CENTER FOR DRUG EVALUATION AND ,
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-688
`
`APPROVED LABELING
`
`

`

`VSenSiparTM (cinacalcet HCI) Tablets
`
`DESCRIPTION
`
`SensiparT’M (cinacalcet hydrochloride) is a calcimimetic agent that increases the
`sensitivity of the calcium-sensing receptor to activation by eittracellular calcium. Its
`empirical formula is C22H22F3N-HC1 with a molecular weight of 393.9 g/mol
`(hydrochloride salt) and 357.4 g/mol (free base). It has one chiral center having an R-
`. absolute configuration. The R-enantiomer is the more potent enantiomer and has been
`’shOwn to be responsible for pharmacodynamic activity.
`
`Cinacalcet HCl is a white to off-white, crystalline solid that is soluble in methanol or
`95% ethanol and slightly soluble in water.
`'
`
`SensiparW tablets are formulated as light—green, film-coated, ovalfshaped tablets for Oral
`administration in strengths of 30 mg, 60 mg, and 90 mg of cinaCalcet HCl as the free base
`equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively).
`Cinacalcet HCl is described chemically as N-[1—(R)-(-)-(1-naphthyl)ethyl]—3-[3-
`(trifluoromethyl)phenyl]-l‘aminopropane hydrochloride and has the following structural
`formula:
`'
`
`F30
`
`oHCl
`
`CH3
`
`O
`
`Inactive Ingredients: SensiparTM tablets are comprised of the active ingredient, and the
`following inactive ingredients: pre-gelatinized starch, microcrystalline cellulose,
`povidone, crOspovidone, colloidal silicon dioxide, and magnesium stearate. Tablets are ‘
`coated with color (Opadry® II green) and clear film-coat (Opadry® clear), camauba wax,
`and Opacode® black ink.
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`
`V
`
`Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is
`a progressive disease, associated with increases in parathyroid hormone (PTH) levels and
`derangements in calcium and phosphorus metabolism. Increased PTH stimulates '
`osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals
`of treatment of secondary hyperparathyroidism are to lOwer levels of PTH, calcium, and
`phosphorus in the blood, in order to prevent progressive bone disease and the systemic
`consequences of disordered mineral metabolism. In CKD patients on dialysis with
`uncontrolled secondary HPT,rreductions in PTH are associated with a favorable impact
`on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis.
`
`The calcium—sensing receptor on the surface of the‘chief cell of the parathyroid gland is
`the principal regulator of PTH secretion. SensiparTM directly lowers PTH levels by
`
`

`

`increasing the sensitivity of the calcium sensing receptor to extracellular calcium. The '
`reduction in PTH is associated with a concomitant decrease in serum calcium levels.
`
`Pharmacokinetics
`
`Absorption and Distribution: Afier oral administration of cinacalcet, maximum plasma
`. concentration (Cm) is achieved in approximately 2 to 6 hours. A food-effect study in .
`healthy volunteers indicated that the Cmax and area under the curve (AUC(o.jnf)) were
`increased 82% and 68%, respectively, when cinacalcet was administered with a high-fat
`meal compared} to fasting. Cm and AUC(o_in0 of cinacalcet were increased 65% and
`50%, respectively, when cinacalcet was administered with a low-fat meal compared to
`fasting.
`
`After absorption, cinacalcet concentrations decline in a biphasic fashion with a terminal
`half-life of 30 to 40 hours. Steady-state drug levels are achieved within 7 days. The mean
`accumulation ratio is approximately 2 with once-daily oral administration. The median
`accumulation ratio is approximately 2 to 5 with twice-daily oral administration. The AUC
`and Cmax of cinacalcet increase proportionally over the dose range of 30 to 180 mg once
`daily. The pharmacokinetic profile of cinacalcet does not change over time with once—
`daily dosing of 30 to 180 mg. The volume of distribution is high (approximately 1000
`L), indicating extensive distribution. Cinacalcet is approximately 93 to 97% bound to
`plasma protein(s). The ratio of blood cinacalcet concentration to plasma cinacalcet
`concentration is 0.80 at a blood cinacalcet concentration of 10 ng/mL.
`
`Metabolism and Excretion: Cinacalcet is metabolized by multiple enzymes, primarily
`CYP3A4, CYP2D6 and CYP1A2. After administration of a 75 mg radiolabeled dose to
`healthy volunteers, cinacalcet was rapidly and extensively metabolized via: 1) oxidative
`N—dealkylation to hydrocinnarnic acid and hydroxy-hydrocinnamic acid, which are
`further metabolized via B-oxidation and glycine conjugation; the oxidative N-
`dealkylation process also generates metabolites that contain the naphthalene ring; and‘ 2)
`oxidation of the naphthalene ring on the parent drug to form dihydrodiols, which are
`further conjugated with glucuronic acid. The plasma concentrations of the major
`circulating metabolites including the cinnamic acid derivatives and glucuronidated
`dihydrodiols markedly exceed parent drug concentrations. The hydrocinnarnic acid
`metabolite was shown to be inactive at concentrations up to 10 11M in a cell-based assay
`measuring calcium-receptor activation. The glucuronide conjugates formed after
`cinacalcet oxidation were shown to have a potency approximately 0.003 times that of
`‘ cinacalcet in a cell-based assay measuring a calcimimetic response. Renal excretion of
`~metabolites was the primary route of elimination of radioactivity. Approximately 80% of '
`the ddsewas recoVered1n the urine and 15%1n the feces.
`
`Special Populations
`
`Hepatic Insufficiency: The disposition of a 50 mg cinacalcet single dose was compared
`in patients with hepatic impairment and subjects with normal hepatic function.
`CinacaICet exposure, AUC(0-inf), was comparable between healthy volunteers and patients
`with mild hepatic impairment. However, in patients with moderate and severe hepatic
`impairment (as indicated by the Child-Pugh method), cinacalcet exposures as defined by
`
`

`

`the AUCmno were 2.4 and 4.2 times higher, respectively, thanthat in normals. The mean .
`half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe
`hepatic impairment, respectively. Protein binding of cinacalcet is not affected by
`impaired hepatic function. See PRECAUTIONS and DOSAGE AND
`ADMINISTRATION.
`
`Renal Insufficiency: The phannacoldnetic profile of a 75 mg SensiparTM single dose in
`patients with mild, moderate, and severe renal insufficiency, and those on hemodialysis
`or peritoneal dialysis is comparable to that in healthy volunteers.
`
`Geriatric Patients: The pharmacokinetic profile of Sensipar"M in geriatric patients (age
`2 65, n = 12) is similar to that for patients who are < 65 years of age (11 = 268).
`Pediatric Patients: The pharmacokinetics of SensiparTM have not been studied1n
`
`patients < 18 years of age
`
`Drug lnteraCtions
`
`An in vitro study indicates that cinacalcet is a strong inhibitor of CYP2D6, but not of
`CYP1A2, CYP2C9, CYP2C19, and CYP3A4.
`
`Ketoconazole: Cinacalcet AUCmino and Cmax increased 2.3 and 2.2 times, respectively,
`when a single 90 mg cinacalcet dose on Day 5 was administered to subjects treated with
`200 mg ketoconazole twice daily for 7 days compared to 90 mg cinacalcet given alone
`(see DOSAGE AND ADMINISTRATION). -
`
`Calcium Carbonate: No significant pharmacokinetic interaction was observed when 1500
`mg calcium carbonate was coadministered with 100 mg cinacalcet.
`
`Pantoprazole: No significant pharmacokinetic interaction was observed when cinacalcet
`90 mg was administered to subjects treated with 80 mg pantoprazole daily for 3 days.
`
`Sevelamer HCl: No significant pharmacokinetic interaction was observed when 2400 mg
`sevelamer HCl was coadministered with 90 mg cinacalcet tablet (subjects subsequently
`received 2400 mg sevelamer HCl two more times on Day 1 and three more times on Day
`2).
`'
`
`'Amitriptyline: Concurrent administration of 25 mg or 100 mg cinacalcet with 50 mg
`amitriptyline increased amitriptyline exposure and nortriptyline (active metabolite)
`exposure by approximately 20% in CYP2D6 extensive metabolizers.
`
`Warfarin: R-and S-warfarin pharmacokinetics and warfarin pharmacodynamics were not
`affected in subjects treated with warfarin 25 mg who received cinacalcet 30 mg twice
`daily. The lack of effect of cinacalcet on the pharmacokinetics of R- and S-warfarin and
`the absence of auto-induction upon multiple dosing in patients indicates that cinacalcet is
`not an inducer of CYP2C9 in humans.
`
`

`

`Phannacodynamics '
`
`Reduction in intact PTH (iPTH) levels correlated with cinacalcet concentrations in CKD
`patients. The nadir in iPTH level occurs approximately 2 to 6.hours post dose,
`corresponding with the Cm of cinacalcet. After steady state is reached, serum calcium
`concentrations remain constant over the dosing interval in CKD patients.’
`
`‘ CLINICAL STUDIES
`
`Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease
`'on Dialysis
`'
`
`Three 6-month, multicenter, randomized, double-blind, placebo-controlled clinical '
`studies of similar design were conducted in CKD patients on dialysis. A total of 665
`patients were randomized to SensiparTM and 471 patients to placebo. The mean age of the
`patients was 54 years, 62% were male, and 52% Caucasian. The average baseline iPTH
`level by the Nichols intact irnmunoradiometric assay (IRMA) was 712 pg/mL, with 26%
`of the patients having a baseline iPTH level > 800 pg/mL. The mean baseline Ca x P ion
`product was 61 mgz/sz. The average duration of dialysis prior to study enrollment was
`67 months. Ninety—six percent of patients were on hemodialysis and 4% peritoneal
`dialysis. At study entry, 66% of the patients were receiving vitamin D sterols and 93%
`
`were receiving phosphate binders. SensiparTM (or placebo) was initiated at a dose of 30
`- mg once daily and titrated every 3 or 4 weeks to a maximum dose of 180 mg once daily
`' to achieve an iPTH of S 250 pg/mL. The dose was not increased if a patient had any of
`the following: iPTH 5 200 pg/mL, serum calcium < 7.8 mg/dL, or any symptoms of
`hypocalcemia. If a patient experienced symptoms of hypocalcemia or had a serum
`calcium < 8.4 mg/dL, calcium supplements and/or calcium—based phosphate binders
`could be increased. If these measures were insufficient, the vitamin D dose could be
`
`'
`
`increased. Approximately 70% of the SensiparTM patients and 80% of the placebo
`patients completed the 6-month studies. In the primary efficacy analysis, 40% of
`SensiparTM patients and 5% of placebo patients achieved an iPTH S 250 pg/mL (p<0.001)’
`(Table 1, Figure 1). Secondary efficacy parameters also improved in patients treated with
`SensiparTM. These studies showed that SensiparTM reduced PTH while lowering Ca x P,
`calcium and phosphdrus levels (Table 1, Figure 2). The median dose of SensiparTM at the
`completion of the studies was 90 mg. Patients with milder disease typically required
`lower doses.
`'
`’
`
`

`

`Table 1. Effects’of SensiparTM on iPTH, Ca x P, Serum Calcium, and Serum Phosphorus in 6-month Phase 3 Studies
`Patients On Dial sis
`
`
`
`
`Placebo
`SensiparTM
`Placebo
`
`Placebo
`Sensipar'l'M
`
`SensiparTM
`(N = 294)
`(N = 101)
`(N= 165)
`-
`(N=166)
`(N= 205)
`(N = 205)
`
`
`
`
`
` iPTH
`
`
`Baseline (pg/mL): Median
`'
`Mean (SD)
`
`
`Evaluation Phase (pg/ml.)
`
`
`Median Percent Change
`
`
`Patients Achieving Primary Endpoint (iPTl-l
`S 250 pg/mL) (%)a
`
`
`Patients Achieving 2 30% Reduction in
`iPTH (%)“
`
`
`
`
`
`
`
`Patients Achieving iP’l‘H S 250 pg/mL and
`Ca x P < 55 mg2/sz (%)
`
`535
`651 (398)
`563
`. +3.8
`4%
`
`'
`
`11%
`
`'
`
`1%
`
`62
`
`59
`
`537
`636 (341)
`275
`48.3
`41%M
`
`556
`630 (317)
`592
`+8.4
`7%
`
`,
`
`61%
`
`A
`
`32%
`
`61
`
`52
`
`12%
`
`‘
`
`5%
`
`61
`
`547
`652 (372)
`' 238
`-54.1
`46%“
`
`.
`
`68%
`
`35%
`
`670
`832 (486)
`737
`+2.3
`6%
`
`«
`
`10%
`
`'
`
`5%
`
`-
`
`.
`
`_
`
`V
`
`61 ,
`
`61
`
`703 '
`848 (685)
`339
`-48.2
`35%“
`
`59%
`1
`
`~
`
`28%
`
`59
`
`Ca )1 P
`Baseline (ng/sz)
`
`‘
`
`1
`
`Evaluation Phase (mgz/dLZ)
`
`Median Percent Change
`-2.0
`~14.9
`
`** p < 0.001 compared to placebo; p:values presented for primary endpoint only
`‘ iPTI-I value based on averaging over the evaluation phase (defined as weeks 13 to 26 in studies 1 and 2 and weeks 17 to 26 in study 3)
`Values shown are medians unless indicated otherwise '
`
`

`

`Table 1 (continued). Effects of SenslparTM on iPTH, Ca x P, Serum Calcium, and Serum PhosphorUs in 6-month Phase 3
`
`Studies Patients on Dial sis '
`
`Placebo
`
`
`
`Sensipar"'M
`Placebo
`
`Placebo
`Sensipar"M
`
`SensiparTM
`‘(N = 294)
`(N = 101)
`
`(N = 165)
`(N =-166)
`(N = 205)
`
`
`
`
`(N = 205)
`
`
`
`Calcium
`_
`>
`_
`‘
`Baseline (mg/dL)
`9.8
`9.8
`9.9
`100
`9.9
`9.8
`
`Evaluation Phase (mg/dL)
`9.9
`9.1
`9.9
`9.1
`10.0
`9.1
`1 Median Percent Change
`+0.5
`-5.5
`+0.1
`-7.4
`+0.3
`-6.0
`
`Phosphorus
`V
`.
`6.1
`6.1
`‘
`' Baseline (mg/dL)
`6.3
`6.1
`6.0
`
`5.9
`5.6
`Evaluation Phase (mg/dL)
`6.0
`5.6
`‘
`5.1
`-12.4 " -5.6
`-2.4
`-9.0
` Median Percent Change
`-1 .0
`
`'
`** p < 0.001 compared to placebo; p—values presented for primary endpoint only
`“
`iPTH value based on averaging over the evaluation phase (defined as weeks 13 to 26 in studies 1 and 2 and weeks 17 to 26 in study 3)
`Values shown are medians unlesslindicated otherwise
`
`
`
`6.0
`
`5.3
`
`‘
`
`.
`
`’
`
`.
`
`‘
`
`.
`
`_
`
`‘
`
`'
`
`

`

`Figure 1. Mean (SE) iPTH Values (Pooled Phase 3 Studies)
`
`60-0 Placebo
`
`9—0-0 SensiparTM
`‘
`
`'
`
`i
`
`“DO
`
`§
`
`§
`
`iPTH(pg/th) §
`
`§
`
`' 0
`
`.—
`
`'fl
`
`§—'-§—~é-—é~-é~-+"§“*é—-é~—§—-§—+— .s
`
`P < 0.001
`
`012 3
`
`4
`
`5
`
`e
`
`7
`
`a 91011121é14151e171s1920§122252421626
`
`Week'
`
`Data are presented for patients who completed the studies; Placebo. (N = 342), SensiparTM (N =
`439).
`'
`
`

`

`Figure 2._ Mean (SE) Ca x P Values (Pooled Phase 3 Studies)
`
`70
`
`90-0 Ptacebo
`
`i m Sensiparm
`
`CaxP(mgldL)2 aS
`
`3:
`
`0
`
`.012 3
`
`4
`
`5
`
`6
`
`7
`
`8 91011121314151617181920212223242525
`Week
`
`Data are presented for patients who completed the studies; Placebo (N = 342), SensiparTM (N =
`439)
`
`Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment.
`
`' SensiparTM decreased iPTH and Ca x P levels regardless of disease severity (i.e., baseline
`iPTH value), duration of dialysis, and whether or not vitamin D sterols were
`administered. Approximately 60% of patients with mild (iPTH 2 300 to s 500 pg/mL),
`41% with moderate (iPTH > 500 to 800 pg/mL), and 11% withsevere (iPTH > 800
`pg/mL) secondary HPT achieved a mean iPTH value of 250 pg/mL. Plasma iPTH levels
`were measured using the Nichols IRMA.
`
`In CKD patients with secondary HPT not on dialysis, the long-term safety and efficacy of
`‘ SensiparTM have not been established. Exploratory investigation indicates that CKD
`patients not on dialysis havean increased risk for hypocalcemia compared to CKD
`patients on dialysis, which may be due to lower baseline calcium levels. In a small,
`short-term study, in which the median dose of cinacalcet was 30 mg at the completion of
`the study, _74% of cinacalcet treated patients experienced at least one serum calcium value
`< 8.4 mg/dL (see PRECAUTIONS, Hypocalcemia).
`
`Parathyroid Carcinoma
`
`Ten patients with parathyroid carcinoma were enrolled in an open-label study. The study
`consisted of 2 phases, a dose-titration phase and a maintenanée phase.
`.
`
`' The range of exposure was 2 to 16 weeks in the titration phase (n = 10) and 16 to 48
`- weeks (n = 3) for the maintenance phase. Baseline mean (SD) serum calcium was 14.7
`
`

`

`(1.8) mg/dL- The range of change from baseline to last measurement was —7.5 to 2.7
`mg/dL during the titration phase and ‘—7.4 to 0.9 mg/dL during the maintenance phase
`(Figure, 3). No patients maintained a serum calcium level within the normal range. The
`- doses ranged from 70 mg twice-daily to 90 mg four times daily for patients in the
`maintenance phase.
`'
`'
`’
`
`Figure 3. Serum Calcium Values in Parathyroid Carcinoma Patients Receiving
`SensiparTM at Baseline, Titration and Maintenance Phase
`
`, 20.0
`
`17.5
`
`
`
`SerumCatcium(mg/d3.)
`
`s33o
`
`12.5
`
`10.0
`
`7.5‘
`
`B
`
`’
`
`T"
`
`4,
`
`7
`
`Sensiparm
`
`.
`
`M
`
`Solid lines represent individual patient data
`B = baseline; T = last value in titration'phase; M = last value in maintenance phase
`Reference lines (dashed) show the normal range for serum calcium values
`
`INDICATIONS AND USAGE
`
`,
`
`SensiparTM is indicated for the treatment of secondary hyperparathyroidism in patients
`with Chronic Kidney Disease on dialysis.
`
`SensiparTM is indicated for the treatment of hypercalcemia in patients with parathyroid
`carcinoma.
`
`CONTRAINDICATIONS
`
`

`

`SensiparTMlS contraindicated1n patients with.hypersensitivity to any component(s) ofthis
`product.
`
`' WARNINGS
`
`Seizures
`
`In three clinical studies of CKD patients on dialysis, 5% of the patients in‘both the
`SensiparTM and placebo groups reported a history of seizure disorder at baseline. During
`the trials, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (9/656)
`of SensiparTM-treated patients and 0.4% (2/470) of placebo-treated patients. Five of the
`nine SensiparTM-treated patients had a history of a seizure disorder and two were
`receiving anti-seizure medication at the time of their seizure. Both placebo-treated
`patients had a history of seizure disorder and were receiving anti-seizure‘medication at
`the time of their seizure. While the basis for the reported difference in seizure rate is not
`clear, the threshold for seizures is lowered by significant reductions in serum calcium
`levels. Therefore, serum calcium levels should be closely monitored in patients receiving
`SensiparTM, particularly in patients with a history of a seizure disorder (see
`PRECAUTIONS, Hypocalcemia).
`
`PRECAUTIONS
`
`General
`
`Hypocalcemia
`
`SensiparTM lowers serum calcium, and therefore patients should be carefully
`monitored for the occurrence of hypocalcemia. Potential manifestations of
`hypocalcemia include paresthesias, myalgias, cramping, tetany, and convulsions.
`
`SensiparTM treatment should not be initiated if serum calcium is less than the lower limit
`of the normal range (8.4 mg/dL). Serum calcium should be measured within 1 week after
`initiation or dose adjustment of SensiparTM. Once the maintenance dose has been
`established, serum calcium should be measured approximately monthly (see DOSAGE
`AND ADMINISTRATION).
`If serum calcium falls below 8.4 mg/dL but remains above 7.5 mg/dL, or if symptoms of
`hypocalcemia occur, calcium-containing phosphate binders and/or vitamin D sterols can
`be used to raise serum calcium. If serum calcium falls below 7.5 mg/dL, or if symptoms
`of hypocalcemia persist and the dose of vitamin D cannot be increased, withhold
`administration of SensiparTM until serum calcium levels reach 8.0 mg/dL, and/or
`symptoms of hypocalcerma have resolved. Treatment should be re--initiated using the
`next lowest dose of SensiparTM (see DOSAGE AND ADMINISTRATION).
`
`-
`
`In the 26-week studies of patients with CKD on dialysis, 66% of patients receiving
`SensiparTM 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.
`.
`
`

`

`In CKD patients with secondary HPT not on dialysis, the long-term safety and efficacy of
`SensiparTM have not been established. Exploratory investigation indicates that CKD
`patients not on dialysis have an increased risk for hypocalcemia compared to CKD
`patients on dialysis, which may be due to lower baseline calcium levels. In a small,
`short-term study,1n which the median dose of cinacalcet was 30 mg at the completion of
`the study, 74% of cinaCalcet treated patients experienced at least one serum calcium value
`< 84 mg/dL.
`
`Adynamic Bone Disease
`
`Adynamic bone diSease may develop if iPTH levels are suppressed below 100 pg/mL
`when assessed using the standard Nichols IRMA. One clinical study evaluated bone
`histomorphometry in patients treated with SensiparlM for one year. Three patients with
`mild hyperparathyroid bone disease at the beginning of the study developed adynamic
`bone disease during treatment with Sensiparm. Two of these patients had iPTH levels
`below 100 pg/mL at multiple time points during the study. In the three 6-month, phase 3
`studies conducted in CKD patients on dialysis, 11% of patients treated with SensiparTM
`had mean iPTH values below 100 pg/mL during the efficacy-assessment phase. If iPTH
`levels decrease below the NKF-K/DOQI recommended target range (150-300 pg/mL) 1 in
`patients treated with SensiparTM, the dose of SensiparTM and/or vitamin D sterols should
`be reduced or therapy discontinued.
`
`Hepatic insufficiency
`
`Cinacalcet exposure as assessed by AUC(0_;,,0 in patients with moderate and severe
`hepatic impairment (as indicated by the Child—Pugh method) were 2.4 and 4.2 times
`higher, respectively, than that in normals. _Patients with moderate and severe hepatic
`impairment should be monitored throughout treatment with SensiparTM (see CLINICAL
`PHARMACOLOGY, Pharrnacokinetics and DOSAGE AND ADMINISTRATION).
`
`information for Patients
`‘It is recommended that SensiparTM be [taken with food or shortly after a meal. Tablets
`should be taken whole and should not be divided.
`
`Laboratory Tests
`
`Patients with CKD on Dialysis with Secondary Hyperparathyroidism
`
`Serum calcium and serum phosphorus should be measured within 1 week and iPTH
`- should be measured 1 to 4 weeks after initiation or dose adjustment of SensiparTM. Once
`the maintenance dose has been established, serum calcium and serum phosphorus should
`be measured approximately monthly, and PTH every 1 to 3 months (see DOSAGE AND
`ADMINISTRATION). All iPTH measurements during the SensiparTM trials were
`obtained using the Nichols IRMA.
`
`

`

`In patients with‘end-stage renal disease, testosterone levels are often below the normal
`range.
`In a placebo-controlled trial in patients with CKD on dialysis, there were
`reductions in total and free testosterone in male patients following six months of
`treatment with SensiparTM. Levels of total testosterone decreased by a median of 15.8%
`- in the SensiparTM-treated patients and by 0.6% in the placebo-treated patients. Levels of
`free testosterone decreased by a median of 31.3% in the SensiparTM-treated patients and
`by 16.3% in the placebo-treated patients. The clinical significance of these reductions in
`serum testosterone is unknown.
`-
`
`Patients with Parathyroid Carcinoma
`
`Serum calcium should be measured within 1 Week after initiation or. dose adjustment of ‘
`SensiparTM. Once maintenance dose levels have been established, serum calcium‘should
`be measured every 2 months (see DOSAGE AND ADMINISTRATION).
`
`' Drug Interactions and/or Drug/Laboratory Test Interactions
`
`See CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Interactions.
`
`Effect of SensiparTM'on other drugs:
`
`' Drugs metabolized by cytochrome P450 2D6 (CYP2D6): SensiparTM is a strong in vitro
`inhibitor of CYP2D6. Therefore, dose adjustments of concomitant medications that are
`predominantly metabolized by CYP2D6 and have a narrow therapeutic index (e.g.,
`flecainide, vinblastine, thioridazine and most tricyclic antidepressants) may be required.
`
`Arnitriptyline: Concurrent administration of 25 mg or 100 mg cinacalcet with 50 mg
`amitriptyline increased amitriptyline exposure and nortriptyline (active metabolite)
`exposureby approximately 20% in CYP2D6 extensive metabolizers.
`
`Effect of other drugs on Sensiparm:
`SensiparTM is metabolized by multiple cytochrome P450 enzyInes, primarily CYP3A4, '
`CYP2D6, and CYP1A2.
`
`Ketoconazole: SensiparTM is metabolized in part by CYP3A4. Co—adrninistration of
`ketoconazole, a strong inhibitor of CYP3A4, increased cinacalcet exposure following a
`single 90 mg dose of SensiparTM by'2.3 fold. Dose adjustment of SensiparTM may be
`required and PTH and serum calcium concentrations should be closely monitored if a
`patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g.,
`,
`. ketoconazole, erythromycin, itraconazole; see DOSAGE AND ADMINISTRATION).
`
`. Carcinogenesis, Mutagenesis, and Impairment of Fertility
`
`Carcinogenicity: Standard lifetime dietary carcinogenicity bioassays were conducted
`in mice and rats. Mice were given dietary doses of 15, 50, 125 mg/kg/day in males and
`30, 70, 200 mg/kg/day in females (exposures up to 2 times those resulting with a human
`' oral dose of 180 mg/day based on AUC comparison). Rats Were given dietary doses of 5,
`15, 35 mg/kg/day in males and 5, 20, 35 mg/kg/day in females (exposures up to 2 times
`those resulting with a human oral dose of 180 [mg/day based on AUC comparison). No
`increased incidence of tumors was observed following treatment with cinacalcet.
`
`

`

`Mutagenicity: Cinacalcet was not genotoxic in the Ames bacterial mutagenicity assay
`or in the Chinese Hamster Ovary (CHO) cell HGPRT forward mutation assay and CHO
`cell chromosomal aberration assay, with and without metabolic activation or in the in
`vivo mouse micronucleus assay.
`
`Impairment of fertility: Female rats were given oral gavage doses of 5, 25, 75
`mg/kg/day beginning 2 weeks before mating and continuing through gestation day 7.
`Male rats were given oral doses 4 weeks prior to mating, during mating (3 weeks) and 2
`_ weeks post-mating. No effects were observedin male or female fertility at 5 and 25
`mg/kg/day (exposures up to 3 times those resulting with a human oral dose of 180
`mg/day based on AUC comparison). At 75 mg/kg/day, there were slight adverse effects
`(slight decreases in body weight and food consumption) in males and females.
`
`Pregnancy Category C
`
`In pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day during gestation
`‘ no teratogenicity was observed at doses up to 50 mg/kg/day (exposure 4 times those
`resulting with a human oral dose of 180 mg/day based on AUC comparison). Decreased
`fetal body weights were observed at all doses (less than _1 to 4 times a human oral dose of
`180 mg/day based 011 AUC comparison) in conjunction with maternal toxicity (decreased
`food consumption and body Weight gain).
`
`In‘pregnant female rabbits given oral gavage doses of 2, 12, 25 mg/kg/day during
`gestation no adverse fetal effects were observed (exposures less than with a human oral
`dose of 180 mg/day based on AUC comparisons). Reductions in maternal food
`' consumption and body weight gain were seen at doses of 12 and 25 mg/kg/day.
`
`In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day during gestation through
`lactation no adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day
`(exposures less than with a human therapeutic dose of 180 mg/day based on AUC
`> comparisOns). Higher doses of 15 and 25 mg/kg/day (exposures 2-3 times a human oral
`dose of 180 mg/day based on AUC comparisons) were accompanied by maternal signs of
`hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in
`postnatal maternal and pup body-weight gain. SensiparTM has been shown to cross the
`placental barrier1n rabbits
`
`There are no adequate and well-controlled studies in pregnant women. SensiparTM should
`be used during pregnancy only if the potential benefit justifies the potential risk to the
`fetus.
`
`Lactating Women
`
`Studies in rats have shown that SensiparTM is excreted in the milk with a high milk-to-
`plasma ratio. It is not known whether this drug is exoreted in human milk. Considering
`these data in rats and because many drugs are excreted in human milk and because of the
`potential for clinically significant adverse reactions in infants from SensiparTM, a decision
`
`

`

`should be made Whether to discontinue nursingor to discontinue the drug, taking into
`account the importance of theng to the lactating woman.
`
`Pediatric Use
`
`The safety and efficacy of SensiparTM in pediatric patients have not been established.
`
`Geriatric Use
`
`Of the 1136 patients enrolled in the SensiparTM phase 3 clinical program, 26% were 2 65
`years old, and 9% were 2 75 years old. No differences in the safety and efficacy of
`SensiparTM were observed in patients greater or less than 65 years of age (see DOSAGE
`AND ADMINISTRATION, Geriatric Patients).
`'
`
`ADVERSE EVENTS
`Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease
`. on Dialysis.
`
`In 3 double-blind placebo-controlled clinical trials, 1126 CKD patients on dialysis
`received study drug (656 SensiparTM, 470 placebo) for up to 6 months. The most
`frequently reported adverse events (incidence of at least 5% in the SensiparTM group and
`greater than placebo) are provided in Table 2. The most frequently reported events in the
`SensiparTM group were nausea and vomiting.
`
`Table 2. Adverse Event Incidence (Z 5%) in Patients On Dialysis
`
`Placebo
`(n = 470)
`
`SensiparTM
`
`(n = 656)
`
`- Nausea
`
`Vomiting
`. Diarrhea
`
`Myalgia
`Dizziness
`
`Hypertension
`Asthenia
`
`Anorexia
`
`.
`
`Pain Chest, Non-Cardiac
`Access Infection
`
`* Included are events that were reported at a greater incidence in the Sensipar‘" group than in the placebo
`group.
`'
`
`

`

`The incidence of serious adverse events (29 % vs. 31%) was similarin the SensiparTM and
`placebo groups, respectively.
`
`12-Month Experience with Sensiparm: Two hundred and sixty-six patients from 2
`phase 3 studies continued to receive SensiparTM or placebo treatment in a 6-month
`double-blind extension study (12-month'total treatinent duration). The incidence and
`nature of adverse events in this study were similar in the two treatment groups, and
`_ comparable to those observed in the phase 3 studies.‘
`
`Parathyroid Carcinonia
`The most frequent adverse events-in this patient group were nausea and vomiting.
`
`Laboratory values: Serum calcium levels should be closely monitored in patients
`receiving Sen'siparTM (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
`
`.
`
`OVERDOSAGE
`
`Doses titrated up to 300 mg once daily have been safely administered to patients 011
`dialysis. Overdosage of SensiparTM may lead to hypocalcemia. In the event of
`overdosage, patients should be monitored for signs and symptoms of hypocalcemia and
`appropriate measures taken to correct serum calcium levels (see PRECAUTIONS).
`
`Since SensiparTM is highly protein bound,‘hemodialysis is not an effective treatment for
`overdosage of SensiparTM.
`
`DOSAGE AND ADMINISTRATION
`SensiparTM tablets should be taken whole and should not be divided. SensiparTM should be
`taken with food or shortly after a meal.
`.
`
`' Dosage must be individualized.
`
`Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease
`on Dialysis
`-
`'
`
`The recommended starting oral, dose of SensiparTM is 30 mg once daily. 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 Sensiparm. SensiparTM should be
`titrated no more frequently than every 2 to 4 weeks through sequential doses of 60, 90,
`120, and 180 mg once daily to target iPTH consistent with the NKF-K/DOQI
`'
`recommendation for CKD patients on dialysis of 150-300 pg/mL.
`
`SensiparTM 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 SensiparTM (see PRECAUTIONS).
`
`Parathyroid Carcinoma
`'
`The recommended starting oral dese of SensiparTM is 30 mg twice daily. .’
`The dosage of Sensipa'rTM should be titrated every 2 to 4vweeks 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.
`
`Special Populations
`
`Geriatric patients: Age does not alter the pharmacokinetics of Sensipar‘”; no dosage
`adjustment is required for geriatric patients.
`
`Patients with renal impairment: Renal impairment does not alter the phannacokinetics
`of Sensiparm; no dosage adjustment is necessary for renal impairment.
`
`Patients with hepatic impairment: Cinacalcet exposures, as assessed by AUC(0-;,,0 , in
`patients with moderate and severe hepatic impairment (as indicated by the Child—Pugh
`method) were 2.4 and 4.2 times higher, respectively, then in normals. In patients with
`moderate and severe hepatic impairment, PTH and serum calcium concentrations should
`be closely monitored throughout treatment with SensiparTM (see CLINICAL
`PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS).
`
`Drug Interactions
`
`SensiparTM is metabolized in part by the enzyme CYP3A4. _Co-administration of
`ketocoriazole, a strong inhibitor of CYP3A4, caused an approximate 2-fold increase in
`.cinacalcet exposure. Dose adjustment of SensiparTM may be required and PTH and serum
`calcium concentrations should be closely monitored if a patient initiates or discontinues
`therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, erythromycin, itraconazole;
`see CLINICAL PHARMACOLOGY, Pharmacokineticsand PRECAUTIONS).
`
`How SUPPLIED
`
`SensiparTM 30 mg tablets