Sensipar

Concurrent administration of 25 mg or 100 mg SENSIPAR 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 concurrently.

Concurrent administration of 90 mg SENSIPAR with 50 mg desipramine, a tricyclic antidepressant metabolized primarily by CYP2D6, increased desipramine exposure by approximately 3.6-fold in CYP2D6 extensive metabolizers.

Co-administration of pantoprazole (80 mg qd) did not alter the pharmacokinetics of SENSIPAR.

SENSIPAR 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.

Co-administration of sevelamer HCl (2400 mg tid) did not alter the pharmacokinetics of SENSIPAR.

Co-administration of calcium carbonate (single 1500 mg dose) did not alter the pharmacokinetics of SENSIPAR.

After oral administration of SENSIPAR (cinacalcet hydrochloride), maximum plasma concentration is achieved in approximately 2 to 6 hours. Administration of SENSIPAR with food results in an approximate 50 to 80% increase in bioavailability. Increases in plasma concentration are similar, regardless of the fat content of the meal.

SENSIPAR (cinacalcet hydrochloride) is an inhibitor of CYP2D6. Therefore, dose adjustments of concomitant medications that are predominantly metabolized by CYP2D6 (e.g., metoprolol) and particularly those with a narrow therapeutic index (e.g., flecainide, vinblastine, thioridazine and most tricyclic antidepressants) may be required.

Based on in vitro data, SENSIPAR is not an inhibitor of other CYP enzymes at concentrations achieved clinically, including CYP1A2, CYP2C9, CYP2C19, and CYP3A4. In vitro studies indicate that SENSIPAR is not an inducer of CYP1A2, CYP2C19 and CYP3A4.

Interactions with laboratory tests have not been established.

Co-administration of SENSIPAR (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 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.

Interactions with herbal products have not been established.

SENSIPAR 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 may be required if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, erythromycin, itraconazole) or inducer (e.g., rifampin, phenytoin) of this enzyme.

SENSIPAR is metabolized by multiple cytochrome P450 enzymes, primarily CYP3A4 and CYP1A2, which limits the potential for other drugs to increase cinacalcet concentrations.

Moderate to severe hepatic impairment (Child-Pugh classification) increases SENSIPAR 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.

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.

Age does not alter the pharmacokinetics of SENSIPAR; no dose adjustment is required for geriatric patients.

Renal impairment does not alter the pharmacokinetics of SENSIPAR; no dosage adjustment is necessary for renal impairment.

The recommended starting dose of SENSIPAR for adults is 30 mg twice per day.

The dosage of SENSIPAR should be titrated sequentially every 2 to 4 weeks through dosages of 30 mg twice daily, 60 mg twice daily, and 90 mg twice daily to reduce serum calcium levels. For further information on higher dosages (90 mg 3 or 4 times daily).

The incidence of serious adverse events (29% vs 31%) and deaths (2% vs 3%) was similar in the SENSIPAR and placebo groups, respectively.

There have been reports of diarrhea, myalgia, rash, and hypersensitivity reactions associated with 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.

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 (see Warnings and Precautions).

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.

One hundred sixty patients with primary HPT or parathyroid carcinoma participated in SENSIPAR clinical trials with exposure for up to 5.5 years.

The safety profile of SENSIPAR in these patient populations is generally consistent with that seen in patients with CKD receiving dialysis. The most frequent adverse drug reactions in these patient populations were nausea and vomiting.

Studies were conducted in patients with CKD receiving dialysis. SENSIPAR (cinacalcet hydrochloride) was safe and generally well tolerated.

Two hundred sixty-six patients from the two pivotal 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 pivotal phase 3 studies.

Serum calcium levels should be monitored in patients receiving SENSIPAR (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 were <1.875 mmol/L, compared with <1% in the placebo group.

Each light green, film-coated, oval-shaped tablet, printed with “AMGEN” on one side and “60” on the opposite side, contains: cinacalcet HCl 60 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pre-gelatinized starch and water. Tablets are coated with colour (Opadry II green) and clear film-coat (Opadry clear), carnauba wax and Opacode black ink. Bottles of 30.

Each light green, film-coated, oval-shaped tablet, printed with “AMGEN” on one side and “30” on the opposite side, contains: cinacalcet HCl 30 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pre-gelatinized starch and water. Tablets are coated with colour (Opadry II green) and clear film-coat (Opadry clear), carnauba wax and Opacode black ink. Bottles of 30.

Each light green, film-coated, oval-shaped tablet, printed with “AMGEN” on one side and “90” on the opposite side, contains: cinacalcet HCl 90 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pre-gelatinized starch and water. Tablets are coated with colour (Opadry II green) and clear film-coat (Opadry clear), carnauba wax and Opacode black ink. Bottles of 30.

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.

Serum calcium 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 levels have been established, serum calcium and serum phosphorus should be measured approximately monthly, and PTH (iPTH) every 1 to 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 does not alter the relationship between iPTH and biPTH.

In clinical trials of CKD patients receiving dialysis, SENSIPAR treatment was not initiated in patients with a serum calcium (corrected for albumin) less than the lower limit of the normal range. Since SENSIPAR lowers serum calcium, patients should be monitored for the occurrence of hypocalcemia.

In CKD patients receiving dialysis who were administered SENSIPAR, 4% of serum calcium values were less than 1.875 mmol/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 (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.

The safety and efficacy of SENSIPAR in pediatric patients have not been established.

There are no studies on the use of SENSIPAR in pregnant women. SENSIPAR was not teratogenic in rabbits when given a dose of 0.4 times, on an area under the curve (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 has been shown to cross the placental barrier in rabbits. Although animal studies have shown no evidence of teratogenicity, SENSIPAR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Due to the potential for 2- to 4-fold higher plasma levels of SENSIPAR, patients with moderate to severe hepatic impairment should be closely monitored when initiating treatment (see Action and Clinical Pharmacology).

Of the 1136 patients enrolled in the SENSIPAR phase 3 clinical program, 26% were >65 years old, while 9% were >75 years old. No overall differences in safety and efficacy of SENSIPAR were observed in patients greater or less than 65 years of age (see Dosage and Administration).

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.

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-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-treated patients.

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, the dose of SENSIPAR and/or vitamin D sterols should be reduced or therapy discontinued.

In three clinical studies of CKD patients receiving dialysis, 5% of the patients in both the SENSIPAR (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-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.

SENSIPAR, 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 tumours in rats and mice of both sexes did not indicate any SENSIPAR-induced carcinogenesis. A decreased incidence of thyroid C-cell adenomas was observed in rats treated with SENSIPAR.

SENSIPAR 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 has no genetic toxicity either with respect to DNA damage, including gene mutations, large scale chromosomal damage, recombinations or numerical changes.

No effects on the ability to drive or operate machinery have been observed.

SENSIPAR had no effect on fertility in animal studies.

It is not known whether SENSIPAR is excreted in human milk. Studies in rats have shown that SENSIPAR is excreted in the milk with a high milk to plasma ratio. A decision should be made whether to discontinue nursing or discontinue SENSIPAR, taking into account the importance of SENSIPAR to the mother.

Mild hepatic impairment did not notably affect the pharmacokinetics of SENSIPAR. 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 pharmacokinetics of SENSIPAR are similar in patients greater than, or less than, 65 years of age. No dosage adjustment based on age is necessary.

Secondary hyperparathyroidism is a progressive disease, which occurs in patients with chronic kidney disease and manifests as increases in parathyroid hormone 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 (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.

Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4 and CYP1A2. The major circulating metabolites are inactive. After administration of a 75 mg radio-labeled 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.

The pharmacokinetic profile of SENSIPAR 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.

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 C_max of cinacalcet. After steady state is reached, serum calcium concentrations remain constant over the dosing interval.

After oral administration of SENSIPAR, maximum plasma concentration is achieved in approximately 2 to 6 hours. The absolute bioavailability of cinacalcet is approximately 25%. Administration of SENSIPAR 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 C_max 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.

The pharmacokinetics of SENSIPAR have not been studied in patients <18 years of age (see Warnings and Precautions).