`
`Sensipar® (cinacalcet) Tablets
`DESCRIPTION
`Sensipar® (cinacalcet) is a calcimimetic agent that increases the sensitivity of the
`calcium-sensing receptor to activation by extracellular calcium. Its empirical formula is
`C22H22F3N⋅HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4
`g/mol (free base). It has one chiral center having an R-absolute configuration. The
`R-enantiomer is the more potent enantiomer and has been shown to be responsible for
`pharmacodynamic activity.
`Cinacalcet is a white to off-white, crystalline solid that is soluble in methanol or 95%
`ethanol and slightly soluble in water.
`Sensipar® tablets are formulated as light-green, film-coated, oval-shaped tablets for oral
`administration in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet as the free base
`equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively).
`Cinacalcet is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-
`(trifluoromethyl)phenyl]-1-aminopropane hydrochloride and has the following structural
`formula:
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`Inactive Ingredients: Sensipar® tablets are comprised of the active ingredient, and the
`following inactive ingredients: pre-gelatinized starch, microcrystalline cellulose,
`povidone, crospovidone, colloidal silicon dioxide, and magnesium stearate. Tablets are
`coated with color (Opadry® II green) and clear film-coat (Opadry® clear), carnauba wax,
`and Opacode® black ink.
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`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is
`a progressive disease, associated with increases in parathyroid hormone (PTH) levels and
`derangements in calcium and phosphorus metabolism. Increased PTH stimulates
`osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals
`of treatment of secondary hyperparathyroidism are to lower levels of PTH, calcium, and
`phosphorus in the blood, in order to prevent progressive bone disease and the systemic
`consequences of disordered mineral metabolism. In CKD patients on dialysis with
`uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact
`on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis.
`The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is
`the principal regulator of PTH secretion. Sensipar® directly lowers PTH levels by
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`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.
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`Pharmacokinetics
`Absorption and Distribution: After oral administration of cinacalcet, maximum plasma
`concentration (Cmax) is achieved in approximately 2 to 6 hours. A food-effect study in
`healthy volunteers indicated that the Cmax and area under the curve (AUC(0-inf)) were
`increased 82% and 68%, respectively, when cinacalcet was administered with a high-fat
`meal compared to fasting. Cmax and AUC(0-inf) of cinacalcet were increased 65% and
`50%, respectively, when cinacalcet was administered with a low-fat meal compared to
`fasting.
`After absorption, cinacalcet concentrations decline in a biphasic fashion with a terminal
`half-life of 30 to 40 hours. Steady-state drug levels are achieved within 7 days. The mean
`accumulation ratio is approximately 2 with once-daily oral administration. The median
`accumulation ratio is approximately 2 to 5 with twice-daily oral administration. The AUC
`and Cmax of cinacalcet increase proportionally over the dose range of 30 to 180 mg once
`daily. The pharmacokinetic profile of cinacalcet does not change over time with once-
`daily dosing of 30 to 180 mg. The volume of distribution is high (approximately 1000
`L), indicating extensive distribution. Cinacalcet is approximately 93 to 97% bound to
`plasma protein(s). The ratio of blood cinacalcet concentration to plasma cinacalcet
`concentration is 0.80 at a blood cinacalcet concentration of 10 ng/mL.
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`Metabolism and Excretion: Cinacalcet is metabolized by multiple enzymes, primarily
`CYP3A4, CYP2D6 and CYP1A2. After administration of a 75 mg radiolabeled dose to
`healthy volunteers, cinacalcet was rapidly and extensively metabolized via: 1) oxidative
`N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are
`further metabolized via 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 to form dihydrodiols, which are
`further conjugated with glucuronic acid. The plasma concentrations of the major
`circulating metabolites including the cinnamic acid derivatives and glucuronidated
`dihydrodiols markedly exceed parent drug concentrations. The hydrocinnamic acid
`metabolite was shown to be inactive at concentrations up to 10 µM in a cell-based assay
`measuring calcium-receptor activation. The glucuronide conjugates formed after
`cinacalcet oxidation were shown to have a potency approximately 0.003 times that of
`cinacalcet in a cell-based assay measuring a calcimimetic response. Renal excretion of
`metabolites was the primary route of elimination of radioactivity. Approximately 80% of
`the dose was recovered in the urine and 15% in the feces.
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`Special Populations
`Hepatic Insufficiency: The disposition of a 50 mg cinacalcet single dose was compared
`in patients with hepatic impairment and subjects with normal hepatic function.
`Cinacalcet exposure, AUC(0-inf), was comparable between healthy volunteers and patients
`with mild hepatic impairment. However, in patients with moderate and severe hepatic
`impairment (as indicated by the Child-Pugh method), cinacalcet exposures as defined by
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`the AUC(0-inf) were 2.4 and 4.2 times higher, respectively, than that in normals. The mean
`half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe
`hepatic impairment, respectively. Protein binding of cinacalcet is not affected by
`impaired hepatic function. See PRECAUTIONS and DOSAGE AND
`ADMINISTRATION.
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`Renal Insufficiency: The pharmacokinetic profile of a 75 mg Sensipar® single dose in
`patients with mild, moderate, and severe renal insufficiency, and those on hemodialysis
`or peritoneal dialysis is comparable to that in healthy volunteers.
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`Geriatric Patients: The pharmacokinetic profile of Sensipar® in geriatric patients (age ≥
`65, n = 12) is similar to that for patients who are < 65 years of age (n = 268).
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`Pediatric Patients: The pharmacokinetics of Sensipar® have not been studied in patients
`< 18 years of age.
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`Drug Interactions
`An in vitro study indicates that cinacalcet is a strong inhibitor of CYP2D6, but not of
`CYP1A2, CYP2C9, CYP2C19, and CYP3A4. In vitro induction studies indicate that
`cinacalcet is not an inducer of CYP450 enzymes.
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`Ketoconazole: Cinacalcet AUC(0-inf) and Cmax increased 2.3 and 2.2 times, respectively,
`when a single 90 mg cinacalcet dose on Day 5 was administered to subjects treated with
`200 mg ketoconazole twice daily for 7 days compared to 90 mg cinacalcet given alone
`(see DOSAGE AND ADMINISTRATION).
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`Calcium Carbonate: No significant pharmacokinetic interaction was observed when a
`single dose of 1500 mg calcium carbonate was coadministered with 100 mg cinacalcet.
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`Pantoprazole: No significant pharmacokinetic interaction was observed when cinacalcet
`90 mg was administered to subjects treated with 80 mg pantoprazole daily for 3 days.
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`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).
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`Desipramine: The effect of cinacalcet (90 mg) on the pharmacokinetics of desipramine
`(50 mg) has been studied in healthy subjects who were CYP2D6 extensive metabolizers.
`The AUC and Cmax of desipramine increased by 3.6 (296.5-446.7%) and 1.75 (157.5-
`194.9%) fold, respectively, in the presence of cinacalcet. This indicates that cinacalcet is
`a strong in vivo inhibitor of CYP2D6 and can increase the blood concentrations of drugs
`metabolized by CYP2D6.
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`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.
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`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.
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`Pharmacodynamics
`Reduction in intact PTH (iPTH) levels correlated with cinacalcet concentrations in CKD
`patients. The nadir in iPTH level occurs approximately 2 to 6 hours post dose,
`corresponding with the Cmax of cinacalcet. After steady state is reached, serum calcium
`concentrations remain constant over the dosing interval in CKD patients.
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`CLINICAL STUDIES
`Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease
`on Dialysis
`Three 6-month, multicenter, randomized, double-blind, placebo-controlled clinical
`studies of similar design were conducted in CKD patients on dialysis. A total of 665
`patients were randomized to Sensipar® and 471 patients to placebo. The mean age of the
`patients was 54 years, 62% were male, and 52% Caucasian. The average baseline iPTH
`level by the Nichols intact immunoradiometric assay (IRMA) was 712 pg/mL, with 26%
`of the patients having a baseline iPTH level > 800 pg/mL. The mean baseline Ca x P ion
`product was 61 mg2/dL2. The average duration of dialysis prior to study enrollment was
`67 months. Ninety-six percent of patients were on hemodialysis and 4% peritoneal
`dialysis. At study entry, 66% of the patients were receiving vitamin D sterols and 93%
`were receiving phosphate binders. Sensipar® (or placebo) was initiated at a dose of 30
`mg once daily and titrated every 3 or 4 weeks to a maximum dose of 180 mg once daily
`to achieve an iPTH of ≤ 250 pg/mL. The dose was not increased if a patient had any of
`the following: iPTH < 200 pg/mL, serum calcium < 7.8 mg/dL, or any symptoms of
`hypocalcemia. If a patient experienced symptoms of hypocalcemia or had a serum
`calcium < 8.4 mg/dL, calcium supplements and/or calcium-based phosphate binders
`could be increased. If these measures were insufficient, the vitamin D dose could be
`increased. Approximately 70% of the Sensipar® patients and 80% of the placebo patients
`completed the 6-month studies. In the primary efficacy analysis, 40% of Sensipar®
`patients and 5% of placebo patients achieved an iPTH ≤ 250 pg/mL (p<0.001) (Table 1,
`Figure 1). Secondary efficacy parameters also improved in patients treated with
`Sensipar®. These studies showed that Sensipar® reduced PTH while lowering Ca x P,
`calcium and phosphorus levels (Table 1, Figure 2). The median dose of Sensipar® at the
`completion of the studies was 90 mg. Patients with milder disease typically required
`lower doses.
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`Similar results were observed when either the iPTH or bio-intact PTH (biPTH) assay was
`used to measure PTH levels in CKD patients on dialysis; treatment with cinacalcet did
`not alter the relationship between iPTH and biPTH.
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`Table 1. Effects of Sensipar® on iPTH, Ca x P, Serum Calcium, and Serum Phosphorus in 6-month Phase 3 Studies
` (Patients on Dialysis)
`Study 1
`Sensipar®
`(N = 205)
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`
`
`
`
`
`
`
`
`
`
`
`Placebo
`(N = 205)
`
`Study 2
`Sensipar®
`(N = 166)
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`Placebo
`(N = 165)
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`Study 3
`Sensipar®
`(N = 294)
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`Placebo
`(N = 101)
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`iPTH
` Baseline (pg/mL): Median
` Mean (SD)
` Evaluation Phase (pg/mL)
` Median Percent Change
`Patients Achieving Primary Endpoint (iPTH
`
`≤ 250 pg/mL) (%)a
`Patients Achieving ≥ 30% Reduction in
`iPTH (%)a
`Patients Achieving iPTH ≤ 250 pg/mL and
`Ca x P < 55 mg2/dL2 (%)
`Ca x P
` Baseline (mg2/dL2)
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`535
`651 (398)
`563
`+3.8
`4%
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`11%
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`1%
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`537
`636 (341)
`275
`-48.3
`41%**
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`61%
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`32%
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`556
`630 (317)
`592
`+8.4
`7%
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`12%
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`5%
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`
`547
`652 (372)
`238
`-54.1
`46%**
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`68%
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`35%
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`670
`832 (486)
`737
`+2.3
`6%
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`10%
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`5%
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`
`
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`
`62
`
`61
`
`61
`
`61
`
`61
`
` Evaluation Phase (mg2/dL2)
`52
`59
`-14.9
`-2.0
` Median Percent Change
`** p < 0.001 compared to placebo; p-values presented for primary endpoint only
`a iPTH value based on averaging over the evaluation phase (defined as weeks 13 to 26 in studies 1 and 2 and weeks 17 to 26 in study 3)
`Values shown are medians unless indicated otherwise
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`
`47
`-19.7
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`57
`-4.8
`
`59
`-3.1
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`
`
`703
`848 (685)
`339
`-48.2
`35%**
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`59%
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`28%
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`59
`
`48
`-15.7
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`Table 1 (continued). Effects of Sensipar® on iPTH, Ca x P, Serum Calcium, and Serum Phosphorus in 6-month Phase 3
`Studies (Patients on Dialysis)
`Study 1
`Sensipar®
`(N = 205)
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`Placebo
`(N = 205)
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`Calcium
` Baseline (mg/dL)
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`Evaluation Phase (mg/dL)
` Median Percent Change
`Phosphorus
`6.1
`6.3
` Baseline (mg/dL)
`5.6
`6.0
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`Evaluation Phase (mg/dL)
`-9.0
`-1.0
` Median Percent Change
`** p < 0.001 compared to placebo; p-values presented for primary endpoint only
`a iPTH value based on averaging over the evaluation phase (defined as weeks 13 to 26 in studies 1 and 2 and weeks 17 to 26 in study 3)
`Values shown are medians unless indicated otherwise
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`
`Study 2
`Sensipar®
`(N = 166)
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`Placebo
`(N = 165)
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`Study 3
`Sensipar®
`(N = 294)
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`Placebo
`(N = 101)
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`
`
`
`
`9.8
`9.9
`+0.5
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`
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`
`
`9.8
`9.1
`-5.5
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`
`
`9.9
`9.9
`+0.1
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`6.1
`5.9
`-2.4
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`10.0
`9.1
`-7.4
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`6.0
`5.1
`-12.4
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`
`9.9
`10.0
`+0.3
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`6.1
`5.6
`-5.6
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`9.8
`9.1
`-6.0
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`6.0
`5.3
`-8.6
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`Figure 1. Mean (SE) iPTH Values (Pooled Phase 3 Studies)
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`Data are presented for patients who completed the studies; Placebo (N = 342), Sensipar® (N =
`439).
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`Figure 2. Mean (SE) Ca x P Values (Pooled Phase 3 Studies)
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`Data are presented for patients who completed the studies; Placebo (N = 342), Sensipar® (N =
`439).
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`Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment.
`Sensipar® decreased iPTH and Ca x P levels regardless of disease severity (i.e., baseline
`iPTH value), duration of dialysis, and whether or not vitamin D sterols were
`administered. Approximately 60% of patients with mild (iPTH ≥ 300 to ≤ 500 pg/mL),
`41% with moderate (iPTH > 500 to 800 pg/mL), and 11% with severe (iPTH > 800
`pg/mL) secondary HPT achieved a mean iPTH value of 250 pg/mL. Plasma iPTH levels
`were measured using the Nichols IRMA.
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`Parathyroid Carcinoma
`Ten patients with parathyroid carcinoma were enrolled in an open-label study. The study
`consisted of 2 phases, a dose-titration phase and a maintenance phase.
`The range of exposure was 2 to 16 weeks in the titration phase (n = 10) and 16 to 48
`weeks (n = 3) for the maintenance phase. Baseline mean (SD) serum calcium was 14.7
`(1.8) mg/dL. The range of change from baseline to last measurement was –7.5 to 2.7
`mg/dL during the titration phase and –7.4 to 0.9 mg/dL during the maintenance phase
`(Figure 3). No patients maintained a serum calcium level within the normal range. The
`doses ranged from 70 mg twice daily to 90 mg four times daily for patients in the
`maintenance phase.
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`Figure 3. Serum Calcium Values in Parathyroid Carcinoma Patients Receiving Sensipar®
`at Baseline, Titration and Maintenance Phase
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`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
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`INDICATIONS AND USAGE
`Sensipar® is indicated for the treatment of secondary hyperparathyroidism in patients
`with Chronic Kidney Disease on dialysis.
`Sensipar® is indicated for the treatment of hypercalcemia in patients with parathyroid
`carcinoma.
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`CONTRAINDICATIONS
`Sensipar® is contraindicated in patients with hypersensitivity to any component(s) of this
`product.
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`WARNINGS
`Seizures
`In three clinical studies of CKD patients on dialysis, 5% of the patients in both the
`Sensipar® and placebo groups reported a history of seizure disorder at baseline. During
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`the trials, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (9/656)
`of Sensipar®-treated patients and 0.4% (2/470) of placebo-treated patients. Five of the
`nine Sensipar®-treated patients had a history of a seizure disorder and two were receiving
`anti-seizure medication at the time of their seizure. Both placebo-treated patients had a
`history of seizure disorder and were receiving anti-seizure medication at the time of their
`seizure. While the basis for the reported difference in seizure rate is not clear, the
`threshold for seizures is lowered by significant reductions in serum calcium levels.
`Therefore, serum calcium levels should be closely monitored in patients receiving
`Sensipar®, particularly in patients with a history of a seizure disorder (see
`PRECAUTIONS, Hypocalcemia).
`Hypotension and/or Worsening Heart Failure
`In postmarketing safety surveillance, isolated, idiosyncratic cases of hypotension and/or
`worsening heart failure have been reported in patients with impaired cardiac function, in
`which a causal relationship to Sensipar® could not be completely excluded and may be
`mediated by reductions in serum calcium levels. Clinical trial data showed hypotension
`occurred in 7% of Sensipar®-treated patients, 12% of placebo-treated patients, and heart
`failure occurred in 2% of patients receiving Sensipar® or placebo.
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`PRECAUTIONS
`General
`Hypocalcemia
`Sensipar® lowers serum calcium, and therefore patients should be carefully
`monitored for the occurrence of hypocalcemia. Potential manifestations of
`hypocalcemia include paresthesias, myalgias, cramping, tetany, and convulsions.
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`Sensipar® treatment should not be initiated if serum calcium is less than the lower limit
`of the normal range (8.4 mg/dL). Serum calcium should be measured within 1 week after
`initiation or dose adjustment of Sensipar®. Once the maintenance dose has been
`established, serum calcium should be measured approximately monthly (see DOSAGE
`AND ADMINISTRATION).
`If serum calcium falls below 8.4 mg/dL but remains above 7.5 mg/dL, or if symptoms of
`hypocalcemia occur, calcium-containing phosphate binders and/or vitamin D sterols can
`be used to raise serum calcium. If serum calcium falls below 7.5 mg/dL, or if symptoms
`of hypocalcemia persist and the dose of vitamin D cannot be increased, withhold
`administration of Sensipar® until serum calcium levels reach 8.0 mg/dL, and/or
`symptoms of hypocalcemia have resolved. Treatment should be re-initiated using the
`next lowest dose of Sensipar® (see DOSAGE AND ADMINISTRATION).
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`In the 26-week studies of patients with CKD on dialysis, 66% of patients receiving
`Sensipar® compared with 25% of patients receiving placebo developed at least one serum
`calcium value < 8.4 mg/dL. Less than 1% of patients in each group permanently
`discontinued study drug due to hypocalcemia.
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`Sensipar® is not indicated for CKD patients not on dialysis. In CKD patients with
`secondary HPT not on dialysis, the long-term safety and efficacy of Sensipar® have not
`been established. Clinical studies indicate that Sensipar®-treated CKD patients not on
`dialysis have an increased risk for hypocalcemia compared to Sensipar®-treated CKD
`patients on dialysis, which may be due to lower baseline calcium levels. In a phase 3
`study of 32 weeks duration and including 404 subjects (302 cinacalcet, 102 placebo), in
`which the median dose for cinacalcet was 60 mg at the completion of the study, 80% of
`Sensipar®-treated patients experienced at least one serum calcium value < 8.4 mg/dL
`compared to 5% of patients receiving placebo.
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`Adynamic Bone Disease
`Adynamic bone disease may develop if iPTH levels are suppressed below 100 pg/mL.
`One clinical study evaluated bone histomorphometry in patients treated with Sensipar®
`for one year. Three patients with mild hyperparathyroid bone disease at the beginning of
`the study developed adynamic bone disease during treatment with Sensipar®. Two of
`these patients had iPTH levels below 100 pg/mL at multiple time points during the study.
`In the three 6-month, phase 3 studies conducted in CKD patients on dialysis, 11% of
`patients treated with Sensipar® had mean iPTH values below 100 pg/mL during the
`efficacy-assessment phase. If iPTH levels decrease below the NKF-K/DOQI
`recommended target range (150-300 pg/mL) 1 in patients treated with Sensipar®, the dose
`of Sensipar® and/or vitamin D sterols should be reduced or therapy discontinued.
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`Hepatic Insufficiency
`Cinacalcet exposure as assessed by AUC(0-inf) in patients with moderate and severe
`hepatic impairment (as indicated by the Child-Pugh method) were 2.4 and 4.2 times
`higher, respectively, than that in normals. Patients with moderate and severe hepatic
`impairment should be monitored throughout treatment with Sensipar® (see CLINICAL
`PHARMACOLOGY, Pharmacokinetics and DOSAGE AND ADMINISTRATION).
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`Information for Patients
`It is recommended that Sensipar® be taken with food or shortly after a meal. Tablets
`should be taken whole and should not be divided.
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`Laboratory Tests
`Patients with CKD on Dialysis with Secondary Hyperparathyroidism
`Serum calcium and serum phosphorus should be measured within 1 week and iPTH
`should be measured 1 to 4 weeks after initiation or dose adjustment of Sensipar®. Once
`the maintenance dose has been established, serum calcium and serum phosphorus should
`be measured approximately monthly, and PTH every 1 to 3 months (see DOSAGE AND
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`ADMINISTRATION). All iPTH measurements during the Sensipar® trials were
`obtained using the Nichols IRMA.
`In patients with end-stage renal disease, testosterone levels are often below the normal
`range. In a placebo-controlled trial in patients with CKD on dialysis, there were
`reductions in total and free testosterone in male patients following six months of
`treatment with Sensipar®. Levels of total testosterone decreased by a median of 15.8% in
`the Sensipar®-treated patients and by 0.6% in the placebo-treated patients. Levels of free
`testosterone decreased by a median of 31.3% in the Sensipar®-treated patients and by
`16.3% in the placebo-treated patients. The clinical significance of these reductions in
`serum testosterone is unknown.
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`Patients with Parathyroid Carcinoma
`Serum calcium should be measured within 1 week after initiation or dose adjustment of
`Sensipar®. Once maintenance dose levels have been established, serum calcium should
`be measured every 2 months (see DOSAGE AND ADMINISTRATION).
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`Drug Interactions and/or Drug/Laboratory Test Interactions
`See CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Interactions.
`Effect of Sensipar® on other drugs:
`Drugs metabolized by cytochrome P450 2D6 (CYP2D6): Sensipar® is a strong in vitro,
`as well as in vivo, inhibitor of CYP2D6. Therefore, dose adjustments of concomitant
`medications that are predominantly metabolized by CYP2D6 and have a narrow
`therapeutic index (e.g., flecainide, vinblastine, thioridazine and most tricyclic
`antidepressants) may be required.
`Desipramine: Concurrent administration of cinacalcet (90 mg) with desipramine (50 mg)
`increased the exposure of desipramine by 3.6 fold in CYP2D6 extensive metabolizers.
`Amitriptyline: Concurrent administration of 25 mg or 100 mg cinacalcet with 50 mg
`amitriptyline increased amitriptyline exposure and nortriptyline (active metabolite)
`exposure by approximately 20% in CYP2D6 extensive metabolizers.
`Effect of other drugs on Sensipar®:
`Sensipar® is metabolized by multiple cytochrome P450 enzymes, primarily CYP3A4,
`CYP2D6, and CYP1A2.
`Ketoconazole: Sensipar® is metabolized in part by CYP3A4. Co-administration of
`ketoconazole, a strong inhibitor of CYP3A4, increased cinacalcet exposure following a
`single 90 mg dose of Sensipar® by 2.3 fold. Dose adjustment of Sensipar® may be
`required and PTH and serum calcium concentrations should be closely monitored if a
`patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g.,
`ketoconazole, erythromycin, itraconazole; see DOSAGE AND ADMINISTRATION).
`
`Carcinogenesis, Mutagenesis, and Impairment of Fertility
`
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`
`Carcinogenicity: Standard lifetime dietary carcinogenicity bioassays were conducted
`in mice and rats. Mice were given dietary doses of 15, 50, 125 mg/kg/day in males and
`30, 70, 200 mg/kg/day in females (exposures up to 2 times those resulting with a human
`oral dose of 180 mg/day based on AUC comparison). Rats were given dietary doses of 5,
`15, 35 mg/kg/day in males and 5, 20, 35 mg/kg/day in females (exposures up to 2 times
`those resulting with a human oral dose of 180 mg/day based on AUC comparison). No
`increased incidence of tumors was observed following treatment with cinacalcet.
`
`Mutagenicity: Cinacalcet was not genotoxic in the Ames bacterial mutagenicity assay
`or in the Chinese Hamster Ovary (CHO) cell HGPRT forward mutation assay and CHO
`cell chromosomal aberration assay, with and without metabolic activation or in the in
`vivo mouse micronucleus assay.
`
`Impairment of Fertility: Female rats were given oral gavage doses of 5, 25, 75
`mg/kg/day beginning 2 weeks before mating and continuing through gestation day 7.
`Male rats were given oral doses 4 weeks prior to mating, during mating (3 weeks) and 2
`weeks post-mating. No effects were observed in male or female fertility at 5 and 25
`mg/kg/day (exposures up to 3 times those resulting with a human oral dose of 180
`mg/day based on AUC comparison). At 75 mg/kg/day, there were slight adverse effects
`(slight decreases in body weight and food consumption) in males and females.
`
`Pregnancy Category C
`In pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day during gestation
`no teratogenicity was observed at doses up to 50 mg/kg/day (exposure 4 times those
`resulting with a human oral dose of 180 mg/day based on AUC comparison). Decreased
`fetal body weights were observed at all doses (less than 1 to 4 times a human oral dose of
`180 mg/day based on AUC comparison) in conjunction with maternal toxicity (decreased
`food consumption and body weight gain).
`
`In pregnant female rabbits given oral gavage doses of 2, 12, 25 mg/kg/day during
`gestation no adverse fetal effects were observed (exposures less than with a human oral
`dose of 180 mg/day based on AUC comparisons). Reductions in maternal food
`consumption and body weight gain were seen at doses of 12 and 25 mg/kg/day.
`
`In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day during gestation through
`lactation no adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day
`(exposures less than with a human therapeutic dose of 180 mg/day based on AUC
`comparisons). Higher doses of 15 and 25 mg/kg/day (exposures 2-3 times a human oral
`dose of 180 mg/day based on AUC comparisons) were accompanied by maternal signs of
`hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in
`postnatal maternal and pup body-weight gain. Sensipar® has been shown to cross the
`placental barrier in rabbits.
`There are no adequate and well-controlled studies in pregnant women. Sensipar® should
`be used during pregnancy only if the potential benefit justifies the potential risk to the
`fetus.
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`Lactating Women
`Studies in rats have shown that Sensipar® is excreted in the milk with a high milk-to-
`plasma ratio. It is not known whether this drug is excreted in human milk. Considering
`these data in rats and because many drugs are excreted in human milk and because of the
`potential for clinically significant adverse reactions in infants from Sensipar®, a decision
`should be made whether to discontinue nursing or to discontinue the drug, taking into
`account the importance of the drug to the lactating woman.
`
`Pediatric Use
`The safety and efficacy of Sensipar® in pediatric patients have not been established.
`
`Geriatric Use
`Of the 1136 patients enrolled in the Sensipar® phase 3 clinical program, 26% were ≥ 65
`years old, and 9% were ≥ 75 years old. No differences in the safety and efficacy of
`Sensipar® were observed in patients greater or less than 65 years of age (see DOSAGE
`AND ADMINISTRATION, Geriatric Patients).
`
`
`ADVERSE EVENTS
`Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease
`on Dialysis
`In 3 double-blind placebo-controlled clinical trials, 1126 CKD patients on dialysis
`received study drug (656 Sensipar®, 470 placebo) for up to 6 months. The most
`frequently reported adverse events (incidence of at least 5% in the Sensipar® group and
`greater than placebo) are provided in Table 2. The most frequently reported events in the
`Sensipar® group were nausea, vomiting, and diarrhea.
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`Table 2. Adverse Event Incidence (≥ 5%) in Patients on Dialysis
`
`
`Placebo
`(n = 470)
`
`(%)
`
`
`
`
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`Sensipar®
`(n = 656)
`
`(%)
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`
`
`
`
`
`
`
`
`
`
`Event*:
`
`
`31
`19
`Nausea
`27
`15
`Vomiting
`21
`20
`Diarrhea
`15
`14
`Myalgia
`10
`8
`Dizziness
`7
`5
`Hypertension
`7
`4
`Asthenia
`6
`4
`Anorexia
`6
`4
`Pain Chest, Non-Cardiac
`5
`4
`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 similar in the Sensipar® and
`placebo groups, respectively.
`
`12-Month Experience with Sensipar®: Two hundred and sixty-six patients from 2
`phase 3 studies continued to receive Sensipar® or placebo treatment in a 6-month double-
`blind extension study (12-month total treatment duration). The incidence and nature of
`adverse events in this study were similar in the two treatment groups, and comparable to
`those observed in the phase 3 studies.
`
`Postmarketing Experience with Sensipar®: Rash, hypersensitivity, diarrhea and
`myalgia have been identified as adverse reactions during post-approval use of Sensipar®.
`Isolated, idiosyncratic cases of hypotension and/or worsening heart failure have been
`reported in Sensipar®-treated patients with impaired cardiac function in postmarketing
`safety surveillance. Because these reactions are reported voluntarily from a population of
`uncertain size, it is not always possible to reliably estimate their frequency or establish a
`causal relationship to drug exposure.
`
`Parathyroid Carcinoma
`The most frequent adverse events in this patient group were nausea and vomiting.
`
`Laboratory values: Serum calcium levels should be closely monitored in patients
`receiving Sensipar® (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
`
`
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`OVERDOSAGE
`Doses titrated up to 300 mg once daily have been safely administered to patients on
`dialysis. Overdosage of Sensipar® may lead to hypocalcemia. In the event of
`overdosage, patients should be monitored for signs and symptoms of hypocalcemia and
`appropriate measures taken to correct serum calcium levels (see PRECAUTIONS).
`Since Sensipar® is highly protein bound, hemodialysis is not an effective treatment for
`overdosage of Sensipar®.
`
`
`DOSAGE AND ADMINISTRATION
`Sensipar® tablets should be taken whole and should not be divided. Sensipar® should be
`taken with food or shortly after a meal.
`
`Dosage must be individualized.
`
`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 PTH 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 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. PTH levels should be assessed no earlier
`than 12 hours after dosing with Sensipar®.
`Sensipar® can