Cinacalcet Hydrochloride

CINACALCET HYDROCHLORIDE- cinacalcet hydrochloride tablet, film coated
Actavis Pharma, Inc.

1 INDICATIONS AND USAGE

1.1 Secondary Hyperparathyroidism

Cinacalcet hydrochloride tablets are indicated for the treatment of secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on dialysis [see Clinical Studies (14.1)].

Limitations of Use:

Cinacalcet hydrochloride tablets are not indicated for use in patients with CKD who are not on dialysis because of an increased risk of hypocalcemia [see Warnings and Precautions (5.1)].

1.2 Parathyroid Carcinoma

Cinacalcet hydrochloride tablets are indicated for the treatment of hypercalcemia in adult patients with Parathyroid Carcinoma [see Clinical Studies (14.2)].

1.3 Primary Hyperparathyroidism

Cinacalcet hydrochloride tablets are indicated for the treatment of severe hypercalcemia in adult patients with primary HPT who are unable to undergo parathyroidectomy [see Clinical Studies (14.3)].

2 DOSAGE AND ADMINISTRATION

2.1 Administration

Cinacalcet hydrochloride tablets should be taken with food or shortly after a meal.

Cinacalcet hydrochloride tablets are administered orally and should always be taken whole and not chewed, crushed, or divided.

2.2 Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

The recommended starting oral dose of cinacalcet is 30 mg once daily. Serum calcium and serum phosphorus should be measured within 1 week and intact parathyroid hormone (iPTH) should be measured 1 to 4 weeks after initiation or dose adjustment of cinacalcet [see Dosage and Administration (2.3)]. Cinacalcet should be titrated no more frequently than every 2 to 4 weeks through sequential doses of 30 mg, 60 mg, 90 mg, 120 mg, and 180 mg once daily to target iPTH levels of 150 to 300 pg/mL. Serum iPTH levels should be assessed no earlier than 12 hours after dosing with cinacalcet.

Cinacalcet can be used alone or in combination with vitamin D sterols and/or phosphate binders.

During dose titration, serum calcium levels should be monitored frequently and if levels decrease below the normal range, appropriate steps should be taken to increase serum calcium levels, such as by providing supplemental calcium, initiating or increasing the dose of calcium-based phosphate binder, initiating or increasing the dose of vitamin D sterols, or temporarily withholding treatment with cinacalcet [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].

2.3 Patients with Parathyroid Carcinoma and Primary Hyperparathyroidism

The recommended starting oral dose of cinacalcet is 30 mg twice daily.

The dose of cinacalcet should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, and 90 mg twice daily, and 90 mg 3 or 4 times daily as necessary to normalize serum calcium levels. Serum calcium should be measured within 1 week after initiation or dose adjustment of cinacalcet [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].

2.4 Monitoring for Hypocalcemia

Once the maintenance dose has been established, serum calcium should be measured approximately monthly for patients with secondary hyperparathyroidism with CKD on dialysis, and every 2 months for patients with parathyroid carcinoma or primary hyperparathyroidism [see Dosage and Administration (2.2, 2.3)].

For secondary hyperparathyroidism patients with CKD on dialysis, if serum calcium falls below 8.4 mg/dL but remains above 7.5 mg/dL, or if symptoms of hypocalcemia occur, calcium-containing phosphate binders and/or vitamin D sterols can be used to raise serum calcium. If serum calcium falls below 7.5 mg/dL, or if symptoms of hypocalcemia persist and the dose of vitamin D cannot be increased, withhold administration of cinacalcet until serum calcium levels reach 8.0 mg/dL and/or symptoms of hypocalcemia have resolved. Treatment should be reinitiated using the next lowest dose of cinacalcet [see Dosage and Administration (2.2)].

3 DOSAGE FORMS AND STRENGTHS

Cinacalcet hydrochloride is available as film-coated tablets.

Cinacalcet hydrochloride tablets are formulated as green, film-coated, oval-shaped tablets marked with “WPI ” on one side and “16 ” or “17 ” or “18 ” on the opposite side of the 30 mg, 60 mg, or 90 mg strengths, respectively.

4 CONTRAINDICATIONS

Cinacalcet treatment initiation is contraindicated if serum calcium is less than the lower limit of the normal range [see Warnings and Precautions (5.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypocalcemia

Cinacalcet lowers serum calcium and can lead to hypocalcemia [see Adverse Reactions (6.1)]. Significant lowering of serum calcium can cause paresthesias, myalgias, muscle spasms, tetany, seizures, QT interval prolongation and ventricular arrhythmia. Life threatening events and fatal outcomes associated with hypocalcemia have been reported in patients treated with cinacalcet, including in pediatric patients. The safety and effectiveness of cinacalcet have not been established in pediatric patients [see Pediatric Use (8.4)].

Cinacalcet is not indicated for patients with CKD not on dialysis [see Indications and Usage (1)]. In patients with secondary HPT and CKD not on dialysis, the long term safety and efficacy of cinacalcet have not been established. Clinical studies indicate that cinacalcet-treated patients with CKD not on dialysis have an increased risk for hypocalcemia compared with cinacalcet-treated patients with CKD on dialysis, which may be due to lower baseline calcium levels. In a phase 3 study of 32 weeks duration and including 404 patients with CKD not on dialysis (302 cinacalcet, 102 placebo), in which the median dose for cinacalcet was 60 mg per day at the completion of the study, 80% of cinacalcet-treated patients experienced at least one serum calcium value < 8.4 mg/dL compared with 5% of patients receiving placebo.

QT Interval Prolongation and Ventricular Arrhythmia

Decreases in serum calcium can also prolong the QT interval, potentially resulting in ventricular arrhythmia. Cases of QT prolongation and ventricular arrhythmia have been reported in patients treated with cinacalcet. Patients with congenital long QT syndrome, history of QT interval prolongation, family history of long QT syndrome or sudden cardiac death, and other conditions that predispose to QT interval prolongation and ventricular arrhythmia may be at increased risk for QT interval prolongation and ventricular arrhythmias if they develop hypocalcemia due to cinacalcet. Closely monitor corrected serum calcium and QT interval in patients at risk receiving cinacalcet.

Seizures

In clinical studies, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (43/3049) of cinacalcet-treated patients and 0.7% (5/687) of placebo-treated patients. While the basis for the reported difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum calcium levels. Monitor serum calcium levels in patients with seizure disorders receiving cinacalcet.

Concurrent administration of cinacalcet with calcium-lowering drugs including other calcium-sensing receptor agonists could result in severe hypocalcemia. Closely monitor serum calcium in patients receiving cinacalcet and concomitant therapies known to lower serum calcium levels.

Educate patients on the symptoms of hypocalcemia and advise them to contact a healthcare provider if they occur.

If corrected serum calcium falls below the lower limit of normal or symptoms of hypocalcemia develop, start or increase calcium supplementation (including calcium, calcium-containing phosphate binders, and/or vitamin D sterols or increases in dialysate calcium concentration). Cinacalcet dose reduction or discontinuation of cinacalcet may be necessary [see Dosage and Administration (2.2)].

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