indications

Treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred (including a history, or presence of, tophus and/or gouty arthritis).

Posology and method of administration

The recommended oral dose of XANTHISTOP is 80 mg once daily without regard to food. If serum uric acid is> 6 mg/dl (357 µmol/l) after 2-4 weeks, XANTHISTOP 120 mg once daily may be considered.

XANTHISTOP works sufficiently quickly to allow retesting of the serum uric acid after 2 weeks. The therapeutic target is to decrease and maintain serum uric acid below 6 mg/dl (357μmol/l).

Gout flare prophylaxis of at least 6 months is recommended

Special populations

Renal insufficiency

No dosage adjustment is necessary in patients with mild or moderate renal impairment. The efficacy and safety have not been fully evaluated in patients with severe renal impairment (creatinine clearance

Hepatic impairment

The recommended dosage in patients with mild hepatic impairment is 80 mg. Limited information is available in patients with moderate hepatic impairment.The efficacy and safety of febuxostat has not been studied in patients with severe hepatic impairment (Child Pugh Class C).

Elderly

No dose adjustment is required in the elderly .

Children and adolescents

As there has been no experience in children and adolescents, the use of febuxostat in such patients is not recommended.

Organ transplant recipients

As there has been no experience in organ transplant recipients, the use of febuxostat in such patients is not recommended .

Contraindications

Hypersensitivity to the active substance or to any of the excipients .

Special warnings and precautions for use

Cardio-vascular disorders

Treatment with febuxostat in patients with ischaemic heart disease or congestive heart failure is not recommended .

Acute gouty attacks (gout flare)

Febuxostat treatment should not be started until an acute attack of gout has completely subsided. As with other urate lowering medicinal products, gout flares may occur during initiation of treatment due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits (see sections 4.8 and 5.1). At treatment initiation with febuxostat flare prophylaxis for at least 6 months with an NSAID or colchicine is recommended .

If a gout flare occurs during febuxostat treatment, it should not be discontinued. The gout flare should be managed concurrently as appropriate for the individual patient. Continuous treatment with febuxostat decreases frequency and intensity of gout flares.

Xanthine deposition

As with other urate lowering medicinal products, in patients in whom the rate of urate formation is greatly increased (e.g. malignant disease and its treatment, Lesch-Nyhan syndrome) the absolute concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract. As there has been no experience with febuxostat, its use in these populations is not recommended.

Mercaptopurine/azathioprine

Febuxostat use is not recommended in patients concomitantly treated with mercaptopurine/azathioprine .

Theophylline

Febuxostat should be used with caution in patients concomitantly treated with theophylline and theophylline levels should be monitored in patients starting febuxostat therapy .

Liver disorders

During the combined phase 3 clinical studies, mild liver function test abnormalities were observed in patients treated with febuxostat (5.0%). Liver function test is recommended prior to the initiation of therapy with febuxostat and periodically thereafter based on clinical judgment .

Thyroid disorders

Increased TSH values (>5.5 µIU/ml) were observed in patients on long-term treatment with febuxostat (5.5%) in the long term open label extension studies. Caution is required when febuxostat is used in patients with alteration of thyroid function .

Lactose

Febuxostat tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interaction with other medicinal products and other forms of interaction

Mercaptopurine/azathioprine

Although interaction studies with febuxostat have not been performed, inhibition of xanthine oxidase (XO) is known to result in an increase in mercaptopurine or azathioprine levels. On the basis of the mechanism of action of febuxostat on XO inhibition concomitant use is not recommended.

Drug interaction studies of febuxostat with cytotoxic chemotherapy have not been conducted. No data is available regarding the safety of febuxostat during cytotoxic therapy.

Theophylline

Although interaction studies have not been performed with febuxostat, inhibition of XO may cause an increase in the theophylline level (inhibition of the metabolism of theophylline has been reported with other XO inhibitors). Hence caution is advised if these active substances are given concomitantly, and theophylline levels should be monitored in patients starting febuxostat therapy.

Naproxen and other inhibitors of glucuronidation

Febuxostat metabolism depends on UGT enzymes. Medicinal products that inhibit glucuronidation, such as NSAIDs and probenecid, could in theory affect the elimination of febuxostat. In healthy subjects concomitant use of febuxostat and naproxen 250mg BID was associated with an increase in febuxostat exposure (Cmax 28%, AUC 41% and t1/2 26%). In clinical studies the use of naproxen or other NSAIDs/Cox-2 inhibitors was not related to any clinically significant increase in adverse events.

Febuxostat can be co-administered with naproxen with no dose adjustment of febuxostat or naproxen being necessary.

Inducers of glucuronidation

Potent inducers of UGT enzymes might possibly lead to increased metabolism and decreased efficacy of febuxostat. Monitoring of serum uric acid is therefore recommended 1-2 weeks after start of treatment with a potent inducer of glucuronidation. Conversely, cessation of treatment of an inducer might lead to increased plasma levels of febuxostat.

Colchicine/indometacin/hydrochlorothiazide/warfarin

Febuxostat can be co-administered with colchicine or indomethacin with no dose adjustment of febuxostat or the co-administered active substance being necessary.

No dose adjustment is necessary for febuxostat when administered with hydrochlorothiazide.

No dose adjustment is necessary for warfarin when administered with febuxostat. Administration of febuxostat (80 mg or 120 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. INR and Factor VII activity were also not affected by the co-administration of febuxostat.

Desipramine/CYP2D6 substrates.

Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro. In a study in healthy subjects, 120 mg XANTHISTOP QD resulted in a mean 22% increase in AUC of desipramine, a CYP2D6 substrate indicating a potential weak inhibitory effect of febuxostat on the CYP2D6 enzyme in vivo. Thus, co administration of febuxostat with other CYP2D6 substrates is not expected to require any dose adjustment for those compounds.

Antacids

Concomitant ingestion of an antacid containing magnesium hydroxide and aluminium hydroxide has been shown to delay absorption of febuxostat (approximately 1 hour) and to cause a 32% decrease in Cmax, but no significant change in AUC was observed. Therefore, febuxostat may be taken without regard to antacid use.

Pregnancy and lactation

Pregnancy

Data on a very limited number of exposed pregnancies have not indicated any adverse effects of febuxostat on pregnancy or on the health of the foetus/new born child. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,embryonal/foetal development or parturition (see section 5.3).The potential risk for human is unknown. Febuxostat should not be used during pregnancy.

Breast feeding

It is unknown whether febuxostat is excreted in human breast milk. Animal studies have shown excretion of this active substance in breast milk and an impaired development of suckling pups. A risk to a suckling infant cannot be excluded. Febuxostat should not be used while breast-feeding.

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. As with other xanthine oxidase inhibitors adverse reactions such as somnolence, dizziness and paraesthesia have been reported. Patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that XANTHISTOP does not adversely affect performance.

Overdose

No case of overdose has been reported. Patients with an overdose should be managed by symptomatic and supportive care.

PHARMACEUTICAL PARTICULARS

Special precautions for storage

  • Keep out of the reach of children.
  • Keep at a temperature not exceeding 30 C , in a dry place.