`
`
`•
`
`•
`
`
`
`
`
` 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 US Approval: 2004
`
`----------------------------RECENT MAJOR CHANGES-------------------------
`
`
`
`Indications and Usage, Primary Hyperparathyroidism (1.3)
`11/2014
`
`
`
`
`Warnings and Precautions, Hypocalcemia (5.1)
`11/2014
`
`----------------------------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)
`
`
`
`
`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-----------------------
`
`For all indications, Sensipar should be taken with food or shortly after a meal
`
`
`
`and should always be taken whole and not divided.
`
`
`Secondary HPT in patients with CKD on dialysis (2.1):
`
`•
`o
`
`
`
`Starting dose is 30 mg once daily.
`
`o
`
`
`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.
`o
`
`
`
`
`
`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 (2.2):
`o
`
`
`
`
`Starting dose is 30 mg twice daily.
`
`o
`
`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.
`
`
`
`---------------------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 (2.3, 5.1)
`
`Adynamic Bone Disease: May develop if iPTH levels are suppressed
`
`
`
`below 100 pg/mL. (5.2)
`Hepatic Impairment: Cinacalcet exposure (i.e. area under the plasma
`
`
`
`
`concentration time curve) is increased in patients with moderate and
`
`
`severe hepatic impairment. Patients should be closely monitored for
`
`
`
`serum calcium, serum phosphorus, and iPTH levels throughout
`
`treatment. (5.3, 8.7)
`
`------------------------------ADVERSE REACTIONS-------------------------------
`
`
`
`
`
`
`
`The most common adverse reactions (i.e., ≥ 25%) associated with Sensipar
`
`
`
`were nausea and vomiting. (6.1, 6.2)
`
`
`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
`
`phosphorous 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------------------
`
`
`
`
`
`• Pregnancy: Sensipar should only be used if the potential benefit justifies
`
`
`
`
`the potential risk to the fetus. Pregnancy registry available. (8.1)
`
`
`
`
`• 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).
`
`
`
`2
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`Revised: 11/2014
`__________________________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`8.6 Renal Impairment
`
`1
`
`
`8.7 Hepatic Impairment
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`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
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
`INDICATIONS AND USAGE
`
`
`1.1 Secondary Hyperparathyroidism
`
`
`1.2 Parathyroid Carcinoma
`
`
`1.3 Primary Hyperparathyroidism
`DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Secondary Hyperparathyroidism in Patients with Chronic Kidney
`
`Disease on Dialysis
`
`
`2.2 Parathyroid Carcinoma and Primary Hyperparathyroidism
`
`
`2.3 Monitoring for Hypocalcemia
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Hypocalcemia
`
`
`5.2 Adynamic Bone Disease
`
`
`5.3 Hepatic Impairment
`ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience with Sensipar
`
`DRUG INTERACTIONS
`
`
`7.1 Strong CYP3A4 Inhibitors
`
`
`7.2 CYP2D6 Substrates
`USE IN SPECIFIC POPULATIONS
`
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`
`
`6
`
`
`7
`
`
`
`8
`
`
`
`Reference ID: 3662356
`
`
`
` 1
`
`

`

`
`
`INDICATIONS AND USAGE
`
`
`Secondary Hyperparathyroidism
`
`
`DOSAGE AND ADMINISTRATION
`
`
`FULL PRESCRIBING INFORMATION
`
`
`1
`
`
`1.1
`
`
`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
`
`
`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
`
`
`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)].
`
`
`
`
`Reference ID: 3662356
`
`Secondary Hyperparathyroidism in Adult Patients with Chronic Kidney Disease on Dialysis
`
`
`
`
`
`
`
`
`
`
`
`
`2
`
`

`

`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
`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
`
`
`
`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
`
`
`
`
`
`
`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.
`
`
`
`
`Reference ID: 3662356
`
`
`CONTRAINDICATIONS
`
`
`3
`
`

`

`
`
`
`
` 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
`
`
`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.
`
`
`ADVERSE REACTIONS
`
`
`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
`
` (n = 470)
`
`
`
`
` (%)
`
`
` 19
`
` 15
`
` 20
`
` 14
`
` 8
`
` 5
`
` 4
`
`
`
`
`
`
` Sensipar
`
` (n = 656)
`
`
`
` (%)
`
`
` 31
`
` 27
`
` 21
`
` 15
`
` 10
`
` 7
`
` 7
`
`
`4
`
`
`
`
`
`
`
`
`
`
` Event*:
`
`
` Nausea
`
`
` Vomiting
`
` Diarrhea
`
` Myalgia
` Dizziness
`
` Hypertension
`
` Asthenia
`
`
`
`
`
`Reference ID: 3662356
`
`

`

`
`
`
` 6
`
` 6
`
` 5
`
` Anorexia
`
` 4
`
`
` 4
` Pain Chest, Non-Cardiac
`
`
`
`
` Dialysis Access Site Infection
`
` 4
` *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 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)
`
` 3699 subject-years
`
`
` 90.9
`
`
` Sensipar (N=1938)
`
` 4044 subject-years
`
`
` 93.2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Percent of subjects reporting
`
`
` Adverse Reactions (%)
`
` Nausea
`
` 29.1
`
` 15.5
` Vomiting
`
`
` 25.6
`
` 13.7
`
` Diarrhea
`
` 20.5
`
` 18.7
`
` Dyspnea
`
` 13.4
`
` 11.5
`
` Cough
`
` 11.7
` 9.8
`
`
` Hypotension
`
` 11.6
` 10.5
`
`
` Headache
`
` 11.5
` 9.6
`
`
` Hypocalcaemia
`
` 11.2
`
` 1.4
`
` Muscle spasms
`
` 11.1
`
` 9.2
`
` Abdominal pain
`
` 10.9
`
` 9.6
`
` Abdominal pain upper
` 8.2
`
`
` 6.3
`
` Hyperkalemia
`
` 8.1
`
` 6.1
` Upper respiratory tract infection
`
` 7.6
`
` 6.3
`
` Dyspepsia
`
` 7.4
`
` 4.6
`
` Dizziness
`
` 7.3
`
` 4.7
` Decreased appetite
`
`
` 5.9
`
` 3.5
`
` Asthenia
`
` 5.4
`
` 3.8
` Constipation
`
` 5.0
`
` 3.8
`
` 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
`
`
`
`
`
`
`
`Reference ID: 3662356
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`
`5
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`

`

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` dehydration and worsening hypercalcemia so careful monitoring of electrolytes is recommended in patients
` with these symptoms.
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`
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` 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),
`
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`
`
`
` 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.
`
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`
`
` Table 3. Adverse Reactions with Frequency ≥10% in a Single Arm, Open-Label Study in Patients with
`
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`
`
` Primary Hyperparathyroidism or Parathyroid Carcinoma
`
`
`
`
`
`
` Parathyroid
`
` Carcinoma
`
` (N=29)
`
`
` Sensipar
`
`
`
` Intractable
`
` pHPT
` (N=17)
`
`
`
`
`
` Total
`
` (N=46)
`
`
` n (%)
`
`
` 28 (97)
`
`
`
` 19 (66)
`
` 15 (52)
` 4 (14)
`
`
` 6 (21)
`
` 6 (21)
`
` 6 (21)
`
` 6 (21)
`
` 5 (17)
`
` 7 (24)
`
` 5 (17)
`
` 5 (17)
`
` 3 (10)
`
` 3 (10)
`
` 6 (21)
`
` 3 (10)
`
` 3 (10)
`
` n (%)
`
`
` 17 (100)
`
`
`
` 10 (59)
`
` 6 (35)
`
` 5 (29)
`
` 2 (12)
`
` 2 (12)
`
` 2 (12)
` 1 (6)
`
`
` 2 (12)
`
` 0 (0)
`
`
` 1 (6)
`
` 1 (6)
` 3 (18)
`
`
` 3 (18)
` 0 (0)
`
` 2 (12)
`
`
` 2 (12)
`
` n (%)
`
` 45 (98)
`
`
`
`
` 29 (63)
`
` 21 (46)
` 9 (20)
`
`
` 8 (17)
`
` 8 (17)
`
` 8 (17)
`
` 7 (15)
`
` 7 (15)
`
` 7 (15)
`
` 6 (13)
`
` 6 (13)
`
` 6 (13)
`
` 6 (13)
`
` 6 (13)
`
` 5 (11)
`
` 5 (11)
`
`
` Number of Subjects Reporting Adverse
`
` Reactions
`
` Nausea
`
` Vomiting
`
`
` Paresthesia
`
` Fatigue
` Fracture
`
` Hypercalcemia
`
` Anorexia
`
` Asthenia
`
` Dehydration
`
` Anemia
` Arthralgia
`
`
` Constipation
`
` Depression
`
` Headache
` Infection Upper Respiratory
`
` Pain Limb
` 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
`
`
`
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`undergo surgery, the most common adverse reactions are listed in Table 4.
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`Reference ID: 3662356
`
`
`6
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`

`

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`
` Table 4. Adverse Reactions Occurring in ≥ 10% of Subjects in a Double-Blind, Placebo-Controlled Study
`
` in Patients with Primary Hyperparathyroidism
`
`
`
`
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`
`
`
` Adverse Reaction
`
`
`
`
` Cinacalcet
`
`Placebo
`
` (N = 33)
`
`(N = 34)
`
` n (%)
`
` n (%)
` Nausea
`
` 10 (30)
`
` 6 (18)
`
`
` 6 (18)
`
` 0 (0)
` Muscle spasms
`
` 4 (12)
`
` 2 (6)
`
` Headache
`
` 4 (12)
`
` 2 (6)
`
` Back pain
`
` 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 7.5mg/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.
`
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`
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`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)].
`
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`
`7
`
`
`7.1
`
`
`Cinacalcet is partially metabolized by CYP3A4. Dose adjustment of Sensipar may be required if a patient
`
`
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`initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole). The iPTH
`
`
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`and serum calcium concentrations should be closely monitored in these patients [see Clinical Pharmacology
`
`
`
`(12.3)].
`
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`Reference ID: 3662356
`
`Strong CYP3A4 Inhibitors
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`7
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`DRUG INTERACTIONS
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` USE IN SPECIFIC POPULATIONS
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` 7.2 CYP2D6 Substrates
`
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`
` 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
`
` 8.1 Pregnancy: Category C
`
` In pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day cinacalcet during gestation, no
`
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`
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`
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` 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
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`
`
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`
`
` observed at all doses (less than 1 to 4 times a human oral dose of 180 mg/day based on AUC comparison) in
`
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` 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
`
`
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`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.
`
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`Women who become pregnant during Sensipar treatment are encouraged to enroll in Amgen’s Pregnancy
`
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`
`
`Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.
`
`
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`8.3 Nursing Mothers
`
`
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`Studies in rats have shown that Sensipar is excreted in the milk with a high milk-to-plasma ratio. It is not
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`
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`known whether this drug is excreted in human milk. Considering these data in rats, and because many drugs are
`
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`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
`
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`
`
`hypocalcaemia [see Warnings and Precautions (5.1)].
`
`
`
`8.5 Geriatric Use
`
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`
`Reference ID: 3662356
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`8
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`

`

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` Of the total number of subjects (n=1136) in clinical studies of Sensipar, 26 percent were 65 and over, and 9
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`
`
`
`
`
` 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
`
`
`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:
`
`
`DESCRIPTION
`
`
`
`
`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.
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`Reference ID: 3662356
`
`
`9
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`

`

`
`
`CLINICAL PHARMACOLOGY
`
`
`
`
`12
`
`
`
`
`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
`
`
`
`
`Reducti