GOTA-D 40/50

Indications

• Osteoarthritis
• Degenerative joint disease

Dosage

Children: Paediatric dosing guidelines for diacerein are not well established, and it is generally not recommended for children. Refer to the BNF for Children for specific information.

Adults: The usual adult dosage is 50 mg taken orally once or twice daily, as directed by a healthcare professional. It is recommended to take diacerein with food to minimize gastrointestinal side effects.

Mechanism of action

Diacerein's active metabolite rhein reduces cartilage destruction by decreasing expression of matrix metalloproteinase (MMP)-1 and -3, while upregulating tissue inhibitor of matrix metalloproteinases. This action helps to mitigate the activity of several MMPs. Additionally, rhein has anti-inflammatory properties that lower the activity of interleukin-1 beta, a cytokine that contributes to inflammation and cartilage degradation. Furthermore, rhein reduces abnormal osteoblast synthetic activity through an unknown mechanism.

Pharmacodynamics

Diacerein decreases inflammation and cartilage destruction, correcting altered osteoblast activity. Its effects are particularly beneficial in the treatment of osteoarthritis, where it helps to slow the progression of joint damage and improve mobility.

Pharmacokinetics

Diacerein is absorbed from the gastrointestinal tract and is metabolized to rhein, which is responsible for its therapeutic effects. The onset of action may take several weeks, reflecting its role as a slow-acting drug in osteoarthritis therapy. The elimination half-life and specific pharmacokinetic parameters can vary based on individual patient factors, but detailed pharmacokinetic data should be referenced in specific clinical guidelines or drug literature.

Contra-indications

• Hypersensitivity to diacerein or any of its components
• Severe liver impairment
• Pregnancy

Adverse effects

• Diarrhea
• Abdominal pain
• Nausea
• Vomiting
• Rash
• Dyspepsia

Interactions

• May enhance the effects of other anti-inflammatory medications
• Caution is advised when taken with other drugs that affect liver metabolism

Precautions

• Use with caution in patients with a history of gastrointestinal disorders
• Monitor liver function tests periodically during therapy
• Not recommended for use in children

Pregnancy

Diacerein is contraindicated in pregnancy due to potential risks to the fetus.

Breast-feeding

It is not known whether diacerein is excreted in human breast milk; caution is advised.

Storage

Store in a cool, dry place, away from light and moisture.

Formulations

• Capsules: 50 mg

Indications

• Chronic hyperuricaemia in gout
• Prophylaxis of hyperuricaemia associated with cancer chemotherapy

Dosage

Adults: Initially 80 mg once daily, may increase to 120 mg once daily based on serum uric acid levels after 2-4 weeks. In the context of cancer therapy, the initial dose is 20 mg once daily, to be started 2 days prior to chemotherapy.

Mechanism of action

Febuxostat inhibits xanthine oxidoreductase (XOR), blocking both its oxidase and dehydrogenase activities. This inhibition reduces the conversion of hypoxanthine and xanthine to uric acid, effectively decreasing serum uric acid levels. By binding to a specific site in the XOR enzyme, febuxostat prevents the formation of reactive oxygen species associated with vascular inflammation.

Pharmacodynamics

Febuxostat is a novel, selective xanthine oxidase inhibitor that reduces serum uric acid levels in a dose-dependent manner. Clinical studies have shown that it can decrease mean serum uric acid concentrations by 40 to 55% at daily doses of 40-80 mg. It primarily functions by mobilizing urate crystals from tissue deposits, which can lead to gout flares; however, it does not inhibit other enzymes involved in purine metabolism.

Pharmacokinetics

Febuxostat is well absorbed following oral administration, with peak plasma concentrations typically reached within 1-2 hours. The drug is extensively metabolized in the liver, primarily through the cytochrome P450 system, and eliminated mainly via urine and feces. The half-life of febuxostat is approximately 5 to 8 hours, allowing for once-daily dosing.

Contra-indications

• Severe hypersensitivity to febuxostat
• History of hypersensitivity to allopurinol
• Severe renal disease

Adverse effects

• Rash
• Nausea
• Vomiting
• Hypersensitivity reactions
• Stevens-Johnson syndrome
• Agranulocytosis
• Anaphylactic shock
• Alopecia
• Angina
• Angioedema
• Immunoblastic T-cell lymphoma
• Aplastic anemia
• Asthenia
• Ataxia
• Boils
• Bradycardia
• Cataracts
• Coma
• Depression
• Diabetes mellitus
• Drowsiness
• Erectile dysfunction
• Fever
• Hyperlipidemia
• Hypertension
• Infertility (male)
• Maculopathy
• Malaise
• Oedema
• Paraesthesia
• Paralysis
• Peripheral neuropathy
• Severe cutaneous adverse reactions (SCARs)
• Stomatitis
• Taste alteration
• Thrombocytopenia
• Vertigo
• Visual impairment

Interactions

• Febuxostat + Azathioprine: Severe (increases exposure)
• Febuxostat + Mercaptopurine: Severe (increases exposure)

Precautions

• Ensure adequate fluid intake (2–3 litres/day)
• Monitor for signs and symptoms of severe hypersensitivity reactions
• Patients with a history of major cardiovascular disease should be monitored closely due to increased risk of cardiovascular death and all-cause mortality

Pregnancy

Toxicity not reported. Use only if no safer alternative and if benefits outweigh risks.

Breast-feeding

Present in milk; not known to be harmful.

Storage

Store below 30 degrees Celsius. Protect from moisture.

Formulations

• Febuxostat 80 mg tablets
• Febuxostat 120 mg tablets

Mechanism of action

Diacerein's active metabolite rhein [DB13174] reduces cartilage destruction by decreasing expression of matrix metalloproteinase (MMP)-1 and -3 as well as upregulating tissue inhibitor of matrix metalloproteinases which serve to reduce the activity of several MMPs. The anti-inflammatory action of rhein reduces the level of interleukin-1beta activity which plays a large role in reduction of extracellular matrix production, MMP activity, and continued inflammation. Rhein reduces abnormal osteoblast synthetic activity through an unknown mechanism.

Pharmacodynamics

Decreases inflammation and cartilage destruction and also corrects altered osteoblast acitivity.

Mechanism of action

Gout is a form of acute arthritis that is characterized by the accumulation of crystals of monosodium urate and urate crystals in or around a joint, leading to inflammation and persistent urate crystal deposition in bones, joints, tissues, and other organs that may exacerbate over time. Hyperuricemia is closely related to gout, whereby it may exist for many years before the first clinical attack of gout; thus, aberrated serum uric acid levels and hyperuricemia are believed to be the biochemical aberration involved in the pathogenesis of gout. Xanthine oxidoreductase (XOR) can act as a xanthine oxidase or xanthine dehydrogenase. In humans, it is a critical enzyme for uric acid production as it catalyzes the oxidation reaction steps from hypoxanthine to xanthine and from xanthine to uric acid in the pathway of purine metabolism. Febuxostat potently inhibits XOR, blocking both its oxidase and dehydrogenase activities. With high affinity, febuxostat binds to XOR in a molecular channel leading to the molybdenum-pterin active site, where [allopurinol] demonstrates relatively weak competitive inhibition. XOR is mainly found in the dehydrogenase form under normal physiological conditions; however, in inflammatory conditions, XOR can be converted into the xanthine oxidase form, which catalyzes reactions that produce reactive oxygen species (ROS), such as peroxynitrite. ROS contribute to vascular inflammation and alterations in vascular function. As febuxostat can inhibit both forms of XOR, it can inhibit ROS formation, oxidative stress, and inflammation. In a rat model, febuxostat suppressed renal ischemia-reperfusion injury by attenuating oxidative stress.

Pharmacodynamics

Febuxostat is a novel, selective xanthine oxidase/dehydrogenase inhibitor that works by decreasing serum uric acid in a dose-dependent manner. In healthy subjects, febuxostat decreased the mean serum uric acid and serum xanthine concentrations, as well as the total urinary uric acid excretion. Febuxostat at daily doses of 40-80 mg reduced the 24-hour mean serum uric acid concentrations by 40 to 55%. Closely related to the drug-induced reduction of serum uric acid levels and mobilization of urate crystals in tissue deposits, febuxostat is associated with gout flares. Unlike [allopurinol] and [oxypurinol], febuxostat has no inhibitory actions against other enzymes involved in purine and pyrimidine synthesis and metabolism, because it does not structurally resemble purines or pyrimidines.