Cinacalcet Hydrochloride

Cinacalcet tablets are a positive modulator of the calcium sensing receptor indicated for:

• •Secondary Hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on dialysis.
  1.1 Secondary Hyperparathyroidism

  Cinacalcet 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 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)].
•  
  Limitations of Use
  : Cinacalcet tablets are not indicated for use in patients with CKD who are not on dialysis
• •Hypercalcemia in adult patients with Parathyroid Carcinoma (PC).
  1.2 Parathyroid Carcinoma

  Cinacalcet tablets are indicated for the treatment of hypercalcemia in adult patients with Parathyroid Carcinoma

  [see Clinical Studies (14.2)]

  .
• •Hypercalcemia in adult patients with primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy.
  1.3 Primary Hyperparathyroidism

  Cinacalcet tablets are indicated for the treatment of hypercalcemia in adult patients with primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy

  [see Clinical Studies (14.3)]

  .

• •Cinacalcet tablets should be taken with food or shortly after a meal
  2.1 Administration

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

  Cinacalcet tablets are administered orally and should always be taken whole and not chewed, crushed, or divided.
  .
• •Tablets should always be taken whole and not divided
  2.1 Administration

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

  Cinacalcet tablets are administered orally and should always be taken whole and not chewed, crushed, or divided.
  .
• •Secondary HPT in patients with CKD on dialysis
  2.2 Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

  The recommended starting oral dose of cinacalcet tablets 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 tablets

  [see Dosage and Administration (2.3)]

  . Cinacalcet tablets should be titrated no more frequently than every 2 to 4 weeks through sequential doses of 30, 60, 90, 120, 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 tablets.

  Cinacalcet tablets 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 tablets

  [see Dosage and Administration (2.4)and Warnings and Precautions (5.1)]

  .
  :
  • •Starting dose is 30 mg once daily.
  • •Titrate dose no more frequently than every 2 to 4 weeks through sequential doses of 30, 60, 90, 120, and 180 mg once daily as necessary to achieve targeted intact parathyroid hormone (iPTH) levels.
  • •iPTH levels should be measured no earlier than 12 hours after most recent dose.
• •Hypercalcemia in patients with PC or hypercalcemia in patients with primary HPT
  2.3 Patients with Parathyroid Carcinoma and Primary Hyperparathyroidism

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

  The dose of cinacalcet tablets 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 tablets

  [see Dosage and Administration (2.4)and Warnings and Precautions (5.1)].
  :
  • •Starting dose is 30 mg twice daily.
  • •Titrate dose every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to normalize serum calcium levels.
• •Once the maintenance dose has been established, monitor serum calcium approximately monthly for patients with secondary HPT and every 2 months for patients with PC or primary HPT
  2.5 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 tablets 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 tablets

  [see Dosage and Administration (2.2)]

  .

Cinacalcet tablets are available as film-coated tablets.

Cinacalcet tablets are formulated as light-green, oval-shaped, film-coated tablets marked with “CN” on one side and “30” or “60” or “90” on the other side of the 30 mg, 60 mg, or 90 mg strengths, respectively.

• •Pediatric Use: A fatal outcome was reported in a pediatric clinical trial patient with severe hypocalcemia. Cinacalcet tablets are not indicated for use in pediatric patients
  8.4 Pediatric Use

  The safety and efficacy of cinacalcet tablets have not been established in pediatric patients.

  The use of cinacalcet tablets for the treatment of secondary HPT in pediatric patients with CKD on dialysis was evaluated in two randomized, controlled studies (Pediatric Study 1 and Study 2) where 47 pediatric patients aged 6 years to less than 18 years received at least one dose of cinacalcet tablets and in one single-arm study (Pediatric Study 3) where 17 pediatric patients aged 28 days to less than 6 years received at least one dose of cinacalcet tablets. Dosing with cinacalcet tablets in Pediatric Study 1 was stopped because of a fatality in a cinacalcet tablets-treated individual. The individual was noted to be severely hypocalcemic at the time of death. The cause of death was multifactorial and a contribution of cinacalcet tablets to the death could not be excluded

  [see Warnings and Precautions (5.1)]

  . Study 1 was terminated and changes to cinacalcet tablets dosing after the fatality were implemented in Pediatric Study 2 and Study 3 to minimize the risk of severe hypocalcemia. The data in Pediatric Studies 2 and 3 were insufficient to establish the safety and efficacy of cinacalcet tablets for the treatment of secondary HPT in pediatric patients with CKD on dialysis. In aggregate, the pediatric studies did not establish a safe and effective cinacalcet tablets dosing regimen for the pediatric population.
  .

• •
  Hypocalcemia:
  Life threatening events and fatal outcomes were reported. Hypocalcemia can prolong QT interval, lower the threshold for seizures, and cause hypotension, worsening heart failure, and/or arrhythmia. Monitor serum calcium carefully for the occurrence of hypocalcemia during treatment
  2.5 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 tablets 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 tablets

  [see Dosage and Administration (2.2)]

  .
  5.1 Hypocalcemia

  Cinacalcet tablets 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 tablets, including in pediatric patients. The safety and effectiveness of cinacalcet tablets have not been established in pediatric patients

  [see Pediatric Use (8.4)].

  Cinacalcet tablets are 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 tablets 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 tablets. 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 tablets. Closely monitor corrected serum calcium and QT interval in patients at risk receiving cinacalcet tablets.

  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 tablets

  .

  Concurrent Administration with Other Calcium-Lowering Drug Products

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

  Patient Education and Hypocalcemia Treatment

  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 tablet dose reduction or discontinuation of cinacalcet tablet may be necessary

  [see Dosage and Administration (2.2)]

  .
• •
  Upper Gastrointestinal (GI) Bleeding
  : Patients with risk factors for upper GI bleeding may be at increased risk. Monitor patients and promptly evaluate and treat any suspected GI bleeding.
  5.2 Upper Gastrointestinal Bleeding

  Cases of gastrointestinal bleeding, mostly upper gastrointestinal bleeding, have occurred in patients using calcimimetics, including cinacalcet tablets, from postmarketing and clinical trial sources. The exact cause of GI bleeding in these patients is unknown.

  Patients with risk factors for upper GI bleeding (such as known gastritis, esophagitis, ulcers or severe vomiting) may be at increased risk for GI bleeding when receiving cinacalcet tablet treatment. Monitor patients for worsening of common GI adverse reactions of nausea and vomiting associated with cinacalcet tablets

  [see Adverse Reactions (6.1)]

  and for signs and symptoms of GI bleeding and ulcerations during cinacalcet tablet therapy. Promptly evaluate and treat any suspected GI bleeding.
• •
  Hypotension, Worsening Heart Failure and/or Arrhythmias
  : In postmarketing safety surveillance, isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function.
  5.3 Hypotension, Worsening Heart Failure and/or Arrhythmias

  In postmarketing safety surveillance, isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function, in which a causal relationship to cinacalcet tablets could not be completely excluded and which may be mediated by reductions in serum calcium levels

  [see Adverse Reactions (6.2)].
• •
  Adynamic Bone Disease
  : May develop if iPTH levels are suppressed below 100 pg/mL.
  5.4 Adynamic Bone Disease

  Adynamic bone disease may develop if iPTH levels are suppressed below 100 pg/mL. One clinical study evaluated bone histomorphometry in patients treated with cinacalcet tablets for 1 year. Three patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with cinacalcet tablets. Two of these patients had iPTH levels below 100 pg/mL at multiple time points during the study. In three 6-month, phase 3 studies conducted in patients with CKD on dialysis, 11% of patients treated with cinacalcet tablets had mean iPTH values below 100 pg/mL during the efficacy-assessment phase. If iPTH levels decrease below 150 pg/mL in patients treated with cinacalcet tablets, the dose of cinacalcet tablets and/or vitamin D sterols should be reduced or therapy discontinued.