Evocaset 1mg 100 tablets ORKEDIA TABLETS 1mg Secondary hyperthyroidism under maintenance dialysis

Secondary hyperparathyroidism in patients on maintenance dialysis; hypercalcemia caused by parathyroid cancer, primary hyperparathyroidism that is not amenable to parathyroidectomy or recurrence after surgery.

1. Basic information of the drug

1. Common name : Evocalcet
2. English name : ORKEDIA TABLETS
3. Product name : オルケディア tablet 1mg, オルケディア tablet 2mg, オルケディア tablet 4mg
4. Dosage form : Tablets (PTP packaging, including desiccant), 1mg identification information is unclear, 2mg and 4mg are white to off-white tablets, both need to be taken out from the PTP sheet.
5. Indications :
   • Secondary hyperparathyroidism under maintenance dialysis;
   • Hypercalcemia caused by parathyroid cancer, primary hyperparathyroidism that cannot be treated with parathyroidectomy or relapses after surgery.
6. Element :
   • Active ingredient: 1mg tablet contains 1mg of Evokaluceto, 2mg tablet contains 2mg, and 4mg tablet contains 4mg;
   • Additives: yellow iron triphosphate, カルナウバロウ, crystalline セルロース, etc. (different specifications vary slightly).
7. Properties : White to off-white tablets, 1mg, 2mg, 4mg specifications have corresponding identification codes, and the specific physical parameters (diameter, thickness, etc.) are not detailed.
8. Storage and shelf life : Store at room temperature, shelf life 3 years.

2. Usage and Dosage

1. Secondary hyperparathyroidism under maintenance dialysis :
   • The starting dose for adults is 1 mg/time, orally once a day; some patients (PTH ≥ 500 pg/mL and blood calcium ≥ 9.0 mg/dL) can start with 2 mg/time, once a day.
   • The dose is adjusted according to PTH and serum calcium concentrations, with a maintenance dose of 1-8 mg/day and a maximum of 12 mg/day; the increment interval is ≥ 2 weeks and the increment is 1 mg.
   • Serum calcium needs to be monitored regularly (≥1 time per week during the initial and adjustment period, and ≥1 time every 2 weeks during the maintenance period). When serum calcium is < 8.4 mg/dL, adjustments (such as reduction in dosage) are required. When it is < 7.5 mg/dL, the drug should be discontinued immediately.
2. Hypercalcemia (parathyroid cancer, etc.) :
   • The starting dose for adults is 2 mg/time, once a day; for those with blood calcium > 12.5 mg/dL, 2 mg/time, twice a day can be used.
   • The dose is adjusted according to the blood calcium concentration. The maximum dose is 6 mg/time, 4 times a day. The increment interval is ≥ 2 weeks and can be adjusted in 1 mg increments if necessary.

3. Taboo

1. Those who have a history of allergy to the ingredients of this drug;
2. Pregnant women or women who may become pregnant (animal studies have shown fetotoxicity).

IV. Precautions

1. Special Populations :
   • Patients with liver dysfunction: The blood drug concentration may be increased in patients with mild/moderate impairment (AUC is 2.18 times and 1.28 times that of healthy people, respectively), so careful monitoring is required.
   • Lactating women: Animal experiments show that the drug enters breast milk, so it is recommended to stop breastfeeding.
   • Children: No efficacy and safety data.
   • Elderly: Physiological functions decline, and dosage reduction should be considered when side effects occur.
2. Patients with comorbidities :
   • Patients with hypocalcemia: Symptoms may be aggravated, blood calcium needs to be monitored, and calcium or vitamin D supplements should be taken if necessary.
   • Others: Be wary of amorphous bone disease and hungry bone syndrome caused by excessive reduction of PTH (overseas reports).
3. Medication Instructions :
   • Monitor PTH (twice a month at the beginning and during the adjustment period, and once a month after stabilization) and blood calcium regularly; patients with hypoalbuminemia need to be evaluated with corrected calcium concentration.
   • The tablets in the PTP package must be taken out before consumption to avoid accidental swallowing of the PTP sheet which may cause damage to the esophagus.

5. Adverse Reactions

1. Serious side effects :
   • Hypocalcemia (16.2%): may manifest as QT prolongation, numbness, muscle spasms, decreased blood pressure, etc., requiring discontinuation of medication and calcium supplementation.
   • QT prolongation (0.6%): Associated with hypocalcemia, ECG monitoring is required.
2. Other common side effects :
   • Digestive system: nausea, vomiting, abdominal discomfort, diarrhea (more than 1%);
   • Circulatory system: arrhythmia (0.5~1%);
   • Mental nerve: dizziness, paresthesia (0.5~1%);
   • Others: abnormal liver function (elevated AST/ALT), pruritus, etc.

6. Drug Interactions

• Co-administration with Theophylline: Theophylline blood concentration may be increased (mechanism unknown), and the effect and concentration of theophylline need to be monitored.

7. Pharmacological Action

• Mechanism of action : As a calcium receptor agonist, it activates calcium receptors on the surface of parathyroid cells, inhibits the secretion and synthesis of parathyroid hormone (PTH), and reduces the concentration of PTH and calcium in the blood.
• Effect : Animal experiments and clinical studies have shown that it can reduce blood PTH and blood calcium and improve hyperparathyroidism.

8. Pharmacokinetics

• Absorption : Bioavailability is 62.7%. It is well absorbed when administered on an empty stomach. Eating can reduce Cmax by 20% but does not affect AUC.
• Distribution : The plasma protein binding rate is 97.8~98.4%, mainly bound to albumin and α1-acid glycoprotein, widely distributed in tissues throughout the body (elimination is slow in tissues such as eyes and skin).
• Metabolism : Mainly metabolized by UGT1A1, UGT1A3, CYP2D6 and CYP3A4, and the metabolites have low activity.
• Excretion : Within 264 hours after administration, 61.2% was excreted via urine, 32.7% was excreted via feces, and no unchanged form was found in urine.
• Special populations : Hemodialysis/peritoneal dialysis does not affect clearance; patients with liver dysfunction have slower metabolism and higher blood drug concentrations.

IX. Clinical Research

1. Secondary hyperparathyroidism :
   • 30-week trial in hemodialysis patients: 72.7% of patients achieved PTH target (60-240pg/mL), which was non-inferior to the control drug; long-term (52 weeks) target achievement rate was 72.3%.
   • 52-week trial in peritoneal dialysis patients: 71.8% of patients achieved PTH targets.
2. Hypercalcemia :
   • 52-week trial of 18 patients: 77.8% of patients had blood calcium controlled below 10.3 mg/dL, with good safety.

10. Packaging specifications

• All are PTP packaging (including desiccant): 100 tablets/box (10 tablets × 10), corresponding to three specifications of 1mg, 2mg, and 4mg.

11. Production Information

Manufacturer : Kyowa Kirin Co., Ltd.