FDA approved label August 1, 2011
`
`
`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
`Initial US Approval: 2004
`
`----------------------------RECENT MAJOR CHANGES-------------------------
`
`
`Indications and Usage: Primary Hyperparathyroidism (1.3)
` 02/2011
`Dosage and Administration: Parathyroid Carcinoma / Primary
`
`Hyperparathyroidism (2.2)
`
`Contraindications: Hypocalcemia (4)
`
`----------------------------INDICATIONS AND USAGE---------------------------
`Sensipar is a calcium-sensing receptor agonist indicated for:
`
`
`• Secondary Hyperparathyroidism (HPT) in patients with chronic kidney
`
`disease (CKD) on dialysis. (1.1)
`
`
`
`• Hypercalcemia in patients with Parathyroid Carcinoma (PC). (1.2)
`
`
`• Severe hypercalcemia in patients with primary HPT who are unable to
`
`undergo parathyroidectomy. (1.3)
`
`02/2011
` 02/2011
`
`
`
`----------------------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.
`
`iPTH levels should be measured no earlier than 12 hours after most
`recent dose.
`
`• Hypercalcemia in patients with PC or severe 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.
`
`o
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`Tablets: 30, 60, and 90 mg tablets (3)
`
`
`
`
`-------------------------------CONTRAINDICATIONS ----------------------------
`Hypocalcemia: Sensipar treatment should not be initiated if serum calcium is
`
`
`less than the lower limit of the normal range. (4, 5.1)
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
`• Hypocalcemia and/or seizures: May occur due to significant reductions in
`serum calcium. (5.1, 5.2)
`
`• Isolated, idiosyncratic occurrences of hypotension, worsening heart failure,
`and/or arrhythmia: Have been reported in patients with impaired cardiac
`
`
`function during Sensipar treatment, which may be mediated by reductions
`
`in serum calcium. (5.3)
`
`• Adynamic bone disease: May develop if iPTH levels are suppressed below
`
`100 pg/mL. (5.4)
`
`
`
`• Laboratory tests: Serum calcium, serum phosphorus, and iPTH levels
`should be monitored during the dose initiation, dose titration, and
`maintenance therapy. (5.6)
`
`• Hepatic Impairment: Cinacalcet exposure is increased in patients with
`
`moderate and severe hepatic impairment. Patients should be closely
`
`monitored throughout treatment. (5.5, 8.7)
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`The most frequently reported adverse reactions (incidence in patients ≥ 5% in
`
`the Sensipar group) were nausea, vomiting, and diarrhea. (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)
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`13
`
`14
`
` INDICATIONS AND USAGE
`
`1.1 Secondary Hyperparathyroidism
`1.2
` Parathyroid Carcinoma
`
`
` Primary Hyperparathyroidism
`1.3
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
` Secondary Hyperparathyroidism in Patients with Chronic Kidney
`2.1
`
`Disease on Dialysis
`
`2.2 Parathyroid Carcinoma and Primary Hyperparathyroidism
`3
`DOSAGE FORMS AND STRENGTHS
`
`4
`CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1
` Hypocalcemia
`5.2
` Seizures
`
`
`5.3 Hypotension and/or Worsening Heart Failure
`5.4 Adynamic Bone Disease
`5.5
` Hepatic Impairment
`5.6 Laboratory Tests
` 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: Category C
`8.3
` Nursing Mothers
`8.4
` Pediatric Use
`8.5
` Geriatric Use
`
`
`
`Revised: 08/2011
`
`__________________________________________________________________________________________________________________________________
`8.6
` Renal Impairment
`FULL PRESCRIBING INFORMATION: CONTENTS*
`8.7
` Hepatic Impairment
`
`10 OVERDOSAGE
`1
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
` NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
` CLINICAL STUDIES
`
`
`
`
`14.1 Secondary Hyperparathyroidism in Patients with Chronic Kidney
`
`Disease on Dialysis
`14.2 Parathyroid Carcinoma
`14.3 Patients with Severe 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.
`
`2
`
`6
`
`7
`
`
`8
`
`
`
`Reference ID: 2981969
`
`1
`
`

`

`
`
`INDICATIONS AND USAGE
`
`
`
`
`Secondary Hyperparathyroidism
`
`
`DOSAGE AND ADMINISTRATION
`
`Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`1
`
`1.1
`
`Sensipar is indicated for the treatment of secondary hyperparathyroidism (HPT) in patients with chronic kidney
`disease (CKD) on dialysis [see Clinical Studies (14.1)].
`
`
`1.2 Parathyroid Carcinoma
`
`
`Sensipar is indicated for the treatment of hypercalcemia in patients with Parathyroid Carcinoma [see Clinical
`
`
`Studies (14.2)].
`
`1.3 Primary Hyperparathyroidism
`
`
`Sensipar is indicated for the treatment of severe hypercalcemia in patients with primary HPT 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. 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 Warnings and
`
`
`Precautions (5.1, 5.6)].
`
`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 [see Warnings and Precautions (5.6)].
`
`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.
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
`
`Reference ID: 2981969
`
`2
`
`

`

`
`
`
`
`Seizures
`
`CONTRAINDICATIONS
`
`
`
`4
`
`Hypocalcemia: Sensipar treatment should not be initiated 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. Potential manifestations of hypocalcemia include paresthesias, myalgias, muscle cramping,
`tetany, and convulsions.
`
`
`
`
`
`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 (2.1)].
`
`
`
`
`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)].
`
`In 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 patients with CKD not on dialysis. 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.
`
`5.2
`
`
`
`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 [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`5.3 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)].
`
`
`
`5.4 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
`
`
`
`Reference ID: 2981969
`
`3
`
`

`

`
`
` 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.
`
`5.5 Hepatic Impairment
`
`
`Cinacalcet exposure, as defined by the Area Under the Curve (AUC0-inf), 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)].
`
`5.6 Laboratory Tests
`
`
`Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis
`
`
`
`
`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 iPTH every 1 to 3 months [see
`
`
`
`Dosage and Administration (2.1)]. Measurements of PTH during the Sensipar studies were obtained using the
`Nichols iPTH immunoradiometric assay (IRMA).
`
`
`In patients with end-stage renal disease, testosterone levels are often below the normal range. In a
`
`placebo-controlled study in patients with CKD on dialysis, there were reductions in total and free testosterone in
`
`male patients following 6 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 or Primary Hyperparathyroidism
`
`
`
`
`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 (2.2)].
`
`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 (incidence of at
`
`
`least 5% in the Sensipar group and greater than placebo) are provided in Table 1. The most frequently reported
`
`adverse reactions in the Sensipar group were nausea, vomiting, and diarrhea.
`
`
`
`Seizures were observed in 1.4% (13/910) of cinacalcet-treated patients and 0.7% (5/641) of placebo-treated
`
`patients across all completed placebo controlled trials.
`
`
`
`
`
`Reference ID: 2981969
`
`4
`
`

`

`
`
`
`
`
`
`Event*:
`
`
`Nausea
`19
`Vomiting
`15
`Diarrhea
`20
`Myalgia
`14
`Dizziness
`8
`Hypertension
`
`5
`Asthenia
`
`4
`Anorexia
`
`4
`Pain Chest, Non-Cardiac
`4
`Access Infection
`4
`*Included are events that were reported at a greater incidence in the Sensipar group than in the placebo group.
`
`Placebo
`(n = 470)
`
`(%)
`
`
`
`
`
`
`
`
`
`Sensipar
`(n = 656)
`
`(%)
`
`31
`27
`21
`15
`10
`7
`
`7
`6
`6
`5
`
`
`
`
`
`
`
`
`
`Table 1. Adverse Reaction Incidence (≥ 5%) in Patients on Dialysis
`
`
`
`The incidence of serious adverse reactions was similar in the Sensipar and placebo groups (29% vs. 31%,
`respectively).
`
`
`12-Month Experience with Sensipar in Secondary Hyperparathyroidism
`
`
`
`
`Two hundred sixty-six patients from two of the phase 3 studies in patients with CKD on dialysis 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 reactions in this long term extension study were comparable to
`those observed in the original phase 3 studies.
`
`
`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 cinacalcet 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 while on 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.
`
`
`
`
`
`
`
`
`
`Reference ID: 2981969
`
`5
`
`

`

`
`
`
`
`
`
`
`
`Preferred Term
`
`
`Table 2. Adverse Reactions Occurring in ≥10% of Total Subjects
`
`Parathyroid
`Carcinoma
`(N=29)
`
`Cinacalcet
`
`
`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)
`
`
`
`
`DRUG INTERACTIONS
`
`
`Strong CYP3A4 Inhibitors
`
`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
`Events
`
`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.
`
`
`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, hypersensitivity reactions (including angioedema and urticaria), diarrhea, and myalgia have been
`
`identified as adverse reactions during postapproval 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.
`
`
`7
`
`7.1
`
`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)].
`
`
`
`
`Reference ID: 2981969
`
`6
`
`

`

`
`
`USE IN SPECIFIC POPULATIONS
`
`
`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
`
`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.
`
` 8.4 Pediatric Use
`
`
`The safety and efficacy of Sensipar in pediatric patients have not been established.
`
`
`8.5 Geriatric Use
`
`
`
`Of the 1136 patients enrolled in the Sensipar phase 3 clinical program in patients with CKD on dialysis,
`
`
`
`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. No dosage adjustment is required for geriatric
`patients [see Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`
`Reference ID: 2981969
`
`7
`
`

`

`
`
`
`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-inf) is increased
`
`by 2.4 and 4.2 fold, respectively, in these patients [see Warnings and Precautions (5.5) 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.
`
`
`12
`
`12.1 Mechanism of Action
`
`
`Secondary HPT in patients with CKD is a progressive disease, associated with increases in PTH levels and
`
`
`
`derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting
`
`
`8
`
`
`CLINICAL PHARMACOLOGY
`
`
`Reference ID: 2981969
`
`

`

`
`
`
`
`in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary HPT are to lower the
`
`
` levels of PTH, calcium, and phosphorus in the blood in order to prevent progressive bone disease and the
` systemic consequences of disordered mineral metabolism. Reductions in PTH are associated with a decrease in
`
`
`
`
`
`
` bone turnover and bone fibrosis in patients with CKD on dialysis and uncontrolled secondary HPT.
`
`The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator
`
`of PTH synthesis and 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. Measurements of PTH during the Sensipar studies were obtained using the
`Nichols IRMA.
`
`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.
`
`
`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-inf) 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-inf) 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
`
`β-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.
`
`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 3 and 4 list the findings from in vivo drug-drug interaction studies.
`
`
`
`
`
`Reference ID: 2981969
`
`9
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`

`

`
`
`
`
`
`
`Table 3. Effect of co-administered drugs on cinacalcet
`
`Co-administered drug and dosing
`
`regimen
`
`200 mg ketoconazole twice daily for
`
` 7 days
`1500 mg calcium carbonate, single dose
`80 mg pantoprazole daily for 3 days
`
`2400 mg sevelamer HCl three times a
`day for 2 days
`
`Dose*
`
`
`
` 90 mg on day 5
`
`Cinacalcet
`Mean change in
`
`AUC
`↑128%
`
`Mean change in
`
`Cmax
`↑116%
`
`100 mg
`
`90 mg on day 3
`
`90 mg on day 1 with first
`
`
`
`dose of sevelamer
`
`↓6%
`↑1%
`↓4%
`
`↓5%
`↓3%
`↓7%
`
`
`
` *Single dose.
`
`
`
`
`Table 4. Effect of cinacalcet co-administration on other drugs
`
`
`
`Name and Dose
`25 mg warfarin*
`
`tablet†
`
`50 mg desipramine†
`
`
`Co-administered drug
`
`
`Mean change in AUC(0-inf)
`↑1 % for R-warfarin
`↓1% S-warfarin
`
`↑264%
`
`
`Mean change in Cmax
`
`↓10 % for R-warfarin
`
`↓12 % for S-warfarin
`
`↑75%
`
`Cinacalcet dosing
`r