SENSIPAR- cinacalcet hydrochloride tablet, coated
For Healthcare Providers >

1. Patient Information
2. Seizures:
3. Hypocalcemia:
4. Upper Gastrointestinal Bleeding:
5. Heart Failure:
6. Manufactured By:

Patient Information ⮝

• Take withFood:Patients should be advised to take Sensipar with food or shortly after a meal. Tablets should be taken whole and should not be divided.

• LaboratoryMonitoring: Patients should be informed of the importance of regular blood tests, in order to monitor the safety and efficacy of Sensipar therapy.

• Common Serious Adverse Reactions: Patients should be advised to report nausea, vomiting, and potential symptoms of hypocalcemia, including tingling/numbness of the skin, muscle pain, and muscle cramping.

Seizures: ⮝

Patients should be queried if they are taking medication to prevent seizures or have had seizures in the past and be advised to report any seizure episodes while on Sensipar therapy.

• Lactation Surveillance Program: Encourage patients who are nursing while on Sensipar treatment to enroll in Amgen s Lactation Surveillance Program. To enroll patients should call 1-800-77-AMGEN (1-800-772-6436).

Hypocalcemia: ⮝

Advise patients to report symptoms of hypocalcemia, including paresthesias, myalgias, muscle spasms, and seizures, to their healthcare provider[see Warnings and Precautions (5.1)].

Upper Gastrointestinal Bleeding: ⮝

Advise patients to report any symptoms of upper gastrointestinal bleeding to their health care provider[see Warnings and Precautions (5.2)].

Heart Failure: ⮝

Advise patients with heart failure that use of Sensipar may worsen their heart failure and additional monitoring may be required[see Warnings and Precautions (5.3)].

Advise patients to report nausea and vomiting to their health care provider[see Adverse Reactions (6.1)].

Advise patients to take Sensipar with food or shortly after a meal and to take the tablets whole and not divide them[see Dosage and Administration (2.1)].

Inform patients of the importance of regular blood tests, in order to monitor the safety and efficacy of Sensipar therapy.

Sensipar(cinacalcet) Tablets

Manufactured By: ⮝

Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799

Patent: http://pat.amgen.com/sensipar/

2004-2019 Amgen Inc. All rights reserved.

www.sensipar.com

1-800-77-AMGEN (1-800-772-6436)

1xxxxxx v13

1. No Title 1572551157
2. No Title 1572551267
3. No Title 1572552425
4. Highlights Of Prescribing Information
5. Indications And Usage
6. Dosage And Administration
7. Dosage Forms And Strengths
8. Contraindications
9. Warnings And Precautions
10. Adverse Reactions
11. Drug Interactions
12. Use In Specific Populations
13. 1 Indications And Usage
14. 2 Dosage And Administration
15. 5 Warnings And Precautions
16. 6 Adverse Reactions
17. 7 Drug Interactions
18. 8 Use In Specific Populations
19. 12 Clinical Pharmacology
20. 13 Nonclinical Toxicology
21. 14 Clinical Studies
22. 1 Indications And Usage
23. 2 Dosage And Administration
24. 3 Dosage Forms And Strengths
25. 4 Contraindications
26. 5 Warnings And Precautions
27. 6 Adverse Reactions
28. 7 Drug Interactions
29. 8 Use In Specific Populations
30. 10 Overdosage
31. 11 Description
32. 12 Clinical Pharmacology
33. 13 Nonclinical Toxicology
34. 14 Clinical Studies
35. 16 How Supplied/storage And Handling
36. Storage
37. Cinacalcet Hydrochloride
38. Principal Display Panel
39. No Title 1572454788
40. How Supplied
41. No Title 1572455420
42. Cinacalcet Hcl
43. Description
44. Clinical Pharmacology
45. Clinical Studies
46. Contraindications
47. Warnings
48. Precautions
49. Adverse Events
50. Overdosage
51. References
52. No Title 1572457199
53. Package Label - Principal Display Panel - Tablet, 60 Mg
54. Recent Major Changes
55. 1 Indications And Usage
56. 2 Dosage And Administration
57. 3 Dosage Forms And Strengths
58. 4 Contraindications
59. 5 Warnings And Precautions
60. 6 Adverse Reactions
61. 7 Drug Interactions
62. 8 Use In Specific Populations
63. 10 Overdosage
64. 11 Description
65. 12 Clinical Pharmacology
66. 13 Nonclinical Toxicology
67. 14 Clinical Studies
68. 16 How Supplied/storage And Handling
69. Package Label - Principal Display Panel - Tablet, 30 Mg

No Title 1572551157 ⮝

[Amgen Logo]

Sensipar (cinacalcet) Tablets
Manufactured by:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799

Patent: http://pat.amgen.com/sensipar/
2004-2014 Amgen Inc. All rights reserved.
www.sensipar.com
1-800-77-AMGEN (1-800-772-6436)
1xxxxxx -, v10

No Title 1572551267 ⮝

Manufactured for: Amgen
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799

2004-2010 Amgen Inc. All rights reserved.

This Product was Repackaged By:

State of Florida DOH Central Pharmacy
104-2 Hamilton Park Drive
Tallahassee, FL 32304
United States

No Title 1572552425 ⮝

2.2 Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

The recommended starting oral dose of Sensipar 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 Sensipar [see Dosage and Administration (2.3)]. Sensipar 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 Sensipar.

Sensipar 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 Sensipar [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 Sensipar is 30 mg twice daily.

The dose of Sensipar 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 Sensipar [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 Sensipar 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 Sensipar [see Dosage and Administration (2.2)].

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use SENSIPAR safely and effectively. See full prescribing information for SENSIPAR.

SENSIPAR (cinacalcet) tablets, for oral use
Initial U.S. Approval: 2004

Indications And Usage ⮝

Sensipar is a calcium-sensing receptor agonist indicated for:

• Secondary Hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on dialysis. (1.1)
  Limitations of Use: Sensipar is not indicated for use in patients with CKD who are not on dialysis

• Hypercalcemia in adult patients with Parathyroid Carcinoma (PC). (1.2)
  
• 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)

Dosage And Administration ⮝

• Sensipar tablets should be taken with food or shortly after a meal (2.1)
  
• Tablets should always be taken whole and not divided (2.1)
  
• Secondary HPT in patients with CKD on dialysis (2.2):
  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):
  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 (2.4)

Dosage Forms And Strengths ⮝

• Tablets: 30, 60, and 90 mg tablets (3)

Contraindications ⮝

Sensipar treatment initiation is contraindicated if serum calcium is less than the lower limit of the normal range. (4, 5.1)

Warnings And Precautions ⮝

• 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. (2.4, 5.1)
  
• 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)
  
• 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)
  
• Adynamic Bone Disease: May develop if iPTH levels are suppressed below 100 pg/mL. (5.4)

Adverse Reactions ⮝

The most common adverse reactions (i.e., 25%) associated with Sensipar were nausea and vomiting. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

• Co-administration with a strong CYP3A4 inhibitor may increase serum levels of cinacalcet. Dose adjustment and monitoring of iPTH serum phosphorus and serum calcium may be required. (7.1)
  
• Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications that are predominantly metabolized by CYP2D6. (7.2)

Use In Specific Populations ⮝

• Pediatric Use: A fatal outcome was reported in a pediatric clinical trial patient with severe hypocalcemia. Sensipar is not indicated for use in pediatric patients. (8.4)

__________________________________________________________________________________________________________________________________

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 3/2019

1 Indications And Usage ⮝

1.1 Secondary Hyperparathyroidism

1.2 Parathyroid Carcinoma

1.3 Primary Hyperparathyroidism

2 Dosage And Administration ⮝

2.1 Administration

2.2 Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

2.3 Patients with Parathyroid Carcinoma and Primary Hyperparathyroidism

2.4 Switching from Parsabiv (etelcalcetide) to Sensipar

2.5 Monitoring for Hypocalcemia

5 Warnings And Precautions ⮝

5.1 Hypocalcemia

5.2 Upper Gastrointestinal Bleeding

5.3 Hypotension, Worsening Heart Failure and/or Arrhythmias

5.4 Adynamic Bone Disease

6 Adverse Reactions ⮝

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 Drug Interactions ⮝

7.1 Strong CYP3A4 Inhibitors

7.2 CYP2D6 Substrates

8 Use In Specific Populations ⮝

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 Clinical Studies ⮝

14.1 Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

14.2 Parathyroid Carcinoma

14.3 Patients with Hypercalcemia Due to Primary Hyperparathyroidism

1 Indications And Usage  ⮝

1.1 Secondary Hyperparathyroidism

Sensipar is 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:

Sensipar is 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

Sensipar is indicated for the treatment of hypercalcemia in adult patients with Parathyroid Carcinoma [see Clinical Studies (14.2)].

1.3 Primary Hyperparathyroidism

Sensipar is 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)].

2 Dosage And Administration  ⮝

2.1 Administration

Sensipar should be taken with food or shortly after a meal.

Sensipar 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 Sensipar 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 Sensipar [see Dosage and Administration (2.3)]. Sensipar 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 Sensipar.

Sensipar 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 Sensipar [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 Sensipar is 30 mg twice daily.

The dose of Sensipar 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 Sensipar [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].

2.4 Switching from Parsabiv (etelcalcetide) to Sensipar

Discontinue etelcalcetide for at least 4 weeks prior to starting Sensipar. Ensure corrected serum calcium is at or above the lower limit of normal prior to Sensipar initiation [see Warnings and Precautions (5.1)]. Initiate Sensipar treatment at a starting dose of 30 mg once daily.

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 Sensipar 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 Sensipar [see Dosage and Administration (2.2)].

3 Dosage Forms And Strengths  ⮝

Sensipar is available as film-coated tablets.

Sensipar tablets are formulated as light-green, film-coated, oval-shaped tablets marked with AMG on one side and 30 or 60 or 90 on the opposite side of the 30 mg, 60 mg, or 90 mg strengths, respectively.

4 Contraindications  ⮝

Sensipar 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

Sensipar 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 Sensipar, including in pediatric patients. The safety and effectiveness of Sensipar have not been established in pediatric patients [see Pediatric Use (8.4)].

Sensipar 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 Sensipar have not been established. Clinical studies indicate that Sensipar-treated patients with CKD not on dialysis have an increased risk for hypocalcemia compared with Sensipar-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 Sensipar-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 Sensipar. 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 Sensipar. Closely monitor corrected serum calcium and QT interval in patients at risk receiving Sensipar.

Seizures

In clinical studies, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (43/3049) of Sensipar-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 Sensipar.

Concurrent Administration with Other Calcium-Lowering Drug Products

Concurrent administration of Sensipar with calcium-lowering drugs including other calcium-sensing receptor agonists could result in severe hypocalcemia. Closely monitor serum calcium in patients receiving Sensipar 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). Sensipar dose reduction or discontinuation of Sensipar may be necessary [see Dosage and Administration (2.2)].

5.2 Upper Gastrointestinal Bleeding

Cases of gastrointestinal bleeding, mostly upper gastrointestinal bleeding, have occurred in patients using calcimimetics, including Sensipar, 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 Sensipar treatment. Monitor patients for worsening of common GI adverse reactions of nausea and vomiting associated with Sensipar [see Adverse Reactions (6.1)] and for signs and symptoms of GI bleeding and ulcerations during Sensipar therapy. Promptly evaluate and treat any suspected GI bleeding.

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 Sensipar could not be completely excluded and which may be mediated by reductions in serum calcium levels [see Adverse Reactions (6.2)].

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 Sensipar for 1 year. Three patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with Sensipar. 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 Sensipar 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 Sensipar, the dose of Sensipar and/or vitamin D sterols should be reduced or therapy discontinued.

6 Adverse Reactions  ⮝

The following adverse reactions are discussed in greater detail in other sections of labeling:

• Hypocalcemia [see Warnings and Precautions (5.1)]
  
• Upper Gastrointestinal Bleeding [see Warnings and Precautions (5.2)]
  
• Hypotension, Worsening Heart Failure and/or Arrhythmias [see Warnings and Precautions (5.3)]
  
• Adynamic Bone Disease [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

In three double-blind, placebo-controlled clinical trials, 1126 patients with CKD on dialysis received study drug (656 Sensipar, 470 placebo) for up to 6 months. The most frequently reported adverse reactions are listed in Table 1.

Seizures were observed in 1.4% (13/910) of Sensipar-treated patients and 0.7% (5/641) of placebo-treated patients across all completed placebo-controlled trials.

Table 1. Adverse Reactions with Frequency 5% in Patients on Dialysis in Short-Term Studies for up to 6 Months

		Placebo	Sensipar
		(n = 470)	(n = 656)
Event*:		(%)	(%)
Nausea		19	31
Vomiting		15	27
Diarrhea		20	21
Myalgia		14	15
Dizziness		8	10
Hypertension		5	7
Asthenia		4	7
Anorexia		4	6
Pain Chest, Non-Cardiac		4	6
Dialysis Access Site Infection		4	5

*Included are events that were reported at a greater incidence in the Sensipar group than in the placebo group.

In a randomized, double-blind placebo-controlled study of 3883 patients with secondary HPT and CKD receiving dialysis in which patients were treated for up to 64 months (mean duration of treatment was 21 months in the Sensipar group), the most frequently reported adverse reactions (incidence of 5% in the Sensipar group and a difference 1% compared to placebo) are listed in Table 2.

Table 2. Frequency of Adverse Reactions in Dialysis Patients Treated for up to 64 Months in a Long-Term Study1

	Placebo (n = 1923)	Sensipar (n = 1938)
	3699 subject-years	4044 subject-years
Percent of subjects reporting Adverse Reactions (%)	90.9	93.2
Nausea	15.5	29.1
Vomiting	13.7	25.6
Diarrhea	18.7	20.5
Dyspnea	11.5	13.4
Cough	9.8	11.7
Hypotension	10.5	11.6
Headache	9.6	11.5
Hypocalcemia	1.4	11.2
Muscle spasms	9.2	11.1
Abdominal pain	9.6	10.9
Abdominal pain upper	6.3	8.2
Hyperkalemia	6.1	8.1
Upper respiratory tract infection	6.3	7.6
Dyspepsia	4.6	7.4
Dizziness	4.7	7.3
Decreased appetite	3.5	5.9
Asthenia	3.8	5.4
Constipation	3.8	5.0

1 Adverse reactions that occurred in 5% frequency in the Sensipar group and a difference 1% compared to the placebo group (Safety Analysis Set).

Crude incidence rate = 100 * Total number of subjects with event/ n

n = Number of subjects receiving at least one dose of study drug.

Additional adverse reaction rates from the long-term, randomized, double-blind placebo-controlled study for Sensipar versus placebo are as follows: seizure (2.5%, 1.6%), rash (2.2%, 1.9%), hypersensitivity reactions (9.4%, 8.3%).

Patients with Parathyroid Carcinoma and Primary Hyperparathyroidism

The safety profile of Sensipar in these patient populations is generally consistent with that seen in patients with CKD on dialysis. Forty six patients were treated with Sensipar in a single-arm study, 29 with Parathyroid Carcinoma and 17 with intractable pHPT. Nine (20%) of the patients withdrew from the study due to adverse events. The most frequent adverse reactions and the most frequent cause of withdrawal in these patient populations were nausea and vomiting. Severe or prolonged cases of nausea and vomiting can lead to dehydration and worsening hypercalcemia so careful monitoring of electrolytes is recommended in patients with these symptoms.

Eight patients died during treatment with Sensipar in this study, 7 with Parathyroid Carcinoma (24%) and 1 (6%) with intractable pHPT. Causes of death were cardiovascular (5 patients), multi-organ failure (1 patient), gastrointestinal hemorrhage (1 patient) and metastatic carcinoma (1 patient). Adverse events of hypocalcemia were reported in three patients (7%).

Seizures were observed in 0.7% (1/140) of cinacalcet-treated patients and 0.0% (0/46) of placebo-treated patients in all clinical studies.

Table 3. Adverse Reactions with Frequency 10% in a Single-Arm, Open-Label Study in Patients with Primary Hyperparathyroidism or Parathyroid Carcinoma

	Sensipar
	Parathyroid Carcinoma (n = 29)		Intractable pHPT (n = 17)	Total (n = 46)
	n (%)	n (%)		n (%)
Number of Subjects Reporting Adverse Reactions	28 (97)	17 (100)		45 (98)
Nausea	19 (66)	10 (59)		29 (63)
Vomiting	15 (52)	6 (35)		21 (46)
Paresthesia	4 (14)	5 (29)		9 (20)
Fatigue	6 (21)	2 (12)		8 (17)
Fracture	6 (21)	2 (12)		8 (17)
Hypercalcemia	6 (21)	2 (12)		8 (17)
Anorexia	6 (21)	1 (6)		7 (15)
Asthenia	5 (17)	2 (12)		7 (15)
Dehydration	7 (24)	0 (0)		7 (15)
Anemia	5 (17)	1 (6)		6 (13)
Arthralgia	5 (17)	1 (6)		6 (13)
Constipation	3 (10)	3 (18)		6 (13)
Depression	3 (10)	3 (18)		6 (13)
Headache	6 (21)	0 (0)		6 (13)
Infection Upper Respiratory	3 (10)	2 (12)		5 (11)
Pain Limb	3 (10)	2 (12)		5 (11)

n = Number of subjects receiving at least one dose of study drug.

pHPT = primary hyperparathyroidism.

In a randomized double-blind, placebo-controlled study of 67 patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo surgery, the most common adverse reactions are listed in Table 4.

Table 4. Adverse Reactions Occurring in 10% of Subjects in a Double-Blind, Placebo-Controlled Study in Patients with Primary Hyperparathyroidism

Adverse Reaction	Placebo (n = 34) n (%)	Cinacalcet (n = 33) n (%)
Nausea	6 (18)	10 (30)
Muscle spasms	0 (0)	6 (18)
Headache	2 (6)	4 (12)
Back pain	2 (6)	4 (12)

n = Number of subjects receiving at least one dose of study drug Coded using MedDRA version 16.0.

Hypocalcemia

In 26-week studies of patients with secondary HPT and CKD on dialysis 66% of patients receiving Sensipar compared with 25% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL, whereas, 29% of patients receiving Sensipar compared with 11% of patients receiving placebo developed at least one serum calcium value less than 7.5 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia.

In a randomized, double-blind, placebo-controlled study in patients with secondary HPT and CKD receiving dialysis in which patients were treated for up to 64 months (mean duration of treatment was 21 months in the cinacalcet group), 75% of patients receiving Sensipar compared with 29% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL and 33% of cinacalcet patients compared with 12% of patients receiving placebo had at least one serum calcium value less than 7.5 mg/dL. Most of the cases of severe hypocalcemia less than 7.5 mg/dL (21/33 = 64%) occurred during the first 6 months. In this trial, 1.1% of patients receiving Sensipar and 0.1% of patients receiving placebo permanently discontinued study drug due to hypocalcemia.

During a placebo-controlled part of a 52-week study in patients with primary HPT who met criteria for parathyroidectomy on the basis of corrected total serum calcium (> 11.3 mg/dL [2.82 mmol/L] and 12.5 mg/dL [3.12 mmol/L]), serum calcium less than 8.4 mg/dL was observed in 6.1% (2/33) of Sensipar-treated patients and 0% (0/34) of placebo-treated patients.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Sensipar. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Rash and hypersensitivity reactions (including angioedema and urticaria), and myalgia
  
• Isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function
  
• Gastrointestinal bleeding

7 Drug Interactions  ⮝

7.1 Strong CYP3A4 Inhibitors

Cinacalcet is partially metabolized by CYP3A4. Dose adjustment of Sensipar may be required if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole). The iPTH and serum calcium concentrations should be closely monitored in these patients [see Clinical Pharmacology (12.3)].

7.2 CYP2D6 Substrates

Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications that are predominantly metabolized by CYP2D6 (e.g., desipramine, metoprolol, and carvedilol) and particularly those with a narrow therapeutic index (e.g., flecainide and most tricyclic antidepressants) [see Clinical Pharmacology (12.3)].

8 Use In Specific Populations  ⮝

8.1 Pregnancy

Risk Summary

Limited case reports of Sensipar use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. In animal reproduction studies, when female rats were exposed to cinacalcet during the period of organogenesis through to weaning at 2-3 times the systemic drug levels (based on AUC) at the maximum recommended human dose (MRHD) of 180 mg/day, peripartum and early postnatal pup loss and reduced pup body weight gain were observed in the presence of maternal hypocalcemia [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day cinacalcet during gestation, no teratogenicity was observed at doses up to 50 mg/kg/day (exposure 4 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Decreased fetal body weights were observed at all doses (less than 1 to 4 times a human oral dose of 180 mg/day based on AUC comparison) in conjunction with maternal toxicity (decreased food consumption and body weight gain).

In pregnant female rabbits given oral gavage doses of 2, 12, 25 mg/kg/day cinacalcet during gestation, no adverse fetal effects were observed (exposures less than with a human oral dose of 180 mg/day based on AUC comparisons). Reductions in maternal food consumption and body weight gain were seen at doses of 12 and 25 mg/kg/day. Cinacalcet has been shown to cross the placental barrier in rabbits.

In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day cinacalcet during gestation through lactation, no adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day (exposures less than with a human therapeutic dose of 180 mg/day based on AUC comparisons). Higher doses of 15 and 25 mg/kg/day cinacalcet (exposures 2 to 3 times a human oral dose of 180 mg/day based on AUC comparisons) were accompanied by maternal signs of hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in postnatal maternal and pup body weight gain.

8.2 Lactation

Risk Summary

There are no data regarding the presence of Sensipar in human milk or effects on the breastfed infant or on milk production. Studies in rats showed that cinacalcet was excreted in the milk. The developmental and health benefits of breastfeeding should be considered along with the mother s clinical need for Sensipar and any potential adverse effects on the breastfed infant from Sensipar or from the underlying maternal condition.

8.4 Pediatric Use

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

The use of Sensipar 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 Sensipar 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 Sensipar. Dosing with Sensipar in Pediatric Study 1 was stopped because of a fatality in a Sensipar-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 Sensipar to the death could not be excluded [see Warnings and Precautions (5.1)]. Study 1 was terminated and changes to Sensipar 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 Sensipar 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 Sensipar dosing regimen for the pediatric population.

8.5 Geriatric Use

Of the total number of subjects (n = 1136) in clinical studies of Sensipar, 26 percent were 65 and over, and 9 percent were 75 and over. No overall differences in the safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Studies (14) and Clinical Pharmacology (12.3)].

8.6 Renal Impairment

No dosage adjustment is necessary for renal impairment [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Patients with moderate and severe hepatic impairment should have serum calcium, serum phosphorus, and iPTH levels monitored closely throughout treatment with Sensipar because cinacalcet exposure (AUC0-infinite) is increased by 2.4 and 4.2 fold, respectively, in these patients [see Clinical Pharmacology (12.3)].

10 Overdosage  ⮝

Overdosage of Sensipar may lead to hypocalcemia. In the event of overdosage, patients should be monitored for signs and symptoms of hypocalcemia and appropriate measures taken to correct serum calcium levels [see Warnings and Precautions (5.1)].

Since Sensipar is highly protein bound, hemodialysis is not an effective treatment for overdosage of Sensipar.

11 Description  ⮝

Sensipar (cinacalcet) is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Sensipar tablets contain the hydrochloride salt of cinacalcet. Its empirical formula is C22H22F3N HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base). It has one chiral center having an R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity.

The hydrochloride salt of cinacalcet is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and slightly soluble in water.

Sensipar tablets are formulated as light-green, film-coated, oval-shaped tablets for oral administration in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet as the free base equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively).

The hydrochloride salt of cinacalcet is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride and has the following structural formula:

Inactive Ingredients

The following are the inactive ingredients in Sensipar tablets: pre-gelatinized starch, microcrystalline cellulose, povidone, crospovidone, colloidal silicon dioxide and magnesium stearate. Tablets are coated with color (Opadry II green), clear film coat (Opadry clear), and carnauba wax.

12 Clinical Pharmacology  ⮝

12.1 Mechanism of Action

The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH synthesis and secretion. Cinacalcet, the active ingredient in Sensipar, directly lowers PTH levels by increasing the sensitivity of the calcium-sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.

12.2 Pharmacodynamics

Reduction in iPTH levels correlated with the plasma cinacalcet concentrations in patients with CKD. The nadir in iPTH level occurs approximately 2 to 6 hours post dose, corresponding with the maximum plasma concentration (Cmax) of cinacalcet. After steady-state cinacalcet concentrations are reached (which occurs within 7 days of dose change), serum calcium concentrations remain constant over the dosing interval in patients with CKD.

Reductions in PTH are associated with a decrease in bone turnover and bone fibrosis in patients with CKD on dialysis and uncontrolled secondary HPT.

12.3 Pharmacokinetics

Absorption and Distribution

After oral administration of cinacalcet, Cmax is achieved in approximately 2 to 6 hours. Cinacalcet Cmax and AUC(0-infinite) were increased by 82% and 68%, respectively, following administration with a high-fat meal compared with fasting in healthy volunteers. The Cmax and AUC(0-infinite) of cinacalcet were increased by 65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared with fasting.

After absorption, cinacalcet concentrations decline in a biphasic fashion with an initial half-life of approximately 6 hours and terminal half-life of 30 to 40 hours. Steady-state drug levels are achieved within 7 days, and the mean accumulation ratio is approximately 2 with once daily oral administration. The median accumulation ratio is approximately 2 to 5 with twice daily oral administration. The AUC and Cmax of cinacalcet increase proportionally over the dose range of 30 to 180 mg once daily. The pharmacokinetic profile of cinacalcet does not change over time with once daily dosing of 30 to 180 mg. The volume of distribution is approximately 1000 L, indicating extensive distribution. Cinacalcet is approximately 93% to 97% bound to plasma protein(s). The ratio of blood cinacalcet concentration to plasma cinacalcet concentration is 0.80 at a blood cinacalcet concentration of 10 ng/mL.

Metabolism and Excretion

Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via -oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug forming dihydrodiols, which are further conjugated with glucuronic acid. The plasma concentrations of the major circulating metabolites, including the cinnamic acid derivatives and glucuronidated dihydrodiols, markedly exceed the parent drug concentrations. The hydrocinnamic acid metabolite and glucuronide conjugates have minimal or no calcimimetic activity. Renal excretion of metabolites was the primary route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the feces.

Specific Populations

Age: Geriatric Population

The pharmacokinetic profile of cinacalcet in geriatric patients (age 65 years, n = 12) is similar to that for patients who are < 65 years of age (n = 268) [see Use in Specific Populations (8.5)].

Hepatic Impairment

The disposition of a 50 mg Sensipar single dose was compared between patients with hepatic impairment and patients with normal hepatic function. Cinacalcet exposure (AUC(0-infinite)) was comparable between healthy volunteers and patients with mild hepatic impairment. However, in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method), cinacalcet exposures (AUC(0-infinite)) were 2.4 and 4.2 fold higher, respectively, than that in healthy volunteers. The mean half-life of cinacalcet increased from 49 hours in healthy volunteers to 65 hours and 84 hours in patients with moderate and severe hepatic impairment, respectively. Protein binding of cinacalcet is not affected by impaired hepatic function [see Use in Specific Populations (8.7)].

Renal Impairment

The pharmacokinetic profile of a 75 mg Sensipar single dose in patients with mild, moderate, and severe renal impairment, and those on hemodialysis or peritoneal dialysis is comparable with that in healthy volunteers [see Use in Specific Populations (8.6)].

Drug Interactions

In vitro studies indicate that cinacalcet is a strong inhibitor of CYP2D6, but not an inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4. In vitro induction studies indicate that cinacalcet is not an inducer of CYP450 enzymes. Tables 5 and 6 list the findings from in vivo drug-drug interaction studies.

Table 5. Effect of co-administered drugs on cinacalcet

Co-administered drug and dosing regimen	Cinacalcet
	Dose*	Mean change in AUC(0-inf)		Mean change in Cmax
200 mg ketoconazole twice daily for 7 days	90 mg on day 5	127%	116%
1500 mg calcium carbonate, single dose	100 mg	6%	5%
80 mg pantoprazole daily for 3 days	90 mg on day 3	1%	3%
2400 mg sevelamer HCl three times a day for 2 days	90 mg on day 1 with first dose of sevelamer	4%	7%

*Single dose.

Table 6. Effect of cinacalcet co-administration on other drugs

Cinacalcet dosing regimen	Co-administered drug
	Name and Dose	Mean change in AUC(0-inf)	Mean change in Cmax
30 mg twice daily for 8 days	25 mg warfarin* tablet	1% for R-warfarin 1% for S-warfarin	10% for R-warfarin 12% for S-warfarin
90 mg daily for 7 days to CYP2D6 extensive metabolizers	50 mg desipramine	264%	75%
90 mg daily for 5 days	2 mg midazolam	5%	5%
25 or 100 mg single dose to CYP2D6 extensive metabolizers	50 mg amitriptyline single dose	21-22% for amitriptyline 17-23% for nortriptyline	13-21% for amitriptyline 11-15% for nortriptyline

*No significant change in prothrombin time.

Single dose on day 5.

Nortriptyline is an active metabolite of amitriptyline.

13 Nonclinical Toxicology  ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity
Standard lifetime dietary carcinogenicity bioassays were conducted in mice and rats. Mice were given cinacalcet at dietary doses of 15, 50, and 125 mg/kg/day in males and 30, 70, and 200 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Rats were given dietary doses of 5, 15, and 35 mg/kg/day in males and 5, 20, and 35 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). No increased incidence of tumors was observed following treatment with cinacalcet.

Mutagenicity
Cinacalcet was not genotoxic in the Ames bacterial mutagenicity assay, nor in the Chinese Hamster Ovary (CHO) cell HGPRT forward mutation assay and CHO cell chromosomal aberration assay, with and without metabolic activation, nor in the in vivo mouse micronucleus assay.

Impairment of Fertility
Female rats were given oral gavage doses of 5, 25, and 75 mg/kg/day cinacalcet beginning 2 weeks before mating and continuing through gestation day 7. Male rats were given oral doses 4 weeks prior to mating, during mating (3 weeks) and 2 weeks postmating. No effects were observed in male or female fertility at 5 and 25 mg/kg/day (exposures up to 3 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). At 75 mg/kg/day, there were slight adverse effects (slight decreases in body weight and food consumption) in males and females.

14 Clinical Studies  ⮝

14.1 Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

Three 6-month, multicenter, randomized, double-blind, placebo-controlled clinical studies of similar design were conducted in patients with CKD on dialysis. A total of 665 patients were randomized to Sensipar and 471 patients to placebo. The mean age of the patients was 54 years, 62% were male, and 52% were Caucasian. The average baseline iPTH level by the Nichols IRMA was 712 pg/mL, with 26% of the patients having a baseline iPTH level > 800 pg/mL. The mean baseline Ca x P product was 61 mg2/dL2. The average duration of dialysis prior to study enrollment was 67 months. Ninety-six percent of patients were on hemodialysis and 4% on peritoneal dialysis. At study entry, 66% of the patients were receiving vitamin D sterols and 93% were receiving phosphate binders. Sensipar (or placebo) was initiated at a dose of 30 mg once daily and titrated every 3 or 4 weeks to a maximum dose of 180 mg once daily to achieve an iPTH of 250 pg/mL. The dose was not increased if a patient had any of the following: iPTH 200 pg/mL, serum calcium < 7.8 mg/dL, or any symptoms of hypocalcemia. If a patient experienced symptoms of hypocalcemia or had a serum calcium < 8.4 mg/dL, calcium supplements and/or calcium-based phosphate binders could be increased. If these measures were insufficient, the vitamin D dose could be increased. Approximately 70% of patients in the Sensipar arm and 80% of the patients in the placebo arm completed the 6-month studies. In the primary efficacy analysis, 40% of the patients on Sensipar and 5% of placebo-treated patients achieved an iPTH 250 pg/mL (p < 0.001) (Table 7, Figure 1). These studies showed that Sensipar reduced iPTH while lowering Ca x P, calcium, and phosphorus levels (Table 7, Figure 2). The median dose of Sensipar at the completion of the studies was 90 mg. Patients with milder disease typically required lower doses.

Similar results were observed when either the iPTH or biointact PTH (biPTH) assay was used to measure PTH levels in CKD patients on dialysis; treatment with cinacalcet did not alter the relationship between iPTH and biPTH.

Table 7. Effects of Sensipar on iPTH, Ca x P, Serum Calcium, and Serum Phosphorus in 6-month Phase 3 Studies (Patients on Dialysis)

				Study 1		Study 2		Study 3
				Placebo	Sensipar	Placebo	Sensipar	Placebo	Sensipar
				(n = 205)	(n = 205)	(n = 165)	(n = 166)	(n = 101)	(n = 294)
iPTH
		Baseline (pg/mL): Median Mean (SD)		535 651 (398)	537 636 (341)	556 630 (317)	547 652 (372)	670 832 (486)	703 848 (685)
		Evaluation Phase (pg/mL)		563	275	592	238	737	339
		Median Percent Change		+3.8	-48.3	+8.4	-54.1	+2.3	-48.2
		Patients Achieving Primary Endpoint (iPTH 250 pg/mL) (%)a		4%	41%**	7%	46%**	6%	35%**
		Patients Achieving 30% Reduction in iPTH (%)a		11%	61%	12%	68%	10%	59%
		Patients Achieving iPTH 250 pg/mL and Ca x P < 55 mg2/dL2 (%)		1%	32%	5%	35%	5%	28%
Ca x P
		Baseline (mg2/dL2)		62	61	61	61	61	59
		Evaluation Phase (mg2/dL2)		59	52	59	47	57	48
		Median Percent Change		-2.0	-14.9	-3.1	-19.7	-4.8	-15.7
Calcium
	Baseline (mg/dL)			9.8	9.8	9.9	10.0	9.9	9.8
	Evaluation Phase (mg/dL)			9.9	9.1	9.9	9.1	10.0	9.1
	Median Percent Change			+0.5	-5.5	+0.1	-7.4	+0.3	-6.0
Phosphorus
	Baseline (mg/dL)			6.3	6.1	6.1	6.0	6.1	6.0
	Evaluation Phase (mg/dL)			6.0	5.6	5.9	5.1	5.6	5.3
	Median Percent Change			-1.0	-9.0	-2.4	-12.4	-5.6	-8.6
** p < 0.001 compared with placebo; p-values presented for primary endpoint only. a iPTH value based on averaging over the evaluation phase (defined as weeks 13 to 26 in studies 1 and 2 and weeks 17 to 26 in study 3). Values shown are medians unless indicated otherwise.

Figure 1. Mean (SE) iPTH Values (Pooled Phase 3 Studies)

Data are presented for patients who completed the studies; Placebo (n = 342), Sensipar (n = 439).

Figure 2. Mean (SE) Ca x P Values (Pooled Phase 3 Studies)

Data are presented for patients who completed the studies; Placebo (n = 342), Sensipar (n = 439).

Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment.

Sensipar decreased iPTH and Ca x P levels regardless of disease severity (i.e., baseline iPTH value), duration of dialysis, and whether or not vitamin D sterols were administered. Approximately 60% of patients with mild (iPTH 300 to 500 pg/mL), 41% with moderate (iPTH > 500 to 800 pg/mL), and 11% with severe (iPTH > 800 pg/mL) secondary HPT achieved a mean iPTH value of 250 pg/mL. Plasma iPTH levels were measured using the Nichols IRMA.

14.2 Parathyroid Carcinoma

Twenty-nine patients with Parathyroid Carcinoma were enrolled in a single-arm, open-label study. The study consisted of two phases, a dose-titration phase and a maintenance phase. Patients initially received 30 mg cinacalcet twice daily and then were titrated every 2 weeks to a maximum dose of 90 mg four times daily. Dosage escalation during the variable-length (2 to 16 weeks) titration phase continued until the serum calcium concentration was 10 mg/dL (2.5 mmol/L), the patient reached the highest possible dosage, or adverse events precluded further dosage increases.

Twenty-nine patients entered the study. The median exposure to cinacalcet was 229 days (range: 1 to 1051). At baseline the mean (SE) serum calcium was 14.1 (0.4) mg/dL. At the end of the titration phase, the mean (SE) serum calcium was 12.4 (0.5) mg/dL, which is a mean reduction of 1.7 (0.6) mg/dL from baseline. Figure 3 illustrates mean serum calcium (mg/dL) over time for all patients still on study at each time point from the beginning of titration to study visit week 80. Daily dose during the study ranged from 30 mg twice daily to 90 mg four times daily.

Figure 3. Serum Calcium Values in Patients with Parathyroid Carcinoma Receiving Sensipar at Baseline, Titration, and Maintenance Phase

n = Number of patients with non-missing values at the timepoint.

End of Titration (EOT) phase could occur at any visit from week 2 to 16. Patients at EOT are those who completed titration.

14.3 Patients with Hypercalcemia Due to Primary Hyperparathyroidism

Seventeen patients with severe hypercalcemia due to primary HPT, who had failed or had contraindications to parathyroidectomy, participated in an open-label, single-arm study. The study consisted of two phases, a dose-titration phase and a maintenance phase. In this trial, severe hypercalcemia was defined as a screening serum calcium level of > 12.5 mg/dL. Patients initially received 30 mg cinacalcet twice daily and then were titrated every 2 weeks to a maximum dose of 90 mg 4 times daily. Dosage escalation during the variable-length (2 to 16 weeks) titration phase continued until the serum calcium concentration was 10 mg/dL (2.5 mmol/L), the patient reached the highest possible dosage, or adverse events precluded further dosage increases.

Seventeen patients entered the study. The median exposure to cinacalcet was 270 days (range: 32 to 1,105). At baseline the mean (SE) serum calcium was 12.7 (0.2) mg/dL. At the end of the titration phase the mean (SE) serum calcium was 10.4 (0.3) mg/dL, which is a mean reduction of 2.3 (0.3) mg/dL from baseline. Figure 4 illustrates mean serum calcium (mg/dL) over time for all patients still on study at each time point from the beginning of titration to study visit week 80. Daily dose during the study ranged from 30 mg twice a day to 90 mg four times a day.

Figure 4. Mean Serum Calcium (SE) at Baseline, End of Titration, and Scheduled Maintenance Visits (Patients with Severe intractable primary HPT)

n = Number of patients with non-missing values at the timepoint.

End of Titration (EOT) phase could occur at any visit from week 2 to 16. Patients at EOT are those who completed titration.

Sixty-seven patients with primary HPT who met criteria for parathyroidectomy on the basis of corrected total serum calcium (> 11.3 mg/dL [2.82 mmol/L] and 12.5 mg/dL [3.12 mmol/L]), but who were unable to undergo parathyroidectomy participated in a randomized, double-blind, placebo-controlled study. A total of 33 patients were randomized to Sensipar and 34 patients randomized to placebo. The mean age of the patients was 72 years, 52% were female, 61% were Caucasian, and 5% were Blacks. The study started with a 12-week titration phase, followed by a 16-week efficacy-assessment phase. Cinacalcet was initiated at a dose of 30 mg twice daily and titrated to maintain a corrected total serum calcium concentration within the normal range. During the efficacy period a significantly higher percentage of cinacalcet-treated patients compared with the placebo-treated patients achieved mean corrected total serum calcium concentration ( 10.3 mg/dL [2.57 mmol/L], 75.8% vs 0%, p < 0.001) and 1 mg/dL [0.25 mmol/L] decrease from baseline in mean corrected total serum calcium concentration (84.8% vs 5.9%, p < 0.001). The median dose of Sensipar at the completion of the study was 60 mg/day.

16 How Supplied/storage And Handling  ⮝

Sensipar 30 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with AMG on one side and 30 on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-073-30)

Sensipar 60 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with AMG on one side and 60 on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-074-30)

Sensipar 90 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with AMG on one side and 90 on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-075-30)

Storage

Store at 25 C (77 F); excursions permitted from 15 C to 30 C (59 F to 86 F). [See USP controlled room temperature].

Storage ⮝

Store at 25 C (77 F); excursions permitted from 15 C to 30 C (59 F to 86 F). [See USP controlled room temperature].

Cinacalcet Hydrochloride ⮝

SENSIPAR cinacalcet hydrochloride tablet, coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-4470(NDC:55513-073) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CINACALCET HYDROCHLORIDE (UNII: 1K860WSG25) (CINACALCET - UNII:UAZ6V7728S) CINACALCET 30 mg

Inactive Ingredients Ingredient Name Strength CARNAUBA WAX (UNII: R12CBM0EIZ) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) CROSPOVIDONE, UNSPECIFIED (UNII: 2S7830E561) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Product Characteristics Color GREEN (light green) Score no score Shape OVAL Size 10mm Flavor Imprint Code AMG;30 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-4470-0 30 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 08/19/2019

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021688 04/04/2004

Labeler - A-S Medication Solutions (830016429)

Establishment
Name	Address	ID/FEI	Business Operations
A-S Medication Solutions		830016429	RELABEL(50090-4470)

Revised: 8/2019 Document Id: a261c7fd-485e-4cfe-b8fa-bde13855fcca 34391-3 Set id: 5475c673-67d1-4fb9-ad57-b1bd1f0039e1 Version: 2 Effective Time: 20190829 A-S Medication Solutions

Principal Display Panel ⮝

AMGEN

NDC 55513-075-30

Sensipar

(cinacalcet) Tablets

Rx Only

30 tablets

90 mg

Each tablet contains:

Cinacalcet 90 mg (equivalent to 99 mg of cinacalcet hydrochloride).

Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F).

See USP controlled room temperature.

Dispense in tight, light-resistant container per USP.

Dosage : See Package Insert.

2004-2018 Amgen Inc. All rights reserved.

Patent : http://pat.amgen.com/sensipar/

Distributed by : Amgen,

One Amgen Center Drive,

Thousand Oaks, CA 91320-1799

Made in Japan

SENSIPAR cinacalcet hydrochloride tablet, coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55513-073 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CINACALCET HYDROCHLORIDE (UNII: 1K860WSG25) (CINACALCET - UNII:UAZ6V7728S) CINACALCET 30 mg

Inactive Ingredients Ingredient Name Strength CARNAUBA WAX (UNII: R12CBM0EIZ) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) CROSPOVIDONE (UNII: 2S7830E561) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE (UNII: FZ989GH94E) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Product Characteristics Color GREEN (light green) Score no score Shape OVAL Size 10mm Flavor Imprint Code AMG;30 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55513-073-30 30 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 04/04/2004

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021688 04/04/2004

SENSIPAR cinacalcet hydrochloride tablet, coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55513-074 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CINACALCET HYDROCHLORIDE (UNII: 1K860WSG25) (CINACALCET - UNII:UAZ6V7728S) CINACALCET 60 mg

Inactive Ingredients Ingredient Name Strength CARNAUBA WAX (UNII: R12CBM0EIZ) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) CROSPOVIDONE (UNII: 2S7830E561) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE (UNII: FZ989GH94E) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Product Characteristics Color GREEN (light green) Score no score Shape OVAL Size 12mm Flavor Imprint Code AMG;60 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55513-074-30 30 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 04/04/2004

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021688 04/04/2004

SENSIPAR cinacalcet hydrochloride tablet, coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55513-075 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CINACALCET HYDROCHLORIDE (UNII: 1K860WSG25) (CINACALCET - UNII:UAZ6V7728S) CINACALCET 90 mg

Inactive Ingredients Ingredient Name Strength CARNAUBA WAX (UNII: R12CBM0EIZ) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) CROSPOVIDONE (UNII: 2S7830E561) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE (UNII: FZ989GH94E) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Product Characteristics Color GREEN (light green) Score no score Shape OVAL Size 14mm Flavor Imprint Code AMG;90 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55513-075-30 30 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 04/04/2004

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021688 04/04/2004

Labeler - Amgen Inc (039976196)

Establishment
Name	Address	ID/FEI	Business Operations
Patheon Inc.		240769596	ANALYSIS(55513-073, 55513-074, 55513-075) , LABEL(55513-073, 55513-074, 55513-075) , MANUFACTURE(55513-073, 55513-074, 55513-075) , PACK(55513-073, 55513-074, 55513-075)

Revised: 3/2019 Document Id: 09076806-c701-4ce9-bc1b-ead21a539c7c 34391-3 Set id: 45028573-13c4-4c8b-ae62-6c75bba97c81 Version: 130 Effective Time: 20190329 Amgen Inc

No Title 1572454788 ⮝

2.2 Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

2.3 Patients with Parathyroid Carcinoma and Primary Hyperparathyroidism

2.4 Monitoring for Hypocalcemia

How Supplied ⮝

Sensipar 30 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with AMG on one side and 30 on the opposite side.

Sensipar 60 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with AMG on one side and 60 on the opposite side.

Sensipar 90 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with AMG on one side and 90 on the opposite side.

They are supplied by State of Florida DOH Central Pharmacy as follows:

NDC	Strength	Quantity/Form	Color	Source Prod. Code
53808-0577-1	30 mg	30 Tablets in a Blister Pack	light green	55513-073
53808-0578-1	60 mg	30 Tablets in a Blister Pack	light green	55513-074

Storage

Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F). [See USP controlled room temperature].

Rx Only

This product, or its use, may be covered by one or more US Patents including US Patent Nos. 6313146, 6211244, 6031003 and 6011068, in addition to others, including patents pending.

No Title 1572455420 ⮝

[Amgen Logo]

Sensipar (cinacalcet) Tablets
Manufactured by:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799

Patent: http://pat.amgen.com/sensipar/
2004-2014 Amgen Inc. All rights reserved.
www.sensipar.com
1-800-77-AMGEN (1-800-772-6436)
1xxxxxx -, v10

Cinacalcet Hcl ⮝

SENSIPAR cinacalcet hydrochloride tablet, coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68151-4740(NDC:55513-073) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CINACALCET HYDROCHLORIDE (UNII: 1K860WSG25) (CINACALCET - UNII:UAZ6V7728S) CINACALCET 30 mg

Inactive Ingredients Ingredient Name Strength CARNAUBA WAX (UNII: R12CBM0EIZ) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) CROSPOVIDONE (UNII: 68401960MK) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONES (UNII: FZ989GH94E) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Product Characteristics Color GREEN (light green) Score no score Shape OVAL Size 10mm Flavor Imprint Code AMG;30 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68151-4740-3 1 in 1 PACKAGE; Type 0: Not a Combination Product 04/04/2004

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021688 04/04/2004

Labeler - Carilion Materials Management (079239644)

Establishment
Name	Address	ID/FEI	Business Operations
Carilion Materials Management		079239644	REPACK(68151-4740)

Revised: 8/2016 Document Id: 7af108a7-38df-4b45-93ec-15a684a00cb1 34391-3 Set id: 8ff022bc-4627-4965-beb1-968deb5b56bc Version: 3 Effective Time: 20160806 Carilion Materials Management

Description ⮝

Sensipar (cinacalcet) is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Its empirical formula is C22H22F3N HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base). It has one chiral center having an R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity.

Cinacalcet is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and slightly soluble in water.

Sensipar tablets are formulated as light-green, film-coated, oval-shaped tablets for oral administration in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet as the free base equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively).

Cinacalcet is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride and has the following structural formula:

Inactive Ingredients: Sensipar tablets are comprised of the active ingredient, and the following inactive ingredients: pre-gelatinized starch, microcrystalline cellulose, povidone, crospovidone, colloidal silicon dioxide, and magnesium stearate. Tablets are coated with color (Opadry II green), clear film-coat (Opadry clear) and carnauba wax.

Clinical Pharmacology ⮝

Mechanism of Action

Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increases in parathyroid hormone (PTH) levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary hyperparathyroidism are to lower levels of PTH, calcium, and phosphorus in the blood, in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis.

The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Sensipar directly lowers PTH levels by increasing the sensitivity of the calcium-sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.

Pharmacokinetics

Absorption and Distribution: After oral administration of cinacalcet, maximum plasma concentration (Cmax) is achieved in approximately 2 to 6 hours. A food-effect study in healthy volunteers indicated that the Cmax and area under the curve (AUC(0-inf)) were increased 82% and 68%, respectively, when cinacalcet was administered with a high-fat meal compared to fasting. Cmax and AUC(0-inf) of cinacalcet were increased 65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared to fasting.

After absorption, cinacalcet concentrations decline in a biphasic fashion with a terminal half-life of 30 to 40 hours. Steady-state drug levels are achieved within 7 days. The mean accumulation ratio is approximately 2 with once-daily oral administration. The median accumulation ratio is approximately 2 to 5 with twice-daily oral administration. The AUC and Cmax of cinacalcet increase proportionally over the dose range of 30 to 180 mg once daily. The pharmacokinetic profile of cinacalcet does not change over time with once-daily dosing of 30 to 180 mg. The volume of distribution is high (approximately 1000 L), indicating extensive distribution. Cinacalcet is approximately 93 to 97% bound to plasma protein(s). The ratio of blood cinacalcet concentration to plasma cinacalcet concentration is 0.80 at a blood cinacalcet concentration of 10 ng/mL.

Metabolism and Excretion: Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6 and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via -oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug to form dihydrodiols, which are further conjugated with glucuronic acid. The plasma concentrations of the major circulating metabolites including the cinnamic acid derivatives and glucuronidated dihydrodiols markedly exceed parent drug concentrations. The hydrocinnamic acid metabolite was shown to be inactive at concentrations up to 10 M in a cell-based assay measuring calcium-receptor activation. The glucuronide conjugates formed after cinacalcet oxidation were shown to have a potency approximately 0.003 times that of cinacalcet in a cell-based assay measuring a calcimimetic response. Renal excretion of metabolites was the primary route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the feces.

Special Populations

Hepatic Insufficiency: The disposition of a 50 mg cinacalcet single dose was compared in patients with hepatic impairment and subjects with normal hepatic function. Cinacalcet exposure, AUC(0-inf), was comparable between healthy volunteers and patients with mild hepatic impairment. However, in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method), cinacalcet exposures as defined by the AUC(0-inf) were 2.4 and 4.2 times higher, respectively, than that in normals. The mean half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively. Protein binding of cinacalcet is not affected by impaired hepatic function. See PRECAUTIONS and DOSAGE AND ADMINISTRATION.

Renal Insufficiency: The pharmacokinetic profile of a 75 mg Sensipar single dose in patients with mild, moderate, and severe renal insufficiency, and those on hemodialysis or peritoneal dialysis is comparable to that in healthy volunteers.

Geriatric Patients: The pharmacokinetic profile of Sensipar in geriatric patients (age 65, n = 12) is similar to that for patients who are < 65 years of age (n = 268).

Pediatric Patients: The pharmacokinetics of Sensipar have not been studied in patients < 18 years of age.

Drug Interactions

An in vitro study indicates that cinacalcet is a strong inhibitor of CYP2D6, but not of CYP1A2, CYP2C9, CYP2C19, and CYP3A4. In vitro induction studies indicate that cinacalcet is not an inducer of CYP450 enzymes.

Ketoconazole: Cinacalcet AUC(0-inf) and Cmax increased 2.3 and 2.2 times, respectively, when a single 90 mg cinacalcet dose on Day 5 was administered to subjects treated with 200 mg ketoconazole twice daily for 7 days compared to 90 mg cinacalcet given alone (see DOSAGE AND ADMINISTRATION).

Calcium Carbonate: No significant pharmacokinetic interaction was observed when a single dose of 1500 mg calcium carbonate was coadministered with 100 mg cinacalcet.

Pantoprazole: No significant pharmacokinetic interaction was observed when cinacalcet 90 mg was administered to subjects treated with 80 mg pantoprazole daily for 3 days.

Sevelamer HCl: No significant pharmacokinetic interaction was observed when 2400 mg sevelamer HCl was coadministered with 90 mg cinacalcet tablet (subjects subsequently received 2400 mg sevelamer HCl two more times on Day 1 and three more times on Day 2).

Desipramine: The effect of cinacalcet (90 mg) on the pharmacokinetics of desipramine (50 mg) has been studied in healthy subjects who were CYP2D6 extensive metabolizers. The AUC and Cmax of desipramine increased by 3.6 (296.5-446.7%) and 1.75 (157.5-194.9%) fold, respectively, in the presence of cinacalcet. This indicates that cinacalcet is a strong in vivo inhibitor of CYP2D6 and can increase the blood concentrations of drugs metabolized by CYP2D6.

Amitriptyline: Concurrent administration of 25 mg or 100 mg cinacalcet with 50 mg amitriptyline increased amitriptyline exposure and nortriptyline (active metabolite) exposure by approximately 20% in CYP2D6 extensive metabolizers.

Warfarin: R- and S-warfarin pharmacokinetics and warfarin pharmacodynamics were not affected in subjects treated with warfarin 25 mg who received cinacalcet 30 mg twice daily. The lack of effect of cinacalcet on the pharmacokinetics of R- and S-warfarin and the absence of auto-induction upon multiple dosing in patients indicates that cinacalcet is not an inducer of CYP2C9 in humans.

Midazolam: There were no significant differences in the pharmacokinetics of midazolam, a CYP3A4 and CYP3A5 substrate, in subjects receiving 90 mg cinacalcet once daily for 5 days and a single dose of 2 mg midazolam on day 5 as compared to those of subjects receiving 2 mg midazolam alone. This suggests that cinacalcet would not affect the pharmacokinetics of drugs predominantly metabolized by CYP3A4 and CYP3A5.

Pharmacodynamics

Reduction in intact PTH (iPTH) levels correlated with cinacalcet concentrations in CKD patients. The nadir in iPTH level occurs approximately 2 to 6 hours post dose, corresponding with the Cmax of cinacalcet. After steady state is reached, serum calcium concentrations remain constant over the dosing interval in CKD patients.

Clinical Studies ⮝

Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

Three 6-month, multicenter, randomized, double-blind, placebo-controlled clinical studies of similar design were conducted in CKD patients on dialysis. A total of 665 patients were randomized to Sensipar and 471 patients to placebo. The mean age of the patients was 54 years, 62% were male, and 52% Caucasian. The average baseline iPTH level by the Nichols intact immunoradiometric assay (IRMA) was 712 pg/mL, with 26% of the patients having a baseline iPTH level > 800 pg/mL. The mean baseline Ca x P ion product was 61 mg2/dL2. The average duration of dialysis prior to study enrollment was 67 months. Ninety-six percent of patients were on hemodialysis and 4% peritoneal dialysis. At study entry, 66% of the patients were receiving vitamin D sterols and 93% were receiving phosphate binders. Sensipar (or placebo) was initiated at a dose of 30 mg once daily and titrated every 3 or 4 weeks to a maximum dose of 180 mg once daily to achieve an iPTH of 250 pg/mL. The dose was not increased if a patient had any of the following: iPTH < 200 pg/mL, serum calcium < 7.8 mg/dL, or any symptoms of hypocalcemia. If a patient experienced symptoms of hypocalcemia or had a serum calcium < 8.4 mg/dL, calcium supplements and/or calcium-based phosphate binders could be increased. If these measures were insufficient, the vitamin D dose could be increased. Approximately 70% of the Sensipar patients and 80% of the placebo patients completed the 6-month studies. In the primary efficacy analysis, 40% of Sensipar patients and 5% of placebo patients achieved an iPTH 250 pg/mL (p<0.001) (Table 1, Figure 1). Secondary efficacy parameters also improved in patients treated with Sensipar . These studies showed that Sensipar reduced PTH while lowering Ca x P, calcium and phosphorus levels (Table 1, Figure 2). The median dose of Sensipar at the completion of the studies was 90 mg. Patients with milder disease typically required lower doses.

Similar results were observed when either the iPTH or bio-intact PTH (biPTH) assay was used to measure PTH levels in CKD patients on dialysis; treatment with cinacalcet did not alter the relationship between iPTH and biPTH.

Table 1. Effects of Sensipar on iPTH, Ca x P, Serum Calcium, and Serum Phosphorus in 6-month Phase 3 Studies (Patients on Dialysis)

		Study 1		Study 2		Study 3
		Placebo (N = 205)	Sensipar (N = 205)	Placebo (N = 165)	Sensipar (N = 166)	Placebo (N = 101)	Sensipar (N = 294)
* iPTH value based on averaging over the evaluation phase (defined as weeks 13 to 26 in studies 1 and 2 and weeks 17 to 26 in study 3) Values shown are medians unless indicated otherwise p < 0.001 compared to placebo; p-values presented for primary endpoint only
iPTH
Baseline (pg/mL):	Median Mean (SD)	535 651 (398)	537 636 (341)	556 630 (317)	547 652 (372)	670 832 (486)	703 848 (685)
Evaluation Phase (pg/mL)		563	275	592	238	737	339
Median Percent Change		+3.8	-48.3	+8.4	-54.1	+2.3	-48.2
Patients Achieving Primary Endpoint (iPTH 250 pg/mL) (%)*		4%	41%	7%	46%	6%	35%
Patients Achieving 30% Reduction in iPTH (%)*		11%	61%	12%	68%	10%	59%
Patients Achieving iPTH 250 pg/mL and Ca x P < 55 mg2/dL2 (%)		1%	32%	5%	35%	5%	28%
Ca x P
Baseline (mg2/dL2)		62	61	61	61	61	59
Evaluation Phase (mg2/dL2)		59	52	59	47	57	48
Median Percent Change		-2.0	-14.9	-3.1	-19.7	-4.8	-15.7
Calcium
Baseline (mg/dL)		9.8	9.8	9.9	10.0	9.9	9.8
Evaluation Phase (mg/dL)		9.9	9.1	9.9	9.1	10.0	9.1
Median Percent Change		+0.5	-5.5	+0.1	-7.4	+0.3	-6.0
Phosphorus
Baseline (mg/dL)		6.3	6.1	6.1	6.0	6.1	6.0
Evaluation Phase (mg/dL)		6.0	5.6	5.9	5.1	5.6	5.3
Median Percent Change		-1.0	-9.0	-2.4	-12.4	-5.6	-8.6

Figure 1. Mean (SE) iPTH Values (Pooled Phase 3 Studies)

Data are presented for patients who completed the studies; Placebo (N = 342), Sensipar (N = 439).

Figure 2. Mean (SE) Ca x P Values (Pooled Phase 3 Studies)

Data are presented for patients who completed the studies; Placebo (N = 342), Sensipar (N = 439).

Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment. Sensipar decreased iPTH and Ca x P levels regardless of disease severity (i.e., baseline iPTH value), duration of dialysis, and whether or not vitamin D sterols were administered. Approximately 60% of patients with mild (iPTH 300 to 500 pg/mL), 41% with moderate (iPTH > 500 to 800 pg/mL), and 11% with severe (iPTH > 800 pg/mL) secondary HPT achieved a mean iPTH value of 250 pg/mL. Plasma iPTH levels were measured using the Nichols IRMA.

Parathyroid Carcinoma

Ten patients with parathyroid carcinoma were enrolled in an open-label study. The study consisted of 2 phases, a dose-titration phase and a maintenance phase.

The range of exposure was 2 to 16 weeks in the titration phase (n = 10) and 16 to 48 weeks (n = 3) for the maintenance phase. Baseline mean (SD) serum calcium was 14.7 (1.8) mg/dL. The range of change from baseline to last measurement was 7.5 to 2.7 mg/dL during the titration phase and 7.4 to 0.9 mg/dL during the maintenance phase (Figure 3). No patients maintained a serum calcium level within the normal range. The doses ranged from 70 mg twice daily to 90 mg four times daily for patients in the maintenance phase.

Figure 3. Serum Calcium Values in Parathyroid Carcinoma Patients Receiving Sensipar at Baseline, Titration and Maintenance Phase

Solid lines represent individual patient data

B = baseline; T = last value in titration phase; M = last value in maintenance phase

Reference lines (dashed) show the normal range for serum calcium values

Contraindications  ⮝

Sensipar is contraindicated in patients with hypersensitivity to any component(s) of this product.

Warnings ⮝

Seizures

In three clinical studies of CKD patients on dialysis, 5% of the patients in both the Sensipar and placebo groups reported a history of seizure disorder at baseline. During the trials, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (9/656) of Sensipar -treated patients and 0.4% (2/470) of placebo-treated patients. Five of the nine Sensipar -treated patients had a history of a seizure disorder and two were receiving anti-seizure medication at the time of their seizure. Both placebo-treated patients had a history of seizure disorder and were receiving anti-seizure medication at the time of their seizure. 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. Therefore, serum calcium levels should be closely monitored in patients receiving Sensipar , particularly in patients with a history of a seizure disorder (see PRECAUTIONS, Hypocalcemia ).

Hypotension and/or Worsening Heart Failure

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 Sensipar could not be completely excluded and which may be mediated by reductions in serum calcium levels. Clinical trial data showed hypotension occurred in 7% of Sensipar -treated patients and 12% of placebo-treated patients, heart failure occurred in 2% of both Sensipar - and placebo-treated patients.

Precautions ⮝

General

Hypocalcemia

Sensipar lowers serum calcium, and therefore patients should be carefully monitored for the occurrence of hypocalcemia. Potential manifestations of hypocalcemia include paresthesias, myalgias, cramping, tetany, and convulsions.

Sensipar treatment should not be initiated if serum calcium is less than the lower limit of the normal range (8.4 mg/dL). Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar . Once the maintenance dose has been established, serum calcium should be measured approximately monthly (see DOSAGE AND ADMINISTRATION).

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 Sensipar until serum calcium levels reach 8.0 mg/dL, and/or symptoms of hypocalcemia have resolved. Treatment should be re-initiated using the next lowest dose of Sensipar (see DOSAGE AND ADMINISTRATION).

In the 26-week studies of patients with CKD on dialysis, 66% of patients receiving Sensipar compared with 25% of patients receiving placebo developed at least one serum calcium value < 8.4 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia.

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

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 Sensipar for one year. Three patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with Sensipar . Two of these patients had iPTH levels below 100 pg/mL at multiple time points during the study. In the three 6-month, phase 3 studies conducted in CKD patients on dialysis, 11% of patients treated with Sensipar had mean iPTH values below 100 pg/mL during the efficacy-assessment phase. If iPTH levels decrease below the NKF-K/DOQI recommended target range (150-300 pg/mL) 1 in patients treated with Sensipar , the dose of Sensipar and/or vitamin D sterols should be reduced or therapy discontinued.

Hepatic Insufficiency

Cinacalcet exposure as assessed by AUC(0-inf) in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method) were 2.4 and 4.2 times higher, respectively, than that in normals. Patients with moderate and severe hepatic impairment should be monitored throughout treatment with Sensipar (see CLINICAL PHARMACOLOGY, Pharmacokinetics and DOSAGE AND ADMINISTRATION).

Information for Patients

It is recommended that Sensipar be taken with food or shortly after a meal. Tablets should be taken whole and should not be divided.

Laboratory Tests

Patients with CKD on Dialysis with Secondary Hyperparathyroidism

Serum calcium and serum phosphorus should be measured within 1 week and iPTH should be measured 1 to 4 weeks after initiation or dose adjustment of Sensipar . Once the maintenance dose has been established, serum calcium and serum phosphorus should be measured approximately monthly, and PTH every 1 to 3 months (see DOSAGE AND ADMINISTRATION). All iPTH measurements during the Sensipar trials were obtained using the Nichols IRMA.

In patients with end-stage renal disease, testosterone levels are often below the normal range. In a placebo-controlled trial in patients with CKD on dialysis, there were reductions in total and free testosterone in male patients following six months of treatment with Sensipar . Levels of total testosterone decreased by a median of 15.8% in the Sensipar -treated patients and by 0.6% in the placebo-treated patients. Levels of free testosterone decreased by a median of 31.3% in the Sensipar -treated patients and by 16.3% in the placebo-treated patients. The clinical significance of these reductions in serum testosterone is unknown.

Patients with Parathyroid Carcinoma

Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar . Once maintenance dose levels have been established, serum calcium should be measured every 2 months (see DOSAGE AND ADMINISTRATION).

Drug Interactions and/or Drug/Laboratory Test Interactions

See CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Interactions.

Effect of Sensipar on other drugs:

Drugs metabolized by cytochrome P450 2D6 (CYP2D6): Sensipar is a strong in vitro, as well as in vivo, inhibitor of CYP2D6. Therefore, dose adjustments of concomitant medications that are predominantly metabolized by CYP2D6 (eg, metoprolol and carvedilol) and particularly those with a narrow therapeutic index (eg, flecainide, vinblastine, thioridazine and most tricyclic antidepressants) may be required.

Desipramine: Concurrent administration of cinacalcet (90 mg) with desipramine (50 mg) increased the exposure of desipramine by 3.6 fold in CYP2D6 extensive metabolizers.

Amitriptyline: Concurrent administration of 25 mg or 100 mg cinacalcet with 50 mg amitriptyline increased amitriptyline exposure and nortriptyline (active metabolite) exposure by approximately 20% in CYP2D6 extensive metabolizers.

Midazolam: There were no significant differences in the pharmacokinetics of midazolam, a CYP3A4 and CYP3A5 substrate, in subjects receiving 90 mg cinacalcet once daily for 5 days and a single dose of 2 mg midazolam on day 5 as compared to those of subjects receiving 2 mg midazolam alone. This suggests that cinacalcet would not affect the pharmacokinetics of drugs predominantly metabolized by CYP3A4 and CYP3A5.

Effect of other drugs on Sensipar :

Sensipar is metabolized by multiple cytochrome P450 enzymes, primarily CYP3A4, CYP2D6, and CYP1A2.

Ketoconazole: Sensipar is metabolized in part by CYP3A4. Co-administration of ketoconazole, a strong inhibitor of CYP3A4, increased cinacalcet exposure following a single 90 mg dose of Sensipar by 2.3 fold. Dose adjustment of Sensipar may be required and PTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, erythromycin, itraconazole; see DOSAGE AND ADMINISTRATION).

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenicity: Standard lifetime dietary carcinogenicity bioassays were conducted in mice and rats. Mice were given dietary doses of 15, 50, 125 mg/kg/day in males and 30, 70, 200 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Rats were given dietary doses of 5, 15, 35 mg/kg/day in males and 5, 20, 35 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). No increased incidence of tumors was observed following treatment with cinacalcet.

Mutagenicity: Cinacalcet was not genotoxic in the Ames bacterial mutagenicity assay or in the Chinese Hamster Ovary (CHO) cell HGPRT forward mutation assay and CHO cell chromosomal aberration assay, with and without metabolic activation or in the in vivo mouse micronucleus assay.

Impairment of Fertility: Female rats were given oral gavage doses of 5, 25, 75 mg/kg/day beginning 2 weeks before mating and continuing through gestation day 7. Male rats were given oral doses 4 weeks prior to mating, during mating (3 weeks) and 2 weeks post-mating. No effects were observed in male or female fertility at 5 and 25 mg/kg/day (exposures up to 3 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). At 75 mg/kg/day, there were slight adverse effects (slight decreases in body weight and food consumption) in males and females.

Pregnancy Category C

In pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day during gestation no teratogenicity was observed at doses up to 50 mg/kg/day (exposure 4 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Decreased fetal body weights were observed at all doses (less than 1 to 4 times a human oral dose of 180 mg/day based on AUC comparison) in conjunction with maternal toxicity (decreased food consumption and body weight gain).

In pregnant female rabbits given oral gavage doses of 2, 12, 25 mg/kg/day during gestation no adverse fetal effects were observed (exposures less than with a human oral dose of 180 mg/day based on AUC comparisons). Reductions in maternal food consumption and body weight gain were seen at doses of 12 and 25 mg/kg/day.

In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day during gestation through lactation no adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day (exposures less than with a human therapeutic dose of 180 mg/day based on AUC comparisons). Higher doses of 15 and 25 mg/kg/day (exposures 2-3 times a human oral dose of 180 mg/day based on AUC comparisons) were accompanied by maternal signs of hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in postnatal maternal and pup body-weight gain. Sensipar has been shown to cross the placental barrier in rabbits.

There are no adequate and well-controlled studies in pregnant women. Sensipar should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactating Women

Studies in rats have shown that Sensipar is excreted in the milk with a high milk-to-plasma ratio. It is not known whether this drug is excreted in human milk. Considering these data in rats and because many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in infants from Sensipar , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the lactating woman.

Pediatric Use

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

Geriatric Use

Of the 1136 patients enrolled in the Sensipar phase 3 clinical program, 26% were 65 years old, and 9% were 75 years old. No differences in the safety and efficacy of Sensipar were observed in patients greater or less than 65 years of age (see DOSAGE AND ADMINISTRATION, Geriatric patients ).

Adverse Events ⮝

Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

In 3 double-blind placebo-controlled clinical trials, 1126 CKD patients on dialysis received study drug (656 Sensipar , 470 placebo) for up to 6 months. The most frequently reported adverse events (incidence of at least 5% in the Sensipar group and greater than placebo) are provided in Table 2. The most frequently reported events in the Sensipar group were nausea, vomiting, and diarrhea.

Table 2. Adverse Event Incidence ( 5%) in Patients on Dialysis

Event*:	Placebo (n = 470) (%)	Sensipar (n = 656) (%)
* Included are events that were reported at a greater incidence in the Sensipar group than in the placebo group.
Nausea	19	31
Vomiting	15	27
Diarrhea	20	21
Myalgia	14	15
Dizziness	8	10
Hypertension	5	7
Asthenia	4	7
Anorexia	4	6
Pain Chest, Non Cardiac	4	6
Access Infection	4	5

The incidence of serious adverse events (29% vs. 31%) was similar in the Sensipar and placebo groups, respectively.

12-Month Experience with Sensipar : Two hundred and sixty-six patients from 2 phase 3 studies continued to receive Sensipar or placebo treatment in a 6-month double-blind extension study (12-month total treatment duration). The incidence and nature of adverse events in this study were similar in the two treatment groups, and comparable to those observed in the phase 3 studies.

Postmarketing Experience with Sensipar : Rash, hypersensitivity reactions (including angioedema and urticaria), diarrhea and myalgia have been identified as adverse reactions during post-approval use of Sensipar . Isolated, idiosyncratic cases of hypotension, worsening heart failure, and/ or arrhythmia have been reported in Sensipar -treated patients with impaired cardiac function in postmarketing safety surveillance. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Parathyroid Carcinoma

The most frequent adverse events in this patient group were nausea and vomiting.

Laboratory values: Serum calcium levels should be closely monitored in patients receiving Sensipar (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Overdosage  ⮝

Doses titrated up to 300 mg once daily have been safely administered to patients on dialysis. Overdosage of Sensipar may lead to hypocalcemia. In the event of overdosage, patients should be monitored for signs and symptoms of hypocalcemia and appropriate measures taken to correct serum calcium levels (see PRECAUTIONS).

Since Sensipar is highly protein bound, hemodialysis is not an effective treatment for overdosage of Sensipar .

References ⮝

1. National Kidney Foundation: K/DOQI clinical practice guidelines: bone metabolism and disease in chronic kidney disease. American Journal of Kidney Disease 4 2:S1-S201, 2003

No Title 1572457199 ⮝

Manufactured for: Amgen
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799

2004-2010 Amgen Inc. All rights reserved.

This Product was Repackaged By:

State of Florida DOH Central Pharmacy
104-2 Hamilton Park Drive
Tallahassee, FL 32304
United States

Package Label - Principal Display Panel - Tablet, 60 Mg ⮝

Amgen

NDC 53808-0578-1

Sensipar

(cinacalcet HCI) Tablets

Rx Only

30 tablets

60 mg

Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F).

See USP controlled room temperature.

SENSIPAR cinacalcet hydrochloride tablet, coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:53808-0577(NDC:55513-073) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CINACALCET HYDROCHLORIDE (UNII: 1K860WSG25) (CINACALCET - UNII:UAZ6V7728S) CINACALCET HYDROCHLORIDE 30 mg

Inactive Ingredients Ingredient Name Strength CARNAUBA WAX (UNII: R12CBM0EIZ) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) CROSPOVIDONE (UNII: 68401960MK) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE (UNII: FZ989GH94E) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Product Characteristics Color GREEN (light green) Score no score Shape OVAL Size 10mm Flavor Imprint Code AMG;30 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:53808-0577-1 30 in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021688 07/01/2009

SENSIPAR cinacalcet hydrochloride tablet, coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:53808-0578(NDC:55513-074) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CINACALCET HYDROCHLORIDE (UNII: 1K860WSG25) (CINACALCET - UNII:UAZ6V7728S) CINACALCET HYDROCHLORIDE 60 mg

Inactive Ingredients Ingredient Name Strength CARNAUBA WAX (UNII: R12CBM0EIZ) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) CROSPOVIDONE (UNII: 68401960MK) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE (UNII: FZ989GH94E) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Product Characteristics Color GREEN (light green) Score no score Shape OVAL Size 12mm Flavor Imprint Code AMG;60 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:53808-0578-1 30 in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021688 07/01/2009

Labeler - State of Florida DOH Central Pharmacy (829348114)

Establishment
Name	Address	ID/FEI	Business Operations
State of Florida DOH Central Pharmacy		829348114	repack

Revised: 6/2010 Document Id: 29dcedcd-efba-436a-8542-99faff58875f 34391-3 Set id: 8f390187-1071-4000-b778-1d21c518cc9c Version: 1 Effective Time: 20100608 State of Florida DOH Central Pharmacy

Recent Major Changes ⮝

Warnings and Precautions, Hypocalcemia (5.1)	5/2017
Warnings and Precautions, Upper Gastrointestinal Bleeding (5.2)	3/2017
Warnings and Precautions, Hypotension, Worsening Heart Failure and/or Arrhythmias (5.3)	5/2017

1 Indications And Usage ⮝

1.1 Secondary Hyperparathyroidism

Sensipar is 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:

Sensipar is not indicated for use in adult 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

Sensipar is indicated for the treatment of hypercalcemia in adult patients with Parathyroid Carcinoma [see Clinical Studies (14.2)].

1.3 Primary Hyperparathyroidism

Sensipar is 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)].

2 Dosage And Administration ⮝

Sensipar tablets should be taken whole and should not be divided. Sensipar should be taken with food or shortly after a meal.

Dosage must be individualized.

2.1 Secondary Hyperparathyroidism in Adult Patients with Chronic Kidney Disease on Dialysis

The recommended starting oral dose of Sensipar 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 Sensipar [see Dosage and Administration (2.3)]. Sensipar 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 Sensipar.

Sensipar 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 Sensipar [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

2.2 Parathyroid Carcinoma and Primary Hyperparathyroidism

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

The dose of Sensipar 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 Sensipar [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

2.3 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 (2.1, 2.2)].

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 Sensipar 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 Sensipar [see Dosage and Administration (2.1)].

3 Dosage Forms And Strengths ⮝

Sensipar tablets are formulated as light-green, film-coated, oval-shaped tablets marked with AMG on one side and 30 or 60 or 90 on the opposite side of the 30 mg, 60 mg, or 90 mg strengths, respectively.

4 Contraindications ⮝

Sensipar 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

Sensipar lowers serum calcium and, therefore, patients should be carefully monitored for the occurrence of hypocalcemia during treatment [see Dosage and Administration (2.1, 2.2, 2.3) and Adverse Reactions (6.1)]. Life threatening events and fatal outcomes associated with hypocalcemia have been reported in patients treated with Sensipar, including pediatric patients [see Pediatric Use (8.4)]. Potential manifestations of hypocalcemia include paresthesias, myalgias, muscle cramping, tetany, and convulsions.

Sensipar 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 Sensipar have not been established. Clinical studies indicate that Sensipar-treated patients with CKD not on dialysis have an increased risk for hypocalcemia compared with Sensipar-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 Sensipar-treated patients experienced at least one serum calcium value < 8.4 mg/dL compared with 5% of patients receiving placebo.

QT Prolongation

Decreases in serum calcium can also prolong the QT interval, potentially resulting in ventricular arrhythmia. Cases of QT prolongation and ventricular arrhythmia secondary to hypocalcemia have been reported in patients treated with Sensipar.

Seizures

In clinical studies, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (43/3049) of Sensipar-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. Therefore, serum calcium levels should be closely monitored in patients receiving Sensipar, particularly in patients with a history of a seizure disorder.

Hypotension and/or Worsening Heart Failure

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 Sensipar could not be completely excluded and which may be mediated by reductions in serum calcium levels [see Adverse Reactions (6.2)].

5.2 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 Sensipar for 1 year. Three patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with Sensipar. 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 Sensipar 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 Sensipar, the dose of Sensipar and/or vitamin D sterols should be reduced or therapy discontinued.

5.3 Hepatic Impairment

Cinacalcet exposure, as defined by the Area Under the Plasma Drug Concentration Time Curve (AUC0-infinite), is increased by 2.4 and 4.2 fold in patients with moderate and severe hepatic impairment, respectively. These patients should be monitored throughout treatment with Sensipar [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

6 Adverse Reactions ⮝

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

In three double-blind, placebo-controlled clinical trials, 1126 patients with CKD on dialysis received study drug (656 Sensipar, 470 placebo) for up to 6 months. The most frequently reported adverse reactions are listed in Table 1.

Seizures were observed in 1.4% (13/910) of Sensipar-treated patients and 0.7% (5/641) of placebo-treated patients across all completed placebo controlled trials.

Table 1. Adverse Reactions with Frequency 5% in Patients on Dialysis in Short-Term Studies for up to 6 Months

* Included are events that were reported at a greater incidence in the Sensipar group than in the placebo group.
	Placebo	Sensipar
	(n = 470)	(n = 656)
Event*:	(%)	(%)
Nausea	19	31
Vomiting	15	27
Diarrhea	20	21
Myalgia	14	15
Dizziness	8	10
Hypertension	5	7
Asthenia	4	7
Anorexia	4	6
Pain Chest, Non-Cardiac	4	6
Dialysis Access Site Infection	4	5

In a randomized, double-blind placebo controlled study of 3,883 patients with secondary HPT and CKD receiving dialysis in which patients were treated for up to 64 months (mean duration of treatment was 21 months in the Sensipar group), the most frequently reported adverse reactions (incidence of 5% in the Sensipar group and a difference 1% compared to placebo) are listed in Table 2.

Table 2. Frequency of Adverse Reactions in Dialysis Patients Treated for up to 64 Months in a Long-Term Study1

	Placebo (N=1923)	Sensipar (N=1938)
	3699 subject-years	4044 subject-years
Percent of subjects reporting Adverse Reactions (%)	90.9	93.2
Nausea	15.5	29.1
Vomiting	13.7	25.6
Diarrhea	18.7	20.5
Dyspnea	11.5	13.4
Cough	9.8	11.7
Hypotension	10.5	11.6
Headache	9.6	11.5
Hypocalcaemia	1.4	11.2
Muscle spasms	9.2	11.1
Abdominal pain	9.6	10.9
Abdominal pain upper	6.3	8.2
Hyperkalemia	6.1	8.1
Upper respiratory tract infection	6.3	7.6
Dyspepsia	4.6	7.4
Dizziness	4.7	7.3
Decreased appetite	3.5	5.9
Asthenia	3.8	5.4
Constipation	3.8	5.0

1 Adverse reactions that occurred in 5% Frequency in the Sensipar group and a difference 1% compared to the placebo group (Safety Analysis Set)
Crude incidence rate = 100 * Total number of subjects with event/ N
N=Number of subjects receiving at least one dose of study drug

Additional adverse reaction rates from the long-term, randomized, double-blind placebo controlled study for Sensipar versus placebo are as follows: seizure (2.5%, 1.6%), rash (2.2%, 1.9%), hypersensitivity reactions (9.4%, 8.3%).

Parathyroid Carcinoma and Primary Hyperparathyroidism

The safety profile of Sensipar in these patient populations is generally consistent with that seen in patients with CKD on dialysis. Forty six patients were treated with Sensipar in a single arm study, 29 with Parathyroid Carcinoma and 17 with intractable pHPT. Nine (20%) of the patients withdrew from the study due to adverse events. The most frequent adverse reactions and the most frequent cause of withdrawal in these patient populations were nausea and vomiting. Severe or prolonged cases of nausea and vomiting can lead to dehydration and worsening hypercalcemia so careful monitoring of electrolytes is recommended in patients with these symptoms.

Eight patients died during treatment with Sensipar in this study, 7 with Parathyroid Carcinoma (24%) and 1 (6%) with intractable pHPT. Causes of death were cardiovascular (5 patients), multi-organ failure (1 patient), gastrointestinal hemorrhage (1 patient) and metastatic carcinoma (1 patient). Adverse events of hypocalcemia were reported in three patients (7%).

Seizures were observed in 0.7% (1/140) of cinacalcet-treated patients and 0.0% (0/46) of placebo-treated patients in all clinical studies.

Table 3. Adverse Reactions with Frequency 10% in a Single Arm, Open-Label Study in Patients with Primary Hyperparathyroidism or Parathyroid Carcinoma

N=Number of subjects receiving at least one dose of study drug. pHPT=primary hyperparathyroidism
	Sensipar
	Parathyroid Carcinoma (N=29)	Intractable pHPT (N=17)	Total (N=46)
	n (%)	n (%)	n (%)
Number of Subjects Reporting Adverse Events	28 (97)	17 (100)	45 (98)
Nausea	19 (66)	10 (59)	29 (63)
Vomiting	15 (52)	6 (35)	21 (46)
Paresthesia	4 (14)	5 (29)	9 (20)
Fatigue	6 (21)	2 (12)	8 (17)
Fracture	6 (21)	2 (12)	8 (17)
Hypercalcemia	6 (21)	2 (12)	8 (17)
Anorexia	6 (21)	1 (6)	7 (15)
Asthenia	5 (17)	2 (12)	7 (15)
Dehydration	7 (24)	0 (0)	7 (15)
Anemia	5 (17)	1 (6)	6 (13)
Arthralgia	5 (17)	1 (6)	6 (13)
Constipation	3 (10)	3 (18)	6 (13)
Depression	3 (10)	3 (18)	6 (13)
Headache	6 (21)	0 (0)	6 (13)
Infection Upper Respiratory	3 (10)	2 (12)	5 (11)
Pain Limb	3 (10)	2 (12)	5 (11)

In a randomized double-blind, placebo-controlled study of 67 patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo surgery, the most common adverse reactions are listed in Table 4.

Table 4. Adverse Reactions Occurring in 10% of Subjects in a Double-Blind, Placebo-Controlled Study in Patients with Primary Hyperparathyroidism

Adverse Reaction	Placebo (N = 34) n (%)	Cinacalcet (N = 33) n (%)
Nausea	6 (18)	10 (30)
Muscle spasms	0 (0)	6 (18)
Headache	2 (6)	4 (12)
Back pain	2 (6)	4 (12)

N=Number of subjects receiving at least one dose of study drug Coded using MedDRA version 16.0

Hypocalcemia

In 26-week studies of patients with secondary HPT and CKD on dialysis 66% of patients receiving Sensipar compared with 25% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL, whereas, 29% of patients receiving Sensipar compared with 11% of patients receiving placebo developed at least one serum calcium value less than 7.5 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia.

In a randomized, double-blind, placebo-controlled study in patients with secondary HPT and CKD receiving dialysis in which patients were treated for up to 64 months (mean duration of treatment was 21 months in the cinacalcet group), 75% of patients receiving Sensipar compared with 29% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL and 33% of cinacalcet patients compared with 12% of patients receiving placebo had at least one serum calcium value less than 7.5 mg/dL. Most of the cases of severe hypocalcemia less than 7.5 mg/dL (21/33=64%) occurred during the first 6 months. In this trial, 1.1% of patients receiving Sensipar and 0.1% of patients receiving placebo permanently discontinued study drug due to hypocalcemia.

During a placebo-controlled part of a 52-week study in patients with primary HPT who met criteria for parathyroidectomy on the basis of corrected total serum calcium (>11.3 mg/dl [2.82 mmol/L] and 12.5 mg/dl [3.12 mmol/L]), serum calcium less than 8.4 mg/dL was observed in 6.1% (2/33) of Sensipar treated patients and 0% (0/34) of placebo treated patients.

6.2 Postmarketing Experience with Sensipar

The following adverse reactions have been identified during postapproval use of Sensipar. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Rash and hypersensitivity reactions (including angioedema and urticaria), and myalgia have been identified as adverse reactions during post approval use of Sensipar. Isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in Sensipar-treated patients with impaired cardiac function in postmarketing safety surveillance [see Warnings and Precautions (5.1)].

7 Drug Interactions ⮝

7.1 Strong CYP3A4 Inhibitors

Cinacalcet is partially metabolized by CYP3A4. Dose adjustment of Sensipar may be required if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole). The iPTH and serum calcium concentrations should be closely monitored in these patients [see Clinical Pharmacology (12.3)].

7.2 CYP2D6 Substrates

Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications that are predominantly metabolized by CYP2D6 (e.g., desipramine, metoprolol, and carvedilol) and particularly those with a narrow therapeutic index (e.g., flecainide and most tricyclic antidepressants) [see Clinical Pharmacology (12.3)].

8 Use In Specific Populations ⮝

8.1 Pregnancy: Category C

In pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day cinacalcet during gestation, no teratogenicity was observed at doses up to 50 mg/kg/day (exposure 4 times those resulting with a human oral dose of 180 mg/day based on Area Under the Curve [AUC] comparison). Decreased fetal body weights were observed at all doses (less than 1 to 4 times a human oral dose of 180 mg/day based on AUC comparison) in conjunction with maternal toxicity (decreased food consumption and body weight gain).

In pregnant female rabbits given oral gavage doses of 2, 12, 25 mg/kg/day cinacalcet during gestation, no adverse fetal effects were observed (exposures less than with a human oral dose of 180 mg/day based on AUC comparisons). Reductions in maternal food consumption and body weight gain were seen at doses of 12 and 25 mg/kg/day. Sensipar has been shown to cross the placental barrier in rabbits.

In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day cinacalcet during gestation through lactation, no adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day (exposures less than with a human therapeutic dose of 180 mg/day based on AUC comparisons). Higher doses of 15 and 25 mg/kg/day cinacalcet (exposures 2 to 3 times a human oral dose of 180 mg/day based on AUC comparisons) were accompanied by maternal signs of hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in postnatal maternal and pup body-weight gain.

There are no adequate and well-controlled studies of Sensipar in pregnant women. Sensipar should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Women who become pregnant during Sensipar treatment are encouraged to enroll in Amgen s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

8.3 Nursing Mothers

Studies in rats have shown that Sensipar is excreted in the milk with a high milk-to-plasma ratio. It is not known whether this drug is excreted in human milk. Considering these data in rats, and because many drugs are excreted in human milk and there is a potential for clinically significant adverse reactions in infants who ingest Sensipar, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the lactating woman.

Women who choose to continue Sensipar treatment while nursing are encouraged to enroll in Amgen s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

8.4 Pediatric Use

The safety and efficacy of Sensipar in pediatric patients have not been established. Sensipar is not indicated for use in pediatric patients. A fatal outcome was reported in a pediatric clinical trial patient with severe hypocalcaemia [see Warnings and Precautions (5.1)].

8.5 Geriatric Use

Of the total number of subjects (n=1136) in clinical studies of Sensipar, 26 percent were 65 and over, and 9 percent were 75 and over. No overall differences in the safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Studies (14) and Clinical Pharmacology (12.3)].

8.6 Renal Impairment

No dosage adjustment is necessary for renal impairment [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Patients with moderate and severe hepatic impairment should have serum calcium, serum phosphorus, and iPTH levels monitored closely throughout treatment with Sensipar because cinacalcet exposure (AUC0-infinite) is increased by 2.4 and 4.2 fold, respectively, in these patients [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

10 Overdosage ⮝

Doses titrated up to 300 mg once daily have been safely administered to patients on dialysis. Overdosage of Sensipar may lead to hypocalcemia. In the event of overdosage, patients should be monitored for signs and symptoms of hypocalcemia and appropriate measures taken to correct serum calcium levels [see Warnings and Precautions (5.1)].

Since Sensipar is highly protein bound, hemodialysis is not an effective treatment for overdosage of Sensipar.

11 Description ⮝

Sensipar (cinacalcet) is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Sensipar tablets contain the hydrochloride salt of cinacalcet. Its empirical formula is C22H22F3N HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base). It has one chiral center having an R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity.

The hydrochloride salt of cinacalcet is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and slightly soluble in water.

Sensipar tablets are formulated as light-green, film-coated, oval-shaped tablets for oral administration in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet as the free base equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively).

The hydrochloride salt of cinacalcet is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride and has the following structural formula:

Inactive Ingredients
The following are the inactive ingredients in Sensipar tablets: pre-gelatinized starch, microcrystalline cellulose, povidone, crospovidone, colloidal silicon dioxide and magnesium stearate. Tablets are coated with color (Opadry II green), clear film coat (Opadry clear), and carnauba wax.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH synthesis and secretion. Cinacalcet, the active ingredient in Sensipar, directly lowers PTH levels by increasing the sensitivity of the calcium-sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.

12.2 Pharmacodynamics

Reduction in iPTH levels correlated with the plasma cinacalcet concentrations in patients with CKD. The nadir in iPTH level occurs approximately 2 to 6 hours post dose, corresponding with the maximum plasma concentration (Cmax) of cinacalcet. After steady-state cinacalcet concentrations are reached (which occurs within 7 days of dose change), serum calcium concentrations remain constant over the dosing interval in patients with CKD.

Reductions in PTH are associated with a decrease in bone turnover and bone fibrosis in patients with CKD on dialysis and uncontrolled secondary HPT.

12.3 Pharmacokinetics

Absorption and Distribution

After oral administration of cinacalcet, Cmax is achieved in approximately 2 to 6 hours. Cinacalcet Cmax and AUC(0-infinite) were increased by 82% and 68%, respectively, following administration with a high-fat meal compared with fasting in healthy volunteers. The Cmax and AUC(0-infinite) of cinacalcet were increased by 65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared with fasting.

After absorption, cinacalcet concentrations decline in a biphasic fashion with a terminal half-life of 30 to 40 hours. Steady-state drug levels are achieved within 7 days, and the mean accumulation ratio is approximately 2 with once daily oral administration. The median accumulation ratio is approximately 2 to 5 with twice daily oral administration. The AUC and Cmax of cinacalcet increase proportionally over the dose range of 30 to 180 mg once daily. The pharmacokinetic profile of cinacalcet does not change over time with once daily dosing of 30 to 180 mg. The volume of distribution is approximately 1000 L, indicating extensive distribution. Cinacalcet is approximately 93% to 97% bound to plasma protein(s). The ratio of blood cinacalcet concentration to plasma cinacalcet concentration is 0.80 at a blood cinacalcet concentration of 10 ng/mL.

Metabolism and Excretion

Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via -oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug forming dihydrodiols, which are further conjugated with glucuronic acid. The plasma concentrations of the major circulating metabolites, including the cinnamic acid derivatives and glucuronidated dihydrodiols, markedly exceed the parent drug concentrations. The hydrocinnamic acid metabolite and glucuronide conjugates have minimal or no calcimimetic activity. Renal excretion of metabolites was the primary route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the feces.

Specific Populations

Age: Geriatric Population
The pharmacokinetic profile of cinacalcet in geriatric patients (age 65 years, n = 12) is similar to that for patients who are < 65 years of age (n = 268) [see Use in Specific Populations (8.5)].

Age: Pediatric Population
The pharmacokinetics of cinacalcet has not been studied in patients < 18 years of age [see Use in Specific Populations (8.4)].

Hepatic Impairment

The disposition of a 50 mg Sensipar single dose was compared between patients with hepatic impairment and patients with normal hepatic function. Cinacalcet exposure (AUC(0-infinite)) was comparable between healthy volunteers and patients with mild hepatic impairment. However, in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method), cinacalcet exposures (AUC(0-infinite)) were 2.4 and 4.2 fold higher, respectively, than that in healthy volunteers. The mean half-life of cinacalcet increased from 49 hours in healthy volunteers to 65 hours and 84 hours in patients with moderate and severe hepatic impairment, respectively. Protein binding of cinacalcet is not affected by impaired hepatic function [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7)].

Renal Impairment

The pharmacokinetic profile of a 75 mg Sensipar single dose in patients with mild, moderate, and severe renal impairment, and those on hemodialysis or peritoneal dialysis is comparable with that in healthy volunteers [see Use in Specific Populations (8.6)].

Drug Interactions

In vitro studies indicate that cinacalcet is a strong inhibitor of CYP2D6, but not an inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4. In vitro induction studies indicate that cinacalcet is not an inducer of CYP450 enzymes. Tables 5 and 6 list the findings from in vivo drug-drug interaction studies.

Table 5. Effect of co-administered drugs on cinacalcet

* Single dose.
Co-administered drug and dosing regimen	Cinacalcet
	Dose*	Mean change in AUC	Mean change in Cmax
200 mg ketoconazole twice daily for 7 days	90 mg on day 5	127%	116%
1500 mg calcium carbonate, single dose	100 mg	6%	5%
80 mg pantoprazole daily for 3 days	90 mg on day 3	1%	3%
2400 mg sevelamer HCl three times a day for 2 days	90 mg on day 1 with first dose of sevelamer	4%	7%

Table 6. Effect of cinacalcet co-administration on other drugs

* No significant change in prothrombin time. Single dose on day 5. Nortriptyline is an active metabolite of amitriptyline.
Cinacalcet dosing regimen	Co-administered drug
	Name and Dose	Mean change in AUC(0-inf)	Mean change in Cmax
30 mg twice daily for 8 days	25 mg warfarin* tablet	1 % for R-warfarin 1% S-warfarin	10 % for R-warfarin 12 % for S-warfarin
90 mg daily for 7 days to CYP2D6 extensive metabolizers	50 mg desipramine	264%	75%
90 mg daily for 5 days	2 mg midazolam	5%	5%
25 or 100 mg single dose to CYP2D6 extensive metabolizers	50 mg amitriptyline single dose	21-22% for amitriptyline 17-23% for nortriptyline	13-21% for amitriptyline 11-15% for nortriptyline

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Standard lifetime dietary carcinogenicity bioassays were conducted in mice and rats. Mice were given cinacalcet at dietary doses of 15, 50, and 125 mg/kg/day in males and 30, 70, and 200 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Rats were given dietary doses of 5, 15, and 35 mg/kg/day in males and 5, 20, and 35 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). No increased incidence of tumors was observed following treatment with cinacalcet.

Mutagenicity

Cinacalcet was not genotoxic in the Ames bacterial mutagenicity assay, nor in the Chinese Hamster Ovary (CHO) cell HGPRT forward mutation assay and CHO cell chromosomal aberration assay, with and without metabolic activation, nor in the in vivo mouse micronucleus assay.

Impairment of Fertility

Female rats were given oral gavage doses of 5, 25, and 75 mg/kg/day cinacalcet beginning 2 weeks before mating and continuing through gestation day 7. Male rats were given oral doses 4 weeks prior to mating, during mating (3 weeks) and 2 weeks postmating. No effects were observed in male or female fertility at 5 and 25 mg/kg/day (exposures up to 3 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). At 75 mg/kg/day, there were slight adverse effects (slight decreases in body weight and food consumption) in males and females.

14 Clinical Studies ⮝

14.1 Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

Three 6-month, multicenter, randomized, double-blind, placebo-controlled clinical studies of similar design were conducted in patients with CKD on dialysis. A total of 665 patients were randomized to Sensipar and 471 patients to placebo. The mean age of the patients was 54 years, 62% were male, and 52% were Caucasian. The average baseline iPTH level by the Nichols IRMA was 712 pg/mL, with 26% of the patients having a baseline iPTH level > 800 pg/mL. The mean baseline Ca x P product was 61 mg2/dL2. The average duration of dialysis prior to study enrollment was 67 months. Ninety-six percent of patients were on hemodialysis and 4% on peritoneal dialysis. At study entry, 66% of the patients were receiving vitamin D sterols and 93% were receiving phosphate binders. Sensipar (or placebo) was initiated at a dose of 30 mg once daily and titrated every 3 or 4 weeks to a maximum dose of 180 mg once daily to achieve an iPTH of 250 pg/mL. The dose was not increased if a patient had any of the following: iPTH 200 pg/mL, serum calcium < 7.8 mg/dL, or any symptoms of hypocalcemia. If a patient experienced symptoms of hypocalcemia or had a serum calcium < 8.4 mg/dL, calcium supplements and/or calcium-based phosphate binders could be increased. If these measures were insufficient, the vitamin D dose could be increased. Approximately 70% of patients in the Sensipar arm and 80% of the patients in the placebo arm completed the 6-month studies. In the primary efficacy analysis, 40% of the patients on Sensipar and 5% of placebo-treated patients achieved an iPTH 250 pg/mL (p < 0.001) (Table 7, Figure 1). These studies showed that Sensipar reduced iPTH while lowering Ca x P, calcium, and phosphorus levels (Table 7, Figure 2). The median dose of Sensipar at the completion of the studies was 90 mg. Patients with milder disease typically required lower doses.

Similar results were observed when either the iPTH or biointact PTH (biPTH) assay was used to measure PTH levels in CKD patients on dialysis; treatment with cinacalcet did not alter the relationship between iPTH and biPTH.

Table 7. Effects of Sensipar on iPTH, Ca x P, Serum Calcium, and Serum Phosphorus in 6-month Phase 3 Studies (Patients on Dialysis)

Values shown are medians unless indicated otherwise.
* iPTH value based on averaging over the evaluation phase (defined as weeks 13 to 26 in studies 1 and 2 and weeks 17 to 26 in study 3). p < 0.001 compared with placebo; p-values presented for primary endpoint only.
		Study 1		Study 2		Study 3
		Placebo	Sensipar	Placebo	Sensipar	Placebo	Sensipar
		(n = 205)	(n = 205)	(n = 165)	(n = 166)	(n = 101)	(n = 294)
iPTH
	Baseline (pg/mL): Median Mean (SD)	535 651 (398)	537 636 (341)	556 630 (317)	547 652 (372)	670 832 (486)	703 848 (685)
	Evaluation Phase (pg/mL)	563	275	592	238	737	339
	Median Percent Change	+3.8	-48.3	+8.4	-54.1	+2.3	-48.2
	Patients Achieving Primary Endpoint (iPTH 250 pg/mL) (%)*	4%	41%	7%	46%	6%	35%
	Patients Achieving 30% Reduction in iPTH (%)*	11%	61%	12%	68%	10%	59%
	Patients Achieving iPTH 250 pg/mL and Ca x P < 55 mg2/dL2 (%)	1%	32%	5%	35%	5%	28%
Ca x P
	Baseline (mg2/dL2)	62	61	61	61	61	59
	Evaluation Phase (mg2/dL2)	59	52	59	47	57	48
	Median Percent Change	-2.0	-14.9	-3.1	-19.7	-4.8	-15.7
Calcium
	Baseline (mg/dL)	9.8	9.8	9.9	10.0	9.9	9.8
	Evaluation Phase (mg/dL)	9.9	9.1	9.9	9.1	10.0	9.1
	Median Percent Change	+0.5	-5.5	+0.1	-7.4	+0.3	-6.0
Phosphorus
	Baseline (mg/dL)	6.3	6.1	6.1	6.0	6.1	6.0
	Evaluation Phase (mg/dL)	6.0	5.6	5.9	5.1	5.6	5.3
	Median Percent Change	-1.0	-9.0	-2.4	-12.4	-5.6	-8.6

Figure 1. Mean (SE) iPTH Values (Pooled Phase 3 Studies)

Data are presented for patients who completed the studies; Placebo (n = 342), Sensipar (n = 439).

Figure 2. Mean (SE) Ca x P Values (Pooled Phase 3 Studies)

Data are presented for patients who completed the studies; Placebo (n = 342), Sensipar (n = 439).

Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment.

Sensipar decreased iPTH and Ca x P levels regardless of disease severity (i.e., baseline iPTH value), duration of dialysis, and whether or not vitamin D sterols were administered. Approximately 60% of patients with mild (iPTH 300 to 500 pg/mL), 41% with moderate (iPTH > 500 to 800 pg/mL), and 11% with severe (iPTH > 800 pg/mL) secondary HPT achieved a mean iPTH value of 250 pg/mL. Plasma iPTH levels were measured using the Nichols IRMA.

14.2 Parathyroid Carcinoma

Twenty-nine patients with Parathyroid Carcinoma were enrolled in a single-arm, open-label study. The study consisted of two phases, a dose-titration phase and a maintenance phase. Patients initially received 30 mg cinacalcet twice daily and then were titrated every 2 weeks to a maximum dose of 90 mg four times daily. Dosage escalation during the variable-length (2 to 16 weeks) titration phase continued until the serum calcium concentration was 10 mg/dL (2.5 mmol/L), the patient reached the highest possible dosage, or adverse events precluded further dosage increases.

Twenty-nine patients entered the study. The median exposure to cinacalcet was 229 days (range: 1 to 1051). At baseline the mean (SE) serum calcium was 14.1 (0.4) mg/dL. At the end of the titration phase, the mean (SE) serum calcium was 12.4 (0.5) mg/dL, which is a mean reduction of 1.7 (0.6) mg/dL from baseline. Figure 3 illustrates mean serum calcium (mg/dL) over time for all patients still on study at each time point from the beginning of titration to study visit week 80. Daily dose during the study ranged from 30 mg twice daily to 90 mg four times daily.

Figure 3. Serum Calcium Values in Patients With Parathyroid Carcinoma Receiving Sensipar at Baseline, Titration, and Maintenance Phase

n = Number of patients with non-missing values at the timepoint.
End of Titration (EOT) phase could occur at any visit from week 2 to 16. Patients at EOT are those who completed titration.

14.3 Patients with Hypercalcemia Due to Primary Hyperparathyroidism

Seventeen patients with severe hypercalcemia due to primary HPT, who had failed or had contraindications to parathyroidectomy, participated in an open-label, single-arm study. The study consisted of two phases, a dose-titration phase and a maintenance phase. In this trial severe hypercalcemia was defined as a screening serum calcium level of > 12.5 mg/dL. Patients initially received 30 mg cinacalcet twice daily and then were titrated every 2 weeks to a maximum dose of 90 mg 4 times daily. Dosage escalation during the variable-length (2 to 16 weeks) titration phase continued until the serum calcium concentration was 10 mg/dL (2.5 mmol/L), the patient reached the highest possible dosage, or adverse events precluded further dosage increases.

Seventeen patients entered the study. The median exposure to cinacalcet was 270 days (range: 32 to 1,105). At baseline the mean (SE) serum calcium was 12.7 (0.2) mg/dL. At the end of the titration phase the mean (SE) serum calcium was 10.4 (0.3) mg/dL, which is a mean reduction of 2.3 (0.3) mg/dL from baseline. Figure 4 illustrates mean serum calcium (mg/dL) over time for all patients still on study at each time point from the beginning of titration to study visit week 80. Daily dose during the study ranged from 30 mg twice a day to 90 mg four times a day.

Figure 4. Mean Serum Calcium (SE) at Baseline, End of Titration, and Scheduled Maintenance Visits (Patients with Severe intractable primary HPT)

n = Number of patients with non-missing values at the timepoint.
End of Titration (EOT) phase could occur at any visit from week 2 to 16. Patients at EOT are those who completed titration.

Sixty-seven patients with primary HPT who met criteria for parathyroidectomy on the basis of corrected total serum calcium (> 11.3 mg/dl [2.82 mmol/L] and 12.5 mg/dl [3.12 mmol/L]), but who were unable to undergo parathyroidectomy participated in a randomized, double-blind, placebo-controlled study. A total of 33 patients were randomized to Sensipar and 34 patients randomized to placebo. The mean age of the patients was 72 years, 52% were female, 61% were Caucasian, and 5% were Blacks. The study started with a 12-week titration phase, followed by a 16-week efficacy assessment phase. Cinacalcet was initiated at a dose of 30 mg twice daily and titrated to maintain a corrected total serum calcium concentration within the normal range. During the efficacy period a significantly higher percentage of cinacalcet treated patients compared with the placebo treated patients achieved mean corrected total serum calcium concentration ( 10.3 mg/dL [2.57 mmol/L], 75.8% vs 0%, p < 0.001) and 1 mg/dL [0.25 mmol/L] decrease from baseline in mean corrected total serum calcium concentration (84.8% vs 5.9%, p < 0.001). The median dose of Sensipar at the completion of the study was 60 mg/day.

16 How Supplied/storage And Handling ⮝

Sensipar 30 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with AMG on one side and 30 on the opposite side, packaged in bottles of 30 tablets. (NDC 54868-5616-0)

Storage

Store at 25 C (77 F); excursions permitted from 15 C to 30 C (59 F to 86 F). [See USP controlled room temperature].

Package Label - Principal Display Panel - Tablet, 30 Mg ⮝

Amgen

NDC 53808-0577-1

Sensipar

(cinacalcet HCI) Tablets

Rx Only

30 tablets

30 mg

Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F).

See USP controlled room temperature.