January 25, 2008
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 3 ADVERSE REACTIONS 6 DRUG INTERACTIONS 8 DOSAGE AND ADMINISTRATION 10 OVERDOSAGE 11 ACTION AND CLINICAL PHARMACOLOGY 11 STORAGE AND STABILITY 13 DOSAGE FORMS, COMPOSITION AND PACKAGING 13
PHARMACEUTICAL INFORMATION 14 CLINICAL TRIALS 15 DETAILED PHARMACOLOGY 18 REFERENCES 19
(cinacalcet hydrochloride)
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Tablet / 30 mg, 60 mg, 90 mg | For a complete listing of the nonmedicinal ingredients see Dosage Forms, Composition and Packaging section. |
SENSIPAR(r) (cinacalcet hydrochloride) is indicated for the treatment of secondary hyperparathyroidism in patients with Chronic Kidney Disease (CKD) receiving dialysis. SENSIPAR(r) controls parathyroid hormone levels, calcium and phosphorous levels, and the serum calcium-phosphorous product (Ca x P), in patients with CKD receiving dialysis.
SENSIPAR(r) (cinacalcet hydrochloride) is contraindicated in patients with hypersensitivity to any of the components of this product. For a complete listing of the nonmedicinal ingredients see DOSAGE FORMS, COMPOSITION AND PACKAGING section.
Seizures
In three clinical studies of CKD patients receiving dialysis, 5% of the patients in both the SENSIPAR(r) (cinacalcet hydrochloride) 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 SENSIPAR(r)-treated patients and 0.4% (2/470) of placebo-treated patients. Five of the nine SENSIPAR(r)-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(r), particularly in patients with a history of a seizure disorder.
Cardiovascular
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(r) 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(r)-treated patients, 12% of placebo-treated patients, and heart failure occurred in 2% of patients receiving SENSIPAR(r) or placebo.
Hypocalcemia
SENSIPAR(r) 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.
In clinical trials of CKD patients receiving dialysis, SENSIPAR(r) treatment was not initiated in patients with a serum calcium (corrected for albumin) less than the lower limit of the normal range. Since SENSIPAR(r) lowers serum calcium, patients should be monitored for the occurrence of hypocalcemia. In CKD patients receiving dialysis or who were administered SENSIPAR(r), 4% calcium values were less than 1.875mmol/L (see ADVERSE REACTIONS). In the event of hypocalcemia, calcium-containing phosphate binders and/or vitamin D sterols can be used to raise serum calcium. If hypocalcemia persists, reduce the dose or discontinue administration of SENSIPAR(r) (see DOSAGE AND ADMINISTRATION). Potential manifestations of hypocalcemia may include paresthesias, myalgias, cramping, tetany, and convulsions. Cinacalcet is not indicated for CKD patients not receiving dialysis. Investigational studies have shown that cinacalcet-treated CKD patients not receiving dialysis have an increased risk for hypocalcemia (serum calcium levels < 8.4 mg/dL [2.1 mmol/L]) compared with cinacalcet- treated CKD patients receiving dialysis, which may be due to lower baseline calcium levels and/or the presence of residual kidney function.
General
Adynamic bone disease may develop if intact parathyroid hormone (iPTH) levels are suppressed below 100 pg/mL. If iPTH levels decrease below the current National Kidney Foundation- Kidney/Disease Outcomes Quality Initiative (NKF-K/DOQI) recommended target range (150- 300 pg/mL) in patients receiving dialysis treated with SENSIPAR(r), the dose of SENSIPAR (r) and/or vitamin D sterols should be reduced or therapy discontinued.
Hepatic Insufficiency
Due to the potential for 2 to 4 fold higher plasma levels of SENSIPAR(r), patients with moderate to severe hepatic impairment should be closely monitored when initiating treatment (see ACTION AND CLINICAL PHARMACOLOGY).
Testosterone Levels
Testosterone levels are often below the normal range in patients with end stage renal disease. In a clinical study of CKD patients receiving dialysis, free testosterone levels decreased by a median of 31.3% in the SENSIPAR(r)-treated patients and by 16.3% in the placebo-treated patients after 6 months of treatment. The clinical significance of these reductions in serum testosterone is unknown. An open label extension of this study showed no further reductions in free and total testosterone concentrations over a period of 3 years in SENSIPAR(r)-treated patients.
Impairment of Fertility
SENSIPAR(r) had no effect on fertility in animal studies.
Special Populations
Of the 1136 patients enrolled in the SENSIPAR(r) phase 3 clinical programme, 26% were >65 years old, while 9% were >75 years old. No overall differences in safety and efficacy of SENSIPAR(r) were observed in patients greater or less than 65 years of age (see DOSAGE AND ADMINISTRATION: Geriatric Patients).
There are no studies on the use of SENSIPAR(r) in pregnant women. SENSIPAR(r) was not teratogenic in rabbits when given a dose of 0.4 times, on an AUC basis, the maximum human dose for secondary HPT (180 mg once daily). There were no effects on fertility in males or females at exposures up to 4 times a human dose of 180 mg/day. In pregnant rats, there were slight decreases in body weight and food consumption at the highest dose. The non-teratogenic dose in rats was 4.4 times, on an AUC basis, the maximum dose for patients with secondary HPT (180 mg once daily). Decreased fetal weights were seen in rats at doses where dams had severe hypocalcemia. SENSIPAR(r) has been shown to cross the placental barrier in rabbits. Although animal studies have shown no evidence of teratogenicity, SENSIPAR(r) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether SENSIPAR(r) is excreted in human milk. Studies in rats have shown that SENSIPAR(r) is excreted in the milk with a high milk to plasma ratio. A decision should be made whether to discontinue nursing or discontinue SENSIPAR(r), taking into account the importance of SENSIPAR(r) to the mother.
The safety and efficacy of SENSIPAR(r) in pediatric patients have not been established.
Carcinogenicity
SENSIPAR(r), administered orally for 104 weeks, showed no evidence of carcinogenic potential in mice and rats. Doses administered to mice and rats resulted in total systemic exposure (AUCs) 2 times the exposures observed in humans. The nature, incidence, and distribution of tumors in rats and mice of both sexes did not indicate any SENSIPAR(r)-induced carcinogenesis. A decreased incidence of thyroid C-cell adenomas was observed in rats treated with SENSIPAR(r).
Mutagenicity
SENSIPAR(r) was negative in the Ames assay, chromosomal aberration assay, Chinese Hamster Ovary HGPRT forward mutation assay, and in the mouse micronucleus assay. These tests indicate that SENSIPAR(r) has no genetic toxicity either with respect to DNA damage, including gene mutations, large scale chromosomal damage, recombinations or numerical changes.
Effect on the Ability to Drive and Use Machines
No effects on the ability to drive or operate machinery have been observed.
Laboratory Monitoring
Patients with CKD and Secondary Hyperparathyroidism: Serum calcium should be measured within 1 week and iPTH should be measured 1 to 4 weeks after initiation or dose adjustment of SENSIPAR(r). Once the maintenance dose levels have been established, serum calcium and serum phosphorus should be measured approximately monthly, and PTH (iPTH) every 1-3 months (see DOSAGE AND ADMINISTRATION). Either the intact PTH (iPTH) or bio-active PTH (biPTH) may be used to measure plasma PTH levels. Treatment with SENSIPAR(r) does not alter the relationship between iPTH and biPTH.
Adverse Drug Reaction Overview
Studies were conducted in patients with CKD receiving dialysis. SENSIPAR(r) (cinacalcet hydrochloride) was safe and generally well tolerated.
Hypocalcemia
SENSIPAR(r) 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 (see WARNINGS AND PRECAUTIONS).
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease Receiving Dialysis
In three double-blind placebo-controlled clinical trials, 1126 CKD patients receiving dialysis received study drug (656 SENSIPAR(r), 470 placebo) for up to six months. Adverse events reported during the studies were typical for the dialysis patient population. The most frequently reported adverse events (incidence of at least 5% in the SENSIPAR(r) treated group) are provided in Table 1. The most frequently reported events in the SENSIPAR(r) group were nausea and vomiting which were generally mild to moderate in severity, brief in duration, and infrequently led to discontinuation of study drug.
Table 1. Adverse Event Incidence (>= 5%) in Patients Receiving Dialysis | ||
|---|---|---|
| Placebo (N = 470) | Cinacalcet (N = 656) | |
| Preferred Term | % | % |
| Nausea | 19 | 31 |
| Vomiting | 15 | 27 |
| Diarrhea | 20 | 21 |
| Headache | 17 | 16 |
| Myalgia | 14 | 15 |
| Pain Abdominal | 14 | 12 |
| Infection Upper Respiratory | 13 | 12 |
| Dizziness | 8 | 10 |
| Dyspnea | 9 | 9 |
| Pain Limb | 10 | 9 |
| Dyspepsia | 8 | 8 |
| Arthralgia | 9 | 7 |
| Fever | 10 | 7 |
| Fatigue | 7 | 7 |
| Hypertension | 5 | 7 |
| Hypotension | 12 | 7 |
| Edema Peripheral | 7 | 7 |
| Asthenia | 4 | 7 |
| Cough | 7 | 6 |
| Pruritus | 7 | 6 |
| Anorexia | 4 | 6 |
| Thrombosis Vascular Access | 7 | 6 |
| Pain Chest, Non-Cardiac | 4 | 6 |
| Access Infection | 4 | 5 |
The incidence of serious adverse events (29% vs 31%) and deaths (2% vs 3%) was similar in the SENSIPAR(r) and placebo groups, respectively.
Month Experience with SENSIPAR(r)
Two hundred and sixty-six patients from the 2 pivotal phase 3 studies continued to receive SENSIPAR(r) 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 2 treatment groups, and comparable to those observed in the pivotal phase 3 studies.
Laboratory values:
Serum calcium levels should be monitored in patients receiving SENSIPAR(r) (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION). In the three phase 3 studies in patients with CKD receiving dialysis, 4% of all serum calcium values in patients receiving SENSIPAR(r) were <1.875mmol/L, compared with <1% in the placebo group.
Post-Market Adverse Drug Reactions
There have been reports of diarrhea, myalgia, rash, and hypersensitivity reactions associated with SENSIPAR(r). Isolated, idiosyncratic cases of hypotension and/or worsening heart failure have been reported in SENSIPAR(r)-treated patients with impaired cardiac function in postmarketing safety surveillance.
Drug-Drug interactions
Drugs metabolized by CYP450 2D6 - SENSIPAR(r) is an inhibitor of CYP2D6. Therefore, dose adjustments of concomitant medications that are predominantly metabolized by CYP2D6 and have a narrow therapeutic index (eg, flecainide, vinblastine, thioridazine and most tricyclic antidepressants) may be required. Desipramine: Concurrent administration of 90 mg SENSIPAR(r) with 50 mg desipramine, a tricyclic antidepressant metabolized primarily by CYP2D6, increased desipramine exposure by approximately 3.6-fold in CYP2D6 extensive metabolizers. Amitriptyline: Concurrent administration of 25 mg or 100 mg SENSIPAR(r) with 50 mg amitriptyline, a tricyclic antidepressant metabolized in part by CYP2D6, increased exposure to amitriptyline and its active metabolite nortriptyline by approximately 20% in extensive metabolizers of CYP2D6 enzymes. Dose reductions of amitriptyline may be required in some subjects receiving SENSIPAR(r) concurrently.
Based on in vitro data, SENSIPAR(r) is not an inhibitor of other CYP enzymes at concentrations achieved clinically, including CYP1A2, CYP2C9, CYP2C19, and CYP3A4. In vitro studies indicate that SENSIPAR(r) is not an inducer of CYP1A2, CYP2C19 and CYP3A4. Midazolam: Co-administration of SENSIPAR(r) (90 mg) with orally administered midazolam (2 mg), a CYP3A4 and CYP3A5 substrate, did not alter the pharmacokinetics of midazolam. These data suggest that SENSIPAR(r) would not affect the pharmacokinetics of those classes of drugs that are metabolized by CYP3A4 and CYP3A5, such as certain immunosuppressants, including cyclosporine and tacrolimus. Warfarin: SENSIPAR(r) does not affect the pharmacokinetics or pharmacodynamics (as measured by prothrombin time and clotting factor VII) of warfarin. 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 CYP3A4, CYP1A2 or CYP2C9 in humans.
SENSIPAR(r) is metabolized by multiple cytochrome P450 enzymes, primarily CYP3A4 and CYP1A2, which limits the potential for other drugs to increase cinacalcet concentrations. Ketoconazole: SENSIPAR(r) is metabolized in part by the enzyme CYP3A4. Co-administration of 200 mg bid of ketoconazole, a strong inhibitor of CYP3A4, caused an approximate 2-fold increase in cinacalcet exposure. Dose adjustment of SENSIPAR(r) may be required if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (eg, ketoconazole, erythromycin, itraconazole) or inducer (e.g., rifampin, phenytoin) of this enzyme. Calcium carbonate: Co-administration of calcium carbonate (single 1500 mg dose) did not alter the pharmacokinetics of SENSIPAR(r). Pantoprazole: Co-administration of pantoprazole (80 mg qd) did not alter the pharmacokinetics of SENSIPAR(r). Sevelamer HCl: Co-administration of sevelamer HCl (2400 mg tid) did not alter the pharmacokinetics of SENSIPAR(r).
Drug-Food Interactions
After oral administration of SENSIPAR(r) (cinacalcet hydrochloride), maximum plasma concentration is achieved in approximately 2-6 hours. Administration of SENSIPAR(r) with food results in an approximate 50%-80% increase in bioavailability. Increases in plasma concentration are similar, regardless of the fat content of the meal.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
SENSIPAR(r) (cinacalcet hydrochloride) is administered orally. Tablets should be taken whole and should not be divided. Take SENSIPAR(r) with food or shortly after a meal (see DRUG INTERACTIONS - Interactions with Food).
The recommended starting oral dose of SENSIPAR(r) is 30 mg once daily. SENSIPAR(r) should be titrated every 2 to 4 weeks to a maximum dose of 180 mg once daily to achieve a target PTH between 1.5 to 5 times the upper limit of normal: In CKD patients, PTH levels should be assessed at least 12 hours after dosing with cinacalcet. Current NKF/KDOQI Bone Metabolism Guidelines for the iPTH, Ca x P, serum phosphorus, and serum calcium targets should be considered.
Table 2. NKF-K/DOQI Bone Metabolism Guidelines for Patients Receiving Dialysis * | |
|---|---|
| Parameter | Target Range |
| iPTH | 16.5-33.0 pmol/L [150-300 pg/mL] |
| Ca x P | < 4.51 mmol 2 /L 2 [< 55 mg 2 /dL 2 ] |
| Phosphorus | 1.13-1.78 mmol/L [3.5-5.5 mg/dL] |
| 'Corrected' calcium | 2.10-2.37 mmol/L [8.4-9.5 mg/dL] |
*Adapted from National Kidney Foundation: K/DOQI clinical practice guidelines: bone metabolism and disease in chronic kidney disease. American Journal of Kidney Disease 4 2:S1-S201, 2003
During dose titration, serum calcium levels should be monitored frequently and if serum calcium levels decrease below the normal range, appropriate steps should be taken to increase serum calcium levels (see WARNINGS AND PRECAUTIONS). Calcium levels should be corrected for albumin or ionized calcium levels should be measured.
Special Populations:
Geriatric patients: Age does not alter the pharmacokinetics of SENSIPAR(r); no dose adjustment is required for geriatric patients. Patients with renal impairment: Renal impairment does not alter the pharmacokinetics of SENSIPAR(r); no dosage adjustment is necessary for renal impairment. Patients with hepatic impairment: Moderate to severe hepatic impairment (Child-Pugh classification) increases SENSIPAR(r) drug concentrations by approximately 2 to 4 fold. In patients with moderate-severe hepatic impairment, PTH and serum calcium concentrations should be closely monitored during dose titration of SENSIPAR(r).
Doses titrated up to 300 mg once daily have been safely administered to patients receiving dialysis. Overdosage of SENSIPAR(r) (cinacalcet hydrochloride) 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). Since SENSIPAR(r) is highly protein bound, hemodialysis is not an effective treatment for overdosage of SENSIPAR(r).
Mechanism of Action
Secondary hyperparathyroidism (SHPT) is a progressive disease, which occurs in patients with chronic kidney disease (CKD) and manifests as increases in parathyroid hormone (PTH) levels and derangements in calcium and phosphorous metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The calcium sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. SENSIPAR(r) (cinacalcet hydrochloride) 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.
Pharmacodynamics
Reduction in iPTH levels is correlated with cinacalcet concentration. 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.
Pharmacokinetics
After oral administration of SENSIPAR(r), maximum plasma concentration is achieved in approximately 2 to 6 hours. The absolute bioavailability of cinacalcet is approximately 25%. Administration of SENSIPAR(r) with food results in an approximate 50 to 80% increase in bioavailability. Increases in plasma concentrations are similar regardless of the fat content of the meal. After absorption, cinacalcet concentrations decline in a biphasic fashion with an initial half-life of approximately 6 hours and a terminal half-life of 30 to 40 hours. Steady state drug levels are achieved within 7 days with minimal accumulation. The AUC and Cmax of cinacalcet increase linearly over the dose range of 30 to 180 mg once daily. The pharmacokinetics of cinacalcet does not change over time. The volume of distribution is high (approximately 1000 L), indicating extensive distribution. Cinacalcet is approximately 97% bound to plasma proteins and distributes minimally into red blood cells.
Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4 and CYP1A2. The major circulating metabolites are inactive. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolized by oxidation followed by conjugation. Renal excretion of metabolites was the prevalent route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the feces.
Special Populations and Conditions
The pharmacokinetics of SENSIPAR(r) are similar in patients greater than, or less than, 65 years of age. No dosage adjustment based on age is necessary.
The pharmacokinetics of SENSIPAR(r) have not been studied in patients < 18 years of age (see WARNINGS AND PRECAUTIONS - Use in Children).
Mild hepatic impairment did not notably affect the pharmacokinetics of SENSIPAR(r). Compared to subjects with normal liver function, average AUC of cinacalcet was approximately 2-fold higher in subjects with moderate impairment and approximately 4-fold higher in subjects with severe impairment (see WARNINGS AND PRECAUTIONS). Because doses are titrated for each subject based on safety and efficacy parameters, no additional dose adjustment is necessary for subjects with hepatic impairment.
The pharmacokinetic profile of SENSIPAR(r) in patients with mild, moderate, and severe renal insufficiency, and those on hemodialysis or peritoneal dialysis is comparable to that in healthy volunteers. No dosage adjustment based on renal function is necessary.
Store at 15o-30oC Shelf-life:
Tablets stored in bottles: 48 months
SENSIPAR(r) (cinacalcet hydrochloride) tablets are composed of: cinacalcet hydrochloride, pre- gelatinized starch, microcrystalline cellulose, povidone, crospovidone, colloidal silicon dioxide, magnesium stearate, and water. Tablets are coated with color (Opadry(r) II green) and clear film- coat (Opadry(r) clear), carnauba wax, and Opacode(r) black ink. SENSIPAR(r) 30 mg tablets are formulated as light green, film-coated, oval-shaped tablets printed with "AMGEN" on one side and "30" on the opposite side, packaged in bottles of 30 tablets. SENSIPAR(r) 60 mg tablets are formulated as light green, film-coated, oval-shaped tablets printed with "AMGEN" on one side and "60" on the opposite side, packaged in bottles of 30 tablets. SENSIPAR(r) 90 mg tablets are formulated as light green, film-coated, oval-shaped tablets printed with "AMGEN" on one side and "90" on the opposite side, packaged in bottles of 30 tablets.
PART II: SCIENTIFIC INFORMATION
Proper name: cinacalcet hydrochloride Chemical name: N-[1-(R)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1- aminopropane hydrochloride Molecular weight: 393.9 g/mol (hydrochloride salt), 357.4 g/mol (free base) Structural formula: Physicochemical properties: Physical Form: White to off white crystalline powder Solubility: Slightly soluble in water and in acetonitrile; freely soluble in methanol, ethanol, methylene chloride, and chloroform; very slightly soluble in hexane; sparingly soluble in isopropyl alcohol pH: 5.1 pKa: 8.72 Partition coefficient (octanol:water): 4.79: log P Melting Point: 178degC to 184degC
Three, 6-month, multicenter, randomized, double-blind, placebo-controlled clinical studies were conducted in CKD patients receiving dialysis with uncontrolled secondary HPT (n=1136). The patient population consisted of both recently established and long-standing dialysis patients, with a range of 1 - 359 months. SENSIPAR(r) was administered either alone or in combination with vitamin D sterols; 34% of patients were not receiving vitamin D sterols at study entry. The majority (> 90%) of patients were receiving phosphate binders. Dose adjustments in phosphate binder therapy were permitted throughout the study. Vitamin D doses remained constant unless the patient developed hypercalcemia, hypocalcemia, or hyperphosphatemia. Patients continued on their previously prescribed drugs including: calcium channel blockers, ACE inhibitors, beta- blockers, hypoglycemics, and lipid lowering agents. SENSIPAR(r) (or placebo) was initiated at a dose of 30 mg and titrated every 3 or 4 weeks to a maximum dose of 180 mg once daily to achieve an iPTH of 11 to 27.5 pmol/L (1.5 to 4 times the upper limit of normal). The severity of secondary HPT ranged from mild to severe (iPTH values of 29.8 to1005.2 pmol/L), with mean (SE) baseline iPTH concentrations across the 3 studies of 78 (2.2) and 72 (2.0) pmol/L for the SENSIPAR(r) and placebo groups, respectively. Significant reductions in iPTH, serum calcium- phosphorus product (Ca x P), calcium, and phosphorus were observed in the SENSIPAR(r)- treated patients compared with placebo-treated patients receiving standard of care, and the results were consistent across the 3 studies (Table 3). Mean iPTH and Ca x P by treatment group for the overall study population during the 6-month treatment period are presented in Figures 1 and 2.
Table 3. Effects of SENSIPAR(r)on iPTH, Ca x P, Serum Calcium, and Serum Phosphorus in 6-month Phase 3 Studies (Patients Receiving Dialysis) | |||||||
|---|---|---|---|---|---|---|---|
| Placebo | Study 1 SENSIPAR (r) | Placebo | Study 2 SENSIPAR (r) | Placebo | Study 3 SENSIPAR (r) | ||
| (N = 205) | (N = 205) | (N = 165) | (N = 166) | (N = 101) | (N = 294) | ||
| iPTH | Baseline (pmol/L) | 69 (2.9) | 67 (2.5) | 67 (2.5) | 69 (3.1) | 88 (5.1) | 90 (4.3) |
| Evaluation Phase (pmol/L) | 74 (3.5) | 41 (2.6) | 73 (3.4) | 38 (3.1) | 90 (5.8) | 56 (3.2) | |
| Percent Change | 9.5 (2.8) | -38.4 (2.9) | 8.7 (2.8) | -47.5 (2.8) | 4.1 (3.4) | -40.3 (2.1) | |
| Patients Achieving Primary | 4% | 41% * * | 7% | 46% * * | 6% | 35% * * | |
| Endpoint (iPTH <= 250 pg/mL; 27.5pmol/L) (%) Patients Achieving >= 30% | 11% | 61% * * | 12% | 68% * * | 10% | 59% * * | |
| Reduction in iPTH (%) Patients Achieving iPTH <= 300 | 9% | 55% * * | 11% | 56% * * | 9% | 45% * * | |
| Ca x P | pg/mL; (33pmol/L) (%) Baseline (mmol 2 /L 2 ) | 4.9 (0.09) | 5 (0.09) | 4.9 (0.01) | 4.9 (0.01) | 4.9 (0.11) | 4.8 (0.08) |
| Evaluation Phase (mmol 2 /L 2 ) | 4.8 (0.08) | 4.2 (1.0) | 4.8 (0.01) | 4.0 (0.10) | 4.7 (0.10) | 4.0 (0.07) | |
| Percent Change | 1.5 (1.8) | -13.0 (1.7) * * | -0.7 (1.9) | -16.7 (2.1) * * | -1.4 (2.4) | -12.8 (1.7) * * | |
| Calcium | |||||||
| Baseline (mmol/L) | 2.48 (0.025) | 2.45 (0.025) | 2.48 (0.025) | 2.5 (0.025) | 2.5 (0.025) | 2.45 (0.0125) | |
| Evaluation Phase (mmol/L) | 2.48 (0.025) | 2.3 (0.025) | 2.48 (0.025) | 2.3 (0.025) | 2.5 (0.025) | 2.28 (0.025) | |
| Percent Change | 0.5 (0.3) | -6.3 (0.6) * * | 0.3 (0.4) | -7.5 (0.6) * * | 0.9 (0.5) | -6.5 (0.6) * * | |
| Phosphorus | |||||||
| Baseline (mmol/L) | 2 (0.032) | 2.03 (0.032) | 2 (0.032) | 1.97 (0.1) | 1.97 (0.032) | 1.97 (0.032) | |
| Evaluation Phase (mmol/L) | 1.94 (0.032) | 1.84 (0.032) | 1.94 (0.1) | 1.74 (0.032) | 1.87 (0.032) | 1.78 (0.032) | |
| Percent Change | 1.1 (1.8) | -7.1 (1.7) * * | -0.9 (1.9) | -9.9 (2.0) * * | -2.2 (2.5) | -7.2 (1.6) * | |
* p < 0.05; * * p < 0.001 compared to placebo
Sensipar(r) Product Monograph Page 16 of 22
Reductions in iPTH and Ca x P occurred within 2 weeks and were maintained for up to 12 months of treatment. SENSIPAR(r) decreased iPTH and Ca x P levels regardless of disease severity (ie, baseline iPTH value), dialysis modality (PD versus HD), duration of dialysis, and whether or not vitamin D sterols were administered. Approximately 60% of patients with mild (iPTH >=33 to <= 55 pmol/L), moderate (iPTH > 55 to 88 pmol/L), or severe (iPTH > 88 pmol/L) secondary HPT achieved a >= 30% reduction in iPTH levels. SENSIPAR(r) treatment reduced iPTH and Ca x P regardless of pre-treatment Ca x P levels.
In CKD patients with uncontrolled secondary HPT, reductions in PTH were associated with a favourable impact on bone specific alkaline phosphatase (BALP), N-telopeptide (N-Tx), bone turnover, bone fibrosis, and incidence of bone fracture.
Preclinical Studies
Studies in a rat model of chronic renal insufficiency (CRI; 5/6 nephrectomy) assessed the effects of cinacalcet HCl treatment on parathyroid gland hyperplasia. Cinacalcet HCl treatment reduced intact PTH (iPTH) and parathyroid cell proliferation to levels comparable to vehicle treated, non- nephrectomized animals, demonstrating that cinacalcet HCl prevented the development of secondary HPT.
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de Boer IH, Gorodetskaya I, Young B, Hsu CY, Chertow GM. The severity of secondary hyperparathyroidism in chronic renal insufficiency is GFR-dependent, race-dependent, and associated with cardiovascular disease. J Am Soc Nephrol. 13(11):2762-9 2002
Drueke TB. The pathogenesis of parathyroid gland hyperplasia in chronic renal failure.
Kidney Int. 48(1):259-72 1995 Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T, Port FK. Association of elevated serum PO4, Ca x P product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol. 12:2131-2138 2001 Goodman WG. Recent developments in the management of secondary hyperparathyroidism. Kidney Int. 59(3):1187-1201 2001 Jones CA, McQuillan GM, Kusek JW, et al. Serum creatinine levels in the US population: third National Health and Nutrition Examination Survey. Am J Kidney Dis 1998; 32:992-999. National Kidney Foundation: K/DOQI clinical practice guidelines: bone metabolism and disease in chronic kidney disease. American Journal of Kidney Disease 4 2:S1-S201, 2003 Nemeth EF, Bennett SA. Tricking the parathyroid gland with novel calcimimetic agents. Nephrology Dialysis Transplantation. 13(8):1923-1925 1998 Quarles LD. Extracellular calcium-sensing receptors in the parathyroid gland, kidney, and other tissues. Curr Opin Nephrol Hypertens. Jul; 12(4):349-55 2003 Rostand SG, Drueke TB. Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure. Kidney Int. 56:383-392 1999 Slatopolsky E, Brown A, Dusso A. Pathogenesis of secondary hyperparathyroidism. Kidney Intl. 56:S14-S19 1999 Spasovski GB, Bervoets ARJ, Behets GJS, et al. Spectrum of renal bone disease in end- stage renal failure patients not yet on dialysis. Nephrol Dial Transplan. 18:1159-1166, 2003 United States Renal Data System. USRDS 2002 Annual Data Report: Atlas of End- Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2002 Block GA, Martin KJ, de Francisco ALM, et al. Cinacalcet for Secondary Hyperparatyroidism in Patients Receiving Hemodialysis. N Engl J Med 350; 15:1516- 1525, 2004.
PART III: CONSUMER INFORMATION
SENSIPAR(r)
(cinacalcet hydrochloride)
This leaflet is part III of a three-part "Product Monograph" published when SENSIPAR(r) was approved for sale in Canada and is designed specifically for consumers. This leaflet is a summary and will not tell you everything about SENSIPAR(r). Contact your doctor or pharmacist if you have any questions about the drug.
ABOUT THIS MEDICATION
What the medication is used for:
SENSIPAR(r) is used to treat a condition called secondary hyperparathyroidism (high-per-pear-uh-THIGH-royd-izm) in
people with chronic kidney disease receiving dialysis.
What it does:
Kidney disease can cause a condition called secondary hyperparathyroidism, which can have a big impact on your health.
Four small glands located behind the thyroid gland in your neck
are called parathyroid glands. They make a hormone called parathyroid hormone (PTH). Normally, PTH makes sure you have just enough calcium and phosphorus in your blood to keep your bones, heart, muscles, nerves and blood vessels working well. When your kidneys are working, PTH keeps your calcium and phosphorus levels normal by moving the right amounts of calcium
WARNINGS AND PRECAUTIONS
BEFORE you use SENSIPAR(r) talk to your doctor or pharmacist if:
You have or had seizures.
You have or had heart problems.
You have or had liver problems.
You have lower blood calcium levels.
You are pregnant, breastfeeding, or plan to do so. SENSIPAR(r) should not be used in children.
INTERACTIONS WITH THIS MEDICATION
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those not prescribed.
Drugs that may interact with SENSIPAR(r) include: ketoconazole, erythromycin, itraconazole, flecainide, vinblastine, thioridazine, rifampin, phenytoin, or medicines such as tricyclic antidepressants (desipramine, amitryptyline).
PROPER USE OF THIS MEDICATION
Usual Adult Dose:
(r)
and phosphorus in and out of your bones.
SENSIPAR
is taken once a day with food or right after a meal.
SENSIPAR(r) tablets must be taken whole and are not to be
When your kidneys aren't working properly, the calcium and phosphorus balance in your body is upset, and your parathyroid
divided. It's best to take SENSIPAR
at the same time each day.
glands send out too much PTH to your body. This condition is
It is important to take SENSIPAR
exactly as your doctor has
called secondary hyperparathyroidism, and it can cause bone
instructed you. Your doctor will tell you how much SENSIPAR
disease and also may be a risk factor for heart disease and
to take. The usual starting dose for SENSIPAR
is one 30 mg
abnormal calcification of blood vessels and other parts of the body.
tablet once daily. Your doctor will order regular blood tests to
SENSIPAR(r) treats secondary hyperparathyroidism by lowering
measure how you are responding to SENSIPAR
and may
PTH. This helps keep calcium and phosphorus within proper levels.
When it should not be used:
You should not take SENSIPAR(r) if you are hypersensitive (allergic) to any of the ingredients in the tablet.
What the medicinal ingredient is:
Cinacalcet hydrochloride
What the important nonmedicinal ingredients are:
Pre-gelatinized starch, microcrystalline cellulose, povidone, crospovidone, colloidal silicon dioxide, magnesium stearate, Opadry(r) II green, clear film-coat (Opadry(r) clear), carnauba wax, and Opacode(r) black ink.
What dosage forms it comes in:
SENSIPAR(r) is available as small, green tablets in strengths of either 30 mg, 60 mg, or 90 mg packaged in bottles of 30 tablets.
increase or decrease your dose based on your PTH, calcium, and
phosphate levels.
Overdose:
Tell your doctor immediately if you think you took more than the recommended dose of SENSIPAR(r).
Missed Dose:
Do not take a double dose to make up for forgotten daily doses. If you have forgotten a dose of SENSIPAR(r), you should take your next daily dose as normal.
SIDE EFFECTS AND WHAT TO DO ABOUT THEM
All medicines have side effects.
If you have any of the following side effects while taking SENSIPAR(r), you should tell your doctor right away.
Hypocalcemia - Low blood calcium level. Signs of hypocalcemia include numbness or tingling around the
mouth, muscle aches or cramps, and seizures. If you have kidney disease not requiring dialysis, you have an increased risk of developing hypocalcemia. The risk of having a seizure is greater if you have had seizures before.
Nausea and vomiting -
This may make it difficult to take your medicines.
Diarrhea and muscle pain
Rash and hypersensitivity (allergic reactions)
REPORTING SUSPECTED SIDE EFFECTS
To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:
toll-free telephone: 866-234-2345
toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca
| SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM | ||||
| Symptom / effect | Talk with your doctor or pharmacist | Stop taking drug and call your doctor or pharmacist | ||
| Only if severe | In all cases | |||
| Common | Nausea and vomiting Diarrhea Muscle pain Hypocalcemia (symptoms include: numbness/ tingling around mouth, muscle aches/cramps, seizures) | 9 9 9 | 9 | |
| Uncommon | Seizures | 9 | 9 | |
By regular mail: National AR Centre
Marketed Health Products Safety and Effectiveness Information Division
Marketed Health Products Directorate Tunney's Pasture, AL 0701C
Ottawa ON K1A 0K9
NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.
MORE INFORMATION
This document plus the full product monograph, prepared for health professionals can be obtained by contacting the sponsor, Amgen Canada Inc., at: 1-866-502-6436
This leaflet was prepared by Amgen Canada Inc. Last revised: January 25, 2008
This is not a complete list of side effects. For any unexpected effects while taking SENSIPAR(r), contact your doctor or pharmacist.
HOW TO STORE IT
Store SENSIPAR(r) tablets at room temperature (15o-30oC).