Diacerein

Mechanism of effect

Diacerein's active metabolite rhein Rhein 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 ⁵. 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 ⁴. Rhein reduces abnormal osteoblast synthetic activity through an unknown mechanism

Pharmacodynamic

Decreases inflammation and cartilage destruction and also corrects altered osteoblast acitivity

Pharmacokinetics

Drug Concentration Levels

A) Time to Peak Concentration

1) Oral: 2.4 hours (fasting state); 5.2 hours (with food)

a) The increase in Tmax value from the fasting to the non-fasting state achieved statistical significance (p less than 0.05)

b) The maximum concentration was 3.2 mg/L, achieved 2.2 hours after administration of a single oral dose of diacerein 50 mg to subjects with normal renal function .

B) Area Under the Curve

1) 20.9 milligram/liter x hour (mg/L x hr) (fasting state); 25.9 mg/L x hr (with food)

a) The difference in AUC between fasting and non-fasting states achieved statistical significance (p less than 0.05) .

ADME

Absorption

A) Bioavailability

1) Oral: 35% to 56%

a) Apparent bioavailability of oral diacerein has been calculated between 35% and 56%

B) Effects of Food

1) Delayed time to peak concentration, increased absorption

a) Concurrent intake of food delays the time to peak concentration from 2.4 hours to 5.2 hours (p less than 0.05), but is associated with a 25% increase in absorption. Therefore, diacerein is best given with food

Distribution

A) Distribution Sites

1) Protein Binding

a) 99% (rhein)

1) The metabolite rhein is 99% protein-bound to plasma albumin and in a lesser percentage to lipoproteins and gamma-immunoglobulins

2) OTHER DISTRIBUTION SITES

a) SYNOVIAL FLUID

1) 0.3 to 3.0 milligrams/liter

B) Distribution Kinetics

1) Volume of Distribution

a) 13.2 liters

Metabolism

A) Metabolism Sites and Kinetics

1) Liver, extensive (rhein)

a) Diacerein is 100% metabolized to rhein following oral dosing, prior to entering systemic circulation. The cell localization (enterocyte or hepatocyte) of this deacetylation has not been definitively identified, but plasma can be ruled out

B) Metabolites

1) Rhein glucuronide (active)

2) Rhein sulfate (active)

Excretion

A) Kidney

1) Renal Clearance (rate)

a) 0.13 liter/hour

2) Renal Excretion (%)

a) 35% to 60%

1) Urinary excretion of diacerein in the form of its metabolites has ranged between 35% and 60%, with approximately 20% as free rhein and 80% as conjugates of rhein

B) Total Body Clearance

1) 1.6 liters/hour

a) Apparent total body clearance of rhein calculated using data from healthy volunteers averages 1.6 L/h

C) Other

1) OTHER EXCRETION

a) Bile, not quantified

1) Biliary excretion is possible, but has not been verified in humans

Elimination Half-life

A) Metabolites

1) Rhein, 7 to 8 hours

Drug indications

Osteoarthritis

Dosage

Normal Dosage

Oral route

Osteoarthritis

a) Initial dose: 50 mg orally daily for 2 to 4 weeks

b) Maintenance dose: 50 mg orally twice daily

Dosage in Renal Failure

A) CrCl less than 40 mL/min: Reduce dose by half

Dosage in Hepatic Insufficiency

A) Avoid use in those with liver disease or a history of liver disease

Dosage in Geriatric Patients

A) Use not recommended in those 65 years or older

Dosage in Other Disease States

A) Discontinue use if diarrhea occurs

Drug contraindications

Hypersensitivity to diacerein

Side effects

Dermatologic Effects

Skin finding

1) Fatal toxic epidermal necrolysis (Lyell's syndrome), possibly induced by diacerein, was reported in a 71-year-old woman. The patient had been treated with 100 mg daily for 3 months for joint pain in the hips, wrists, and shoulders. The patient also received spiramycin 3 weeks prior to onset of toxic epidermal necrolysis

Endocrine/Metabolic Effects

Hypokalemia

1) One week following the start of diacerein 100 mg daily, a 90-year-old woman was hospitalized for hypokalemia following 4 days of severe diarrhea. She presented with a potassium blood level of 1.5mmol/L, blood pressure 80/40 mm/Hg, blood sodium level of 140 mmol/L, creatinine of 70 micromoles/liter, and bicarbonate level of 37 mmol/L. Rehydration fluids with added potassium were administered parenterally. Diacerein was discontinued one week following admission. The diarrhea ceased 10 days after admission, with a return to normal of blood pressure (130/70 mm Hg) and potassium (5.2 mmol/L). Tests for other pathological reasons for diarrhea were negative. The patient's age and weight (34 kg) added to the severity of this case

Gastrointestinal Effects

Diarrhea

1) Incidence: Up to 54.4%

2) General Information

a) Most cases started during the first weeks of treatment

b) In clinical studies, 3.5% to 9.3% discontinued due to diarrhea.

3) Prevention and Management

a) Initiate therapy at half the normal dose for 2 to 4 weeks. Discontinue if diarrhea occurs

b) Do not use in patients age 65 years and older

4) Adult Clinical Trials

a) Osteoarthritis (oral route): up to 54.4%

Hepatic Effects

Hepatotoxicity

Increased liver enzymes

Injury of liver

Hepatotoxicity

1) A case of acute hepatitis was reported in a 65-year-old woman 7 days after initiating diacerein 100 mg per day for treatment of osteoarthritis

Increased liver enzymes

1) Prevention and Management

a) Avoid use in patients with liver disease and monitor for early signs of liver problems

2) Postmarketing

a) Elevated serum liver enzymes have been reported

Injury of liver

1) Incidence: 0.03%

2) Prevention and Management

a) Avoid use in patients with liver disease and monitor for early signs of liver problems

3) Postmarketing

a) Cases of symptomatic acute hepatic injury have been reported. The estimated proportion of patients who developed diacerein-induced liver injury is 0.03%

Renal Effects

Discolored urine

1) Urine discoloration was reported in 14.4% of patients administered diacerein for 90 days

Alerts

A) Gastrointestinal: Severe diarrhea has been reported; discontinue use if diarrhea develops

B) Hepatic: Symptomatic acute hepatic injury has been reported; monitoring recommended

C) Hepatic: Increased liver enzymes have been reported; monitoring recommended

D) Hepatic: History of liver disease; avoid use

E) Renal: Renal insufficiency; dosage adjustment may be necessary

F) Special populations: Age older than 65 years; not recommended due to risks associated with severe diarrhea

Points of recommendation

In 2014 the European Medicines Agency (EMA’s) Pharmacovigilance and Risk Assessment Committee (PRAC) performed a review of diacerein-containing medicines over concerns about its gastrointestinal and liver effects. As a result, the PRAC has introduced additional proposals to manage diacerein’s risks and was satisfied that with new restrictions diacerein’s benefit on pain outweighs the side effects for osteoarthritis treatment.^[6] The following recommendations have been made around the use of diacerein:

Due to the potential complications that can occur as a result of diarrhea in older adults, diacerein is no longer recommended in patients aged 65 years and above.
It is also advised that patients start treatment on half the normal dose (i.e. 50 mg daily instead of 100 mg daily), and should stop taking diacerein if diarrhea occurs.
It should not be used in any patient with liver disease or a history of liver disease, and doctors should be monitoring their patients for early signs of liver problems.
The use of diacerein is to be limited to treating symptoms of osteoarthritis affecting the hip or knee.
Diacerein should not be administered during pregnancy and lactation.

The PRAC concluded that the benefit-risk balance of diacerein-containing medicinal products remained favourable in the symptomatic treatment osteoarthritis, subject to the agreed changes to the product information and conditions.

GENERIC DRUG INFO

suppliment

Drug information of Diacerein