Orkedia

Product Description: See Table 1.

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Evocalcet is a white powder. It is soluble in N,N-dimethylformamide, very slightly soluble in acetonitrile and ethanol (99.5), and practically insoluble in water.
Physicochemical Properties: Nonproprietary name: Evocalcet.
Chemical name: 2-{4-[(3S)-3-{[(1R)-1-(Naphthalen-1-yl)ethyl]amino}pyrrolidin-1-yl]phenyl}acetic acid.
Molecular formula: C₂₄H₂₆N₂O₂.
Molecular weight: 374.48.
Melting point: ca. 177°C (decomposition).
Partition coefficient: logP = 1.00.
Composition: See Table 2.

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Pharmacology: Mechanism of Action: Evocalcet exerts its effect via calcium receptors on the surface of parathyroid cells. The calcium receptors regulate PTH biosynthesis in addition to PTH secretion. Evocalcet acts on the calcium receptors and primarily inhibits PTH secretion, thereby decreasing blood PTH concentrations.
Pharmacological Effect: Evocalcet given as a single oral dose or repeated oral doses reduced blood PTH and calcium levels in normal rats, normal mice, and partially nephrectomized rats.
Pharmacodynamics: Clinical Studies: Clinical Studies for Efficacy and Safety: Secondary hyperparathyroidism in patients on maintenance dialysis: Phase III comparative study in Japan (Hemodialysis): In this study, evocalcet or an active control drug (cinacalcet hydrochloride) was orally administered once daily for 30 weeks to patients with secondary hyperparathyroidism on hemodialysis. The dose of evocalcet was adjusted within the range of 1 to 8 mg (starting dose, 1 mg; however, 2 mg for patients with an intact PTH level of ≥ 500 pg/mL), while the dose of cinacalcet hydrochloride was adjusted within the range of 12.5 to 100 mg (starting dose, 25 mg). The proportions of subjects who achieved the target average intact PTH level of ≥ 60 - ≤ 240 pg/mL between Weeks 28 and 30 of treatment were 72.7% (184/253 subjects) in the evocalcet group and 76.7% (204/266 subjects) in the cinacalcet HCl group. The difference (evocalcet minus cinacalcet hydrochloride) in the target achievement rate (two-sided 95% CI for the difference) was -4.0% (-11.4 to 3.5%), and evocalcet was demonstrated to be non-inferior to cinacalcet hydrochloride (noninferiority margin: -15%).
The frequency of drug-related TEAEs was 44.8% (142/317 subjects) in the evocalcet group. Common drug-related TEAEs were adjusted calcium decreased in 11.7% (37/317), nausea in 5.0% (16/317), vomiting in 4.4% (14/317), blood calcium decreased and hypocalcemia in 3.5% (11/317) each, diarrhea and abdominal discomfort in 3.2% (10/317) each, and decreased appetite in 2.5% (8/317).
Phase III long-term treatment study in Japan (Hemodialysis): In this study, evocalcet was orally administered once daily for 52 weeks to a total of 137 patients with secondary hyperparathyroidism on hemodialysis. With a starting dose of 1 mg (2 mg for patients with an intact PTH level of ≥ 500 pg/mL and a corrected serum calcium level of ≥ 9.0 mg/dL), the dose of evocalcet was adjusted within the range of 1 to 12 mg. The proportion of subjects who achieved the target intact PTH level of ≥ 60 - ≤ 240 pg/mL at Week 52 of treatment was 72.3% (see Precautions Concerning Dosage and Administration: Secondary hyperparathyroidism in patients on maintenance dialysis under Precautions).
The frequency of drug-related TEAEs was 35.0% (48/137 subjects). Common drug-related TEAEs were adjusted calcium decreased in 7.3% (10/137), nausea and abdominal discomfort in 5.1% (7/137) each, vomiting and blood calcium decreased in 3.6% (5/137) each, and diarrhea, constipation, abdominal pain, and chest discomfort in 1.5% (2/137) each.
Phase III general study in Japan (Peritoneal Dialysis): In this study, evocalcet was orally administered once daily for 52 weeks to 39 patients with secondary hyperparathyroidism on peritoneal dialysis. With a starting dose of 1 mg (2 mg for patients with an intact PTH level of ≥ 500 pg/mL and a corrected serum calcium level of ≥ 9.0 mg/dL), the dose of evocalcet was adjusted within the range of 1 to 12 mg. The proportion of subjects who achieved the target average intact PTH level of ≥ 60 - ≤ 240 pg/mL between Weeks 30 and 32 of treatment was 71.8% (see Precautions Concerning Dosage and Administration: Secondary hyperparathyroidism in patients on maintenance dialysis under Precautions).
The frequency of drug-related TEAEs was 46.2% (18/39 subjects). Common drug-related TEAEs were adjusted calcium decreased in 17.9% (7/39) and blood calcium decreased in 5.1% (2/39).
Hypercalcaemia in patients with parathyroid carcinoma and hypercalcaemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy or patients with recurrent primary hyperparathyroidism after parathyroidectomy: Phase III study in Japan: In this study, evocalcet was orally administered for 52 weeks to a total of 18 patients with hypercalcemia in parathyroid carcinoma or primary hyperparathyroidism who are unable to undergo parathyroidectomy or relapse after parathyroidectomy. With a starting dose of 2 mg once daily (2 mg/dose twice daily was allowed for patients with a corrected serum calcium level of > 12.5 mg/dL), the dose of evocalcet was adjusted within the range of 2 to 6 mg and one to four times daily. The number and proportion (95% CI) of subjects in whom corrected serum calcium levels were maintained at 10.3 mg/dL or lower for 2 weeks between the start of treatment and Week 24 were 14 subjects and 77.8% (52.4, 93.6%), and the lower limit of the 95% CI exceeded a set threshold of 11%.
The frequency of drug-related TEAEs was 44.4% (8/18 subjects). Observed drug-related TEAEs were nausea in 11.1% (2/18) and abdominal discomfort, dyspepsia, vomiting, viral infection, taste abnormality, cough, eczema, and hypertension in 5.6% (1/18) each.
Pharmacokinetics: Blood Level: Single dose: Healthy adult subjects: Evocalcet was administered as a single oral dose of 1, 3, 6, 12, and 20 mg^Note to healthy adult subjects in the fasted state. The plasma concentration-time curves and pharmacokinetic parameters are shown as follows. The C_max and AUC_0-∞ of evocalcet in plasma increased in proportion to dose. (See Figure 1 and Table 3.)
^Note)The approved maximum dose of ORKEDIA is 12 mg per dose for secondary hyperparathyroidism in patients undergoing maintenance dialysis, and 6 mg per dose for hypercalcemia in patients with parathyroid carcinoma or primary hyperparathyroidism who are unable to undergo parathyroidectomy or relapse after parathyroidectomy.

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Single dose: Patients with secondary hyperparathyroidism: Evocalcet was administered as a single oral dose of 1, 4, and 12 mg to patients with secondary hyperparathyroidism on hemodialysis and 1 mg to patients with secondary hyperparathyroidism on peritoneal dialysis. The plasma concentration-time curves and pharmacokinetic parameters are shown as follows. The C_max and AUC_0-∞ of evocalcet in plasma after a single dose increased in proportion to dose in patients with secondary hyperparathyroidism on hemodialysis. (See Figure 2 and Table 4.)

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Multiple doses: Healthy adult subjects: The pharmacokinetic parameters of evocalcet in healthy adult subjects who received multiple oral doses of 6 or 12 mg once daily after a meal are shown as follows. Plasma evocalcet concentrations reached a steady state immediately after the start of repeated administration, regardless of dose, and no significant accumulation of evocalcet in plasma was observed. (See Table 5.)

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Multiple doses: Patients with hypercalcemia in parathyroid carcinoma, and hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy or patients with recurrent primary hyperparathyroidism after parathyroidectomy: The pharmacokinetic parameters of evocalcet in patients with hypercalcemia with parathyroid carcinoma, and hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy or patients with recurrent primary hyperparathyroidism after parathyroidectomy who received multiple oral doses as in the following table are shown as follows. (See Table 6.)

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Absorption: Bioavailability: After administration of evocalcet as a single oral dose of 1 mg and ¹⁴C-evocalcet as an intravenous dose of 4 µg to non-Japanese healthy adult subjects, the absolute bioavailability of evocalcet was 62.7%.
Effects of Food: When evocalcet was administered as a single oral dose of 2 mg to healthy adult subjects after a meal, the C_max of evocalcet was about 20% lower than that after administration in the fasted state, while no effect of food was observed on the AUC_0-t of evocalcet.
Distribution: Distribution to blood cells and plasma protein binding: The in vitro distribution of evocalcet to human blood cells ranged from 5.2 to 9.2% and the human plasma protein binding of evocalcet ranged from 97.8 to 98.4%. The major proteins that bound to evocalcet in plasma were albumin and alpha-1 acid glycoprotein. The plasma protein binding rates in healthy adult subjects and patients with hepatic impairment were similar, ranging from 97.9 to 98.2% (see Interactions).
Tissue penetration: After administration of ¹⁴C-evocalcet as a single oral dose to male rats (albino and pigmented rats), the radioactivity was distributed to throughout most of the body. In albino rats, high radioactivity concentrations were detected in the harderian gland and liver. Pigmented rats had a higher radioactivity concentration in the eyeballs than that in albino rats. In addition, the elimination of radioactivity from the eyeballs, pigmented skin, and uveal tract in pigmented rats was slower than that in albino rats, suggesting that the administered radioactivity derived from ¹⁴C-KHK7580 could bind for melanin.
Metabolism: In an in vitro study using ¹⁴C-evocalcet, the UGT and CYP isozymes that contribute to the metabolism of evocalcet were suggested to be UGT1A1, UGT1A3, CYP2D6, and CYP3A4. However, the amount of metabolites produced in the human liver microsomes was extremely small, accounting for less than 4% of radioactivity in the sample.
When ¹⁴C-evocalcet was administered as a single oral dose of 1 mg to non-Japanese healthy adult subjects, the amount of the unchanged compound was larger than the amount of any other metabolite in the plasma, and the C_max and AUC_0-72 ratios of the unchanged compound relative to the total radioactivity were 95.5% and 80.0%, respectively. The active metabolites, i.e. taurine conjugate and glycine conjugate were detected as the major metabolites in the plasma, the ratios of these metabolites relative to the total radioactivity were 7.5% and 3.1%, respectively, in terms of C_max and 11.2% and 8.5%, respectively, in terms of AUC_0-72.
Excretion: When ¹⁴C-evocalcet was administered as a single oral dose of 1 mg to non-Japanese healthy adult subjects, 32.7% and 61.2% of the administered dose of radioactivity were excreted in feces and urine, respectively, by 264 hours post-dose. While 8.6% of the administered dose was excreted unchanged in the feces, the unchanged compound was not detected in the urine.
Patients with Specific Backgrounds: Patients with hepatic impairment: When evocalcet was administered as a single oral dose of 1 mg to patients with mild and moderate (Child-Pugh Classes A and B) hepatic impairment, the AUC_0-∞ values were 2.18 and 1.28 times, respectively, higher than the AUC_0-∞ value in healthy adult subjects. C_max values were 1.10 and 0.91 times, respectively, of C_max value in the healthy subjects, without significant differences (see Precautions Concerning Patients with Specific Backgrounds: Patients with Hepatic Impairment under Precautions).
Patients on dialysis: After evocalcet was administered as an oral dose of 1 or 4 mg to patients with secondary hyperparathyroidism on hemodialysis, blood was collected from the arterial side and vein side of the dialyzer at the same time, and plasma evocalcet concentrations in the two samples were determined. It was revealed that evocalcet was not eliminated by dialysis. Evocalcet was also administered as an oral dose of 1 mg to patients with secondary hyperparathyroidism on peritoneal dialysis. The dialysis elimination rate of evocalcet, as calculated based on the concentration of evocalcet in dialysis wastewater, was ≤ 2.33%, and evocalcet was hardly excreted in the dialysis wastewater.
Drug-Drug Interaction: Theophylline: Evocalcet was administered as repeated oral doses of 6 mg once daily from Days 4 through 20 to healthy adult subjects, together with oral theophylline 100 mg administered on Days 1 and 18. The C_max and AUC_0-t values of theophylline after repeated administration with evocalcet were 1.15 times (90% confidential interval [CI]: 1.10 to 1.20) and 1.26 times (90% CI: 1.19 to 1.33), respectively, of the C_max and AUC_0-t values obtained after administration of theophylline alone, and the upper limit of the 90% CI of AUC_0-t exceeded the threshold value of 1.25 (see Interactions).

Secondary hyperparathyroidism in patients on maintenance dialysis.
Hypercalcaemia in patients with parathyroid carcinoma and hypercalcaemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy or patients with recurrent primary hyperparathyroidism after parathyroidectomy.

Secondary hyperparathyroidism in patients on maintenance dialysis: The usual starting dosage for adults is 1 mg of evocalcet administered orally once daily. The starting dose may be 2 mg once daily, depending on the patient's condition. The subsequent oral dose is adjusted within the range from 1 to 8 mg once daily while parathyroid hormone (PTH) and serum calcium levels of the patient are closely monitored. The dose may be increased up to 12 mg once daily if the patient has an inadequate response.
Hypercalcaemia in patients with parathyroid carcinoma and hypercalcaemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy or patients with recurrent primary hyperparathyroidism after parathyroidectomy: The usual starting dosage for adults is 2 mg of evocalcet administered orally once daily. The starting dose may be 2 mg twice daily depending on the serum calcium levels of the patient. The subsequent oral dose is adjusted depending on the serum calcium levels of the patient, and may be increased to a maximum of 6 mg 4 times daily.

Symptoms: The overdose of ORKEDIA is considered to induce hypocalcemia.
Measures: Observe the signs and symptoms of hypocalcemia. If hypocalcemia has occurred or may possibly occur, the physician must consider the need to administer calcium preparation by intravenous drip infusion, etc. ORKEDIA is not eliminated by hemodialysis (see Clinically Significant Adverse Reactions: Hypocalcemia (16.2%) under Adverse Reactions).

ORKEDIA is contraindicated to the following patients: Patients with a history of hypersensitivity to any component of this product; Pregnant or possibly pregnant women (see Pregnant Women under Use in Pregnancy & Lactation).

Precautions Concerning Dosage and Administration: Secondary hyperparathyroidism in patients on maintenance dialysis: Since evocalcet decreases blood calcium levels, the physician must confirm that the patient's serum calcium level is not low (>=8.4 mg/dL, as a guide) before starting administration.
If the dose needs to be increased, the dose should be increased in 1 mg increments at intervals of at least 2 weeks.
If the patient has a high PTH level (an intact PTH level of ≥ 500 pg/mL, as a guide) and a serum calcium level of ≥ 9.0 mg/dL, the physician should consider the starting dose with 2 mg of evocalcet once daily [see Pharmacology: Pharmacodynamics: Phase III long-term treatment study in Japan (Hemodialysis) and Phase III general study in Japan (Peritoneal Dialysis) under Actions].
Measure serum calcium levels at least once a week at the start of treatment and at the time of dose adjustment and at least once every 2 weeks during the maintenance period. Take actions, as shown in the following table, when the serum calcium level decreases to < 8.4 mg/dL (see Important Precautions as follows; Precautions Concerning Patients with Specific Backgrounds: Patients with Complication or History of Diseases, etc.: Patients with hypocalcemia as follows; and Clinically Significant Adverse Reactions: Hypocalcemia (16.2%) under Adverse Reactions). (See Table 7.)

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It is desirable to measure a serum calcium level before an oral dose to appropriately evaluate the efficacy and safety of this drug. In the case of hypoalbuminemia (i.e., serum albumin level of < 4.0 g/dL), it is desirable to use a corrected calcium level^Note as an indicator.
Measure PTH levels periodically to maintain PTH levels within the target range. Measure PTH levels twice monthly at the start of treatment and at the time of dose adjustment (about 3 months after the start of treatment as a guide). It is desirable to measure PTH levels once monthly after confirming that the PTH level has become almost stable. It is desirable to measure a PTH level before an oral dose in order to appropriately evaluate the efficacy and safety of this drug.
Hypercalcaemia in patients with parathyroid carcinoma and hypercalcaemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy or patients with recurrent primary hyperparathyroidism after parathyroidectomy: It is desirable to measure serum calcium levels twice a week as a guide at the start of treatment and at the time of dose adjustment, and periodically during the maintenance period.
In the case of serum calcium level exceeding 12.5 mg/dL, consider the initial dose of 2 mg/dose twice daily.
In the case requiring dose adjustment, increase/decrease doses by referring to the following table. As a general rule, increase doses step by step with intervals of at least two weeks. If the serum calcium level is difficult to control, the dose may be increased or decreased by 1 mg. (See Table 8.)

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Interrupt the treatment immediately if a serum calcium level decreases to 7.5 mg/dL or lower. In addition, consider administrating calcium and/or vitamin D preparations if required (see Important Precautions as follows; Precautions Concerning Patients with Specific Backgrounds: Patients with Complication or History of Diseases, etc.: Patients with hypocalcemia as follows; and Clinically Significant Adverse Reactions: Hypocalcemia (16.2%) under Adverse Reactions).
In the case of hypoalbuminemia (i.e., serum albumin level of < 4.0 g/dL), it is desirable to use a corrected calcium level^Note as an indicator.
^Note)How to calculate a corrected calcium level: Corrected calcium level (mg/dL) = Serum calcium level (mg/dL) - Serum albumin level (g/dL) + 4.0.
Important Precautions: Measure serum calcium levels periodically and pay careful attention to prevent the occurrence of hypocalcemia during treatment with ORKEDIA. When hypocalcemia has occurred or may possibly occur, the physician should consider reducing the dose of ORKEDIA, etc., as well as the need to administer calcium and/or vitamin D preparations. When the patient discontinued using calcium or vitamin D preparation during treatment with ORKEDIA, the physician should pay attention to the occurrence of hypocalcemia (see Precautions Concerning Dosage and Administration: Secondary hyperparathyroidism in patients on maintenance dialysis and Hypercalcaemia in patients with parathyroid carcinoma and hypercalcaemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy or patients with recurrent primary hyperparathyroidism after parathyroidectomy as previously mentioned; Precautions Concerning Patients with Specific Backgrounds: Patients with Complication or History of Diseases, etc.: Patients with hypocalcemia as follows; and Clinically Significant Adverse Reactions: Hypocalcemia (16.2%) under Adverse Reactions).
Observe the patient's condition frequently at the start of treatment and at the time of dose adjustment of ORKEDIA, and pay attention to the occurrence of adverse reactions.
Precautions Concerning Patients with Specific Backgrounds: Patients with Complication or History of Diseases, etc.: Patients with hypocalcemia: ORKEDIA may aggravate hypocalcemia (see Precautions Concerning Dosage and Administration: Secondary hyperparathyroidism in patients on maintenance dialysis and Hypercalcaemia in patients with parathyroid carcinoma and hypercalcaemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy or patients with recurrent primary hyperparathyroidism after parathyroidectomy as previously mentioned; Important Precautions as previously mentioned ; and Clinically Significant Adverse Reactions: Hypocalcemia (16.2%) under Adverse Reactions).
Patients with Hepatic Impairment: Blood evocalcet concentrations may increase (see Pharmacology: Pharmacokinetics: Patients with Specific Backgrounds: Patients with hepatic impairment under Actions). In addition, since the safety and efficacy have not been established in patients with severe hepatic impairment, administration of this drug is not recommended.
Precaution Concerning Use: Precautions Concerning the Dispensing of the Drug: Instruct the patient to remove an ORKEDIA tablet from the blister before taking the tablet. It has been reported that, after accidental swallowing of a blister, the sharp hard edges of the blister pierced and penetrated the esophageal mucosa, resulting in serious complications, such as mediastinitis.
Other Precautions: Information Based on Clinical Use: In foreign countries, it was reported that patients developed adynamic bone disease due to an excessive decrease in PTH induced by calcium receptor agonists.
In foreign countries, it was reported that patients developed hungry bone syndrome with hypocalcemia and hypophosphatemia due to a rapid decrease in PTH after administration of calcium receptor agonists.
Use in Children: Clinical studies with the efficacy and safety in pediatric subjects have not been conducted.
Use in the Elderly: If any adverse reaction occurs in an elderly patient, the physician must take appropriate measures, such as dose reduction. In general, the elderly have decreased physiological function.

Pregnant Women: Do not administer ORKEDIA to pregnant or possibly pregnant women. If a patient is found to be pregnant during treatment, the patient must discontinue ORKEDIA therapy immediately. In animal studies (rats), placental transfer, high stillbirth index, low live birth index, and low body weight in the offspring were observed (see Contraindications).
Breast-feeding Women: Breast-feeding is not recommended.
In animal study (rats), evocalcet was transferred into breast milk.
In animal study (rats), offspring growth retardation, etc. was observed.

Since the following adverse reactions may occur, patients should be carefully monitored. If any abnormalities occur, appropriate measures including treatment discontinuation should be taken.
Clinically Significant Adverse Reactions: Hypocalcemia (16.2%): If symptoms derived from hypocalcemia (QT prolongation, numbness, muscle spasms, discomfort, arrhythmia, decreased blood pressure, convulsions, etc.) occur, the physician must check serum calcium levels and consider the need to administer calcium and/or vitamin D preparations (see Precautions Concerning Dosage and Administration: Secondary hyperparathyroidism in patients on maintenance dialysis and Hypercalcaemia in patients with parathyroid carcinoma and hypercalcaemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy or patients with recurrent primary hyperparathyroidism after parathyroidectomy under Precautions; Important Precautions under Precautions; Precautions Concerning Patients with Specific Backgrounds: Patients with Complication or History of Diseases, etc.: Patients with hypocalcemia under Precautions; QT prolongation (0.6%) as follows; and Measures under Overdosage).
QT prolongation (0.6%): see Hypocalcemia (16.2%) as previously mentioned.
Other Adverse Reactions: See Table 9.

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Precautions for Co-administration: ORKEDIA should be administered with caution when co-administered with the following: See Table 10.

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Store below 25 °C.
Protect from light.

Other Agents Affecting Metabolism

H05BX06 - evocalcet ; Belongs to the class of other anti-parathyroid agents. Used in the management of calcium homeostasis.

P₁S₁S₃