Sensipar

         Secondary Hyperparathyroidism

Sensipar is indicated for the treatment of secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on dialysis [see Clinical Studies ( 14.1)]. 

Limitations of Use:

Sensipar is not indicated for use in patients with CKD who are not on dialysis because of an increased risk of hypocalcemia [see Warnings and Precautions ( 5.1)].

         Parathyroid Carcinoma

Sensipar is indicated for the treatment of hypercalcemia in adult patients with Parathyroid Carcinoma [see Clinical Studies ( 14.2)].

         Primary Hyperparathyroidism

Sensipar is indicated for the treatment of hypercalcemia in adult patients with primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy [see Clinical Studies ( 14.3)].

         Administration

Sensipar should be taken with food or shortly after a meal.

Sensipar tablets are administered orally and should always be taken whole and not chewed, crushed, or divided.

         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 intact parathyroid hormone (iPTH) should be measured 1 to 4 weeks after initiation or dose adjustment of Sensipar [see Dosage and Administration ( 2.3)]. Sensipar should be titrated no more frequently than every 2 to 4 weeks through sequential doses of 30, 60, 90, 120, and 180 mg once daily to target iPTH levels of 150 to 300 pg/mL. Serum iPTH levels should be assessed no earlier than 12 hours after dosing with Sensipar.

Sensipar can be used alone or in combination with vitamin D sterols and/or phosphate binders.

During dose titration, serum calcium levels should be monitored frequently and if levels decrease below the normal range, appropriate steps should be taken to increase serum calcium levels, such as by providing supplemental calcium, initiating or increasing the dose of calcium-based phosphate binder, initiating or increasing the dose of vitamin D sterols, or temporarily withholding treatment with Sensipar [see Dosage and Administration ( 2.4) and Warnings and Precautions ( 5.1)].

         Patients with Parathyroid Carcinoma and Primary Hyperparathyroidism

The recommended starting oral dose of Sensipar is 30 mg twice daily.

The dose of Sensipar should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, and 90 mg twice daily, and 90 mg 3 or 4 times daily as necessary to normalize serum calcium levels.  Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar [see Dosage and Administration ( 2.4) and Warnings and Precautions ( 5.1)]. 

         Switching from Parsabiv (etelcalcetide) to Sensipar

Discontinue etelcalcetide for at least 4 weeks prior to starting Sensipar. Ensure corrected serum calcium is at or above the lower limit of normal prior to Sensipar initiation [see Warnings and Precautions ( 5.1)]. Initiate Sensipar treatment at a starting dose of 30 mg once daily.

         Monitoring for Hypocalcemia 

Once the maintenance dose has been established, serum calcium should be measured approximately monthly for patients with secondary hyperparathyroidism with CKD on dialysis, and every 2 months for patients with parathyroid carcinoma or primary hyperparathyroidism [see Dosage and Administration ( 2.2, 2.3)].

For secondary hyperparathyroidism patients with CKD on dialysis, if serum calcium falls below 8.4 mg/dL but remains above 7.5 mg/dL, or if symptoms of hypocalcemia occur, calcium-containing phosphate binders and/or vitamin D sterols can be used to raise serum calcium. If serum calcium falls below 7.5 mg/dL, or if symptoms of hypocalcemia persist and the dose of vitamin D cannot be increased, withhold administration of Sensipar until serum calcium levels reach 8.0 mg/dL and/or symptoms of hypocalcemia have resolved. Treatment should be reinitiated using the next lowest dose of Sensipar [see Dosage and Administration ( 2.2)].

         Pregnancy

Risk Summary

Limited case reports of Sensipar use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. In animal reproduction studies, when female rats were exposed to cinacalcet during the period of organogenesis through to weaning at 2-3 times the systemic drug levels (based on AUC) at the maximum recommended human dose (MRHD) of 180 mg/day, peripartum and early postnatal pup loss and reduced pup body weight gain were observed in the presence of maternal hypocalcemia [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day cinacalcet during gestation, no teratogenicity was observed at doses up to 50 mg/kg/day (exposure 4 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Decreased fetal body weights were observed at all doses (less than 1 to 4 times a human oral dose of 180 mg/day based on AUC comparison) in conjunction with maternal toxicity (decreased food consumption and body weight gain).

In pregnant female rabbits given oral gavage doses of 2, 12, 25 mg/kg/day cinacalcet during gestation, no adverse fetal effects were observed (exposures less than with a human oral dose of 180 mg/day based on AUC comparisons). Reductions in maternal food consumption and body weight gain were seen at doses of 12 and 25 mg/kg/day.  Cinacalcet has been shown to cross the placental barrier in rabbits.

In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day cinacalcet during gestation through lactation, no adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day (exposures less than with a human therapeutic dose of 180 mg/day based on AUC comparisons). Higher doses of 15 and 25 mg/kg/day cinacalcet (exposures 2 to 3 times a human oral dose of 180 mg/day based on AUC comparisons) were accompanied by maternal signs of hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in postnatal maternal and pup body weight gain.

         Lactation 

Risk Summary

There are no data regarding the presence of Sensipar in human milk or effects on the breastfed infant or on milk production. Studies in rats showed that cinacalcet was excreted in the milk.  The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Sensipar and any potential adverse effects on the breastfed infant from Sensipar or from the underlying maternal condition.

         Pediatric Use

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

The use of Sensipar for the treatment of secondary HPT in pediatric patients with CKD on dialysis was evaluated in two randomized, controlled studies (Pediatric Study 1 and Study 2) where 47 pediatric patients aged 6 years to less than 18 years received at least one dose of Sensipar and in one single-arm study (Pediatric Study 3) where 17 pediatric patients aged 28 days to less than 6 years received at least one dose of Sensipar. Dosing with Sensipar in Pediatric Study 1 was stopped because of a fatality in a Sensipar-treated individual. The individual was noted to be severely hypocalcemic at the time of death. The cause of death was multifactorial and a contribution of Sensipar to the death could not be excluded [see Warnings and Precautions ( 5.1)].  Study 1 was terminated and changes to Sensipar dosing after the fatality were implemented in Pediatric Study 2 and Study 3 to minimize the risk of severe hypocalcemia. The data in Pediatric Studies 2 and 3 were insufficient to establish the safety and efficacy of Sensipar for the treatment of secondary HPT in pediatric patients with CKD on dialysis. In aggregate, the pediatric studies did not establish a safe and effective Sensipar dosing regimen for the pediatric population.

         Geriatric Use

Of the total number of subjects (n = 1136) in clinical studies of Sensipar, 26 percent were 65 and over, and 9 percent were 75 and over. No overall differences in the safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Studies ( 14) and Clinical Pharmacology ( 12.3)].

         Renal Impairment

No dosage adjustment is necessary for renal impairment [see Clinical Pharmacology ( 12.3)].

         Hepatic Impairment

Patients with moderate and severe hepatic impairment should have serum calcium, serum phosphorus, and iPTH levels monitored closely throughout treatment with Sensipar because cinacalcet exposure (AUC0-infinite) is increased by 2.4 and 4.2 fold, respectively, in these patients [see Clinical Pharmacology ( 12.3)].

         Hypocalcemia

Sensipar lowers serum calcium and can lead to hypocalcemia [see Adverse Reactions ( 6.1)].  Significant lowering of serum calcium can cause paresthesias, myalgias, muscle spasms, tetany, seizures, QT interval prolongation and ventricular arrhythmia.  Life threatening events and fatal outcomes associated with hypocalcemia have been reported in patients treated with Sensipar, including in pediatric patients.  The safety and effectiveness of Sensipar have not been established in pediatric patients [see Pediatric Use ( 8.4)].  

Sensipar is not indicated for patients with CKD not on dialysis [see Indications and Usage ( 1)].  In patients with secondary HPT and CKD not on dialysis, the long-term safety and efficacy of Sensipar have not been established.  Clinical studies indicate that Sensipar-treated patients with CKD not on dialysis have an increased risk for hypocalcemia compared with Sensipar-treated patients with CKD on dialysis, which may be due to lower baseline calcium levels.  In a phase 3 study of 32 weeks duration and including 404 patients with CKD not on dialysis (302 cinacalcet, 102 placebo), in which the median dose for cinacalcet was 60 mg per day at the completion of the study, 80% of Sensipar-treated patients experienced at least one serum calcium value < 8.4 mg/dL compared with 5% of patients receiving placebo.

QT Interval Prolongation and Ventricular Arrhythmia

Decreases in serum calcium can also prolong the QT interval, potentially resulting in ventricular arrhythmia. Cases of QT prolongation and ventricular arrhythmia have been reported in patients treated with Sensipar. Patients with congenital long QT syndrome, history of QT interval prolongation, family history of long QT syndrome or sudden cardiac death, and other conditions that predispose to QT interval prolongation and ventricular arrhythmia may be at increased risk for QT interval prolongation and ventricular arrhythmias if they develop hypocalcemia due to Sensipar.  Closely monitor corrected serum calcium and QT interval in patients at risk receiving Sensipar.

Seizures

In clinical studies, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (43/3049) of Sensipar-treated patients and 0.7% (5/687) of placebo-treated patients. While the basis for the reported difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum calcium levels. Monitor serum calcium levels in patients with seizure disorders receiving Sensipar.

Concurrent Administration with Other Calcium-Lowering Drug Products

Concurrent administration of Sensipar with calcium-lowering drugs including other calcium-sensing receptor agonists could result in severe hypocalcemia.  Closely monitor serum calcium in patients receiving Sensipar and concomitant therapies known to lower serum calcium levels.

Patient Education and Hypocalcemia Treatment

Educate patients on the symptoms of hypocalcemia and advise them to contact a healthcare provider if they occur.  If corrected serum calcium falls below the lower limit of normal or symptoms of hypocalcemia develop, start or increase calcium supplementation (including calcium, calcium-containing phosphate binders, and/or vitamin D sterols or increases in dialysate calcium concentration).  Sensipar dose reduction or discontinuation of Sensipar may be necessary [see Dosage and Administration ( 2.2)].

         Upper Gastrointestinal Bleeding

Cases of gastrointestinal bleeding, mostly upper gastrointestinal bleeding, have occurred in patients using calcimimetics, including Sensipar, from postmarketing and clinical trial sources. The exact cause of GI bleeding in these patients is unknown.

Patients with risk factors for upper GI bleeding (such as known gastritis, esophagitis, ulcers or severe vomiting) may be at increased risk for GI bleeding when receiving Sensipar treatment. Monitor patients for worsening of common GI adverse reactions of nausea and vomiting associated with Sensipar [see Adverse Reactions ( 6.1)] and for signs and symptoms of GI bleeding and ulcerations during Sensipar therapy. Promptly evaluate and treat any suspected GI bleeding.

           Hypotension, Worsening Heart Failure and/or Arrhythmias

In postmarketing safety surveillance, isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function, in which a causal relationship to Sensipar could not be completely excluded and which may be mediated by reductions in serum calcium levels [see Adverse Reactions ( 6.2)].

         Adynamic Bone Disease

Adynamic bone disease may develop if iPTH levels are suppressed below 100 pg/mL. One clinical study evaluated bone histomorphometry in patients treated with Sensipar for 1 year. Three patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with Sensipar. Two of these patients had iPTH levels below 100 pg/mL at multiple time points during the study. In three 6-month, phase 3 studies conducted in patients with CKD on dialysis, 11% of patients treated with Sensipar had mean iPTH values below 100 pg/mL during the efficacy-assessment phase. If iPTH levels decrease below 150 pg/mL in patients treated with Sensipar, the dose of Sensipar and/or vitamin D sterols should be reduced or therapy discontinued.