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
`
`----------------------------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):
`
`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 (2.3):
`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.
`
`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)
`
`
`
`
`
`-------------------------------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)
`
`sP Kd2PKh iqirluslO tOQlcil cltusSp-i0 )PThk)h tDydT
`gd(:)kH STCPKDkh:PT kh /zM99zGGztgel- ,/
`zM99zGG6zI8≥I3 PK aOt kh
`
`/zM99zaOt z/9MM PK %%%UC(kUyPLYDd(%kh)o U
`
`zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
`zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzOcqe S-slctusSp-i
`
` 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
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`Tablets: 30, 60, and 90 mg tablets (3)
`
`__________________________________________________________________________________________________________________________________
`8.4 Pediatric Use
`FULL PRESCRIBING INFORMATION: CONTENTS*
`8.5 Geriatric Use
`8.6 Renal Impairment
`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
`
`6
`
`7
`
`8
`
`Reference ID: 4411701
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`1
`
`1
`
`2
`
`INDICATIONS AND USAGE
`1.1 Secondary Hyperparathyroidism
`1.2 Parathyroid Carcinoma
`1.3 Primary Hyperparathyroidism
`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
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`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
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`DRUG INTERACTIONS
`7.1 Strong CYP3A4 Inhibitors
`7.2 CYP2D6 Substrates
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`
`

`

`FULL PRESCRIBING INFORMATION
`
`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
`
`2
`
`Reference ID: 4411701
`
`

`

`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.
`
`3
`
`Reference ID: 4411701
`
`

`

`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.
`
`4
`
`Reference ID: 4411701
`
`

`

`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
`(n = 470)
`(%)
`Event*:
`19
`Nausea
`15
`Vomiting
`20
`Diarrhea
`14
`Myalgia
`8
`Dizziness
`5
`Hypertension
`4
`Asthenia
`4
`Anorexia
`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.
`
`Sensipar
`(n = 656)
`(%)
`31
`27
`21
`15
`10
`7
`7
`6
`6
`5
`
`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.
`
`Reference ID: 4411701
`
`5
`
`

`

`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 (%)
`29.1
`15.5
`Nausea
`25.6
`13.7
`Vomiting
`20.5
`18.7
`Diarrhea
`13.4
`11.5
`Dyspnea
`11.7
`9.8
`Cough
`11.6
`10.5
`Hypotension
`11.5
`9.6
`Headache
`11.2
`1.4
`Hypocalcemia
`11.1
`9.2
`Muscle spasms
`10.9
`9.6
`Abdominal pain
`8.2
`6.3
`Abdominal pain upper
`8.1
`6.1
`Hyperkalemia
`7.6
`6.3
`Upper respiratory tract infection
`7.4
`4.6
`Dyspepsia
`7.3
`4.7
`Dizziness
`5.9
`3.5
`Decreased appetite
`5.4
`3.8
`Asthenia
`5.0
`3.8
`Constipation
`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.
`
`6
`
`Reference ID: 4411701
`
`

`

`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)
`
`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.
`
`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)
`
`Intractable
`pHPT
`(n = 17)
`
`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)
`
`Total
`(n = 46)
`
`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)
`
`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 (%)
`6 (18)
`Nausea
`0 (0)
`Muscle spasms
`2 (6)
`Headache
`2 (6)
`Back pain
`n = Number of subjects receiving at least one dose of study drug Coded using MedDRA version 16.0.
`
`Cinacalcet
`(n = 33)
`n (%)
`10 (30)
`6 (18)
`4 (12)
`4 (12)
`
`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
`
`7
`
`Reference ID: 4411701
`
`

`

`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
`DRUG INTERACTIONS
`
`7
`
`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].
`
`8
`
`Reference ID: 4411701
`
`

`

`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
`
`9
`
`Reference ID: 4411701
`
`

`

`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-amino