Sensipar Drug Information

Secondary Hyperparathyroidism Sensipar is indicated for the treatment of secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on dialysis. 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.

Parathyroid Carcinoma Sensipar is indicated for the treatment of hypercalcemia in adult patients with Parathyroid Carcinoma.

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.

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. 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.

Patients with Parathyroid Carcinoma and Primary Hyperparathyroidism The recommended starting oral dose of Sensipar is 30 mg twice daily.

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. 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. 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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis In three double-blind, placebo-controlled clinical trials, 1126 patients with CKD on dialysis received study drug (656 Sensipar, 470 placebo) for up to 6 months. The most frequently reported adverse reactions are listed in Table 1.

Table 1. Table 2. Frequency of Adverse Reactions in Dialysis Patients Treated for up to 64 Months in a Long-Term Study 1 Additional adverse reaction rates from the long-term, randomized, double-blind placebo-controlled study for Sensipar versus placebo are as follows: seizure hypersensitivity reactions (9.4%, 8.3%).

Patients with Parathyroid Carcinoma and Primary Hyperparathyroidism The safety profile of Sensipar in these patient populations is generally consistent with that seen in patients with CKD on dialysis. Forty six patients were treated with Sensipar in a single-arm study, 29 with Parathyroid Carcinoma and 17 with intractable pHPT. Nine (20%) of the patients withdrew from the study due to adverse events.

The most frequent adverse reactions and the most frequent cause of withdrawal in these patient populations were nausea and vomiting. Severe or prolonged cases of nausea and vomiting can lead to dehydration and worsening hypercalcemia so careful monitoring of electrolytes is recommended in patients with these symptoms. Adverse events of hypocalcemia were reported in three patients (7%).

Table 3. Adverse Reactions with Frequency ≥ 10% in a Single-Arm, Open-Label Study in Patients with Primary Hyperparathyroidism or Parathyroid Carcinoma In a randomized double-blind, placebo-controlled study of 67 patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo surgery, the most common adverse reactions are listed in Table 4. Table 4.

Adverse Reactions Occurring in ≥ 10% of Subjects in a Double - Blind, Placebo - Controlled Study in Patients with Primary Hyperparathyroidism In 26-week studies of patients with secondary HPT and CKD on dialysis 66% of patients receiving Sensipar compared with 25% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL, whereas, 29% of patients receiving Sensipar compared with 11% of patients receiving placebo developed at least one serum calcium value less than 7.5 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia. In a randomized, double-blind, placebo-controlled study in patients with secondary HPT and CKD receiving dialysis in which patients were treated for up to 64 months (mean duration of treatment was 21 months in the cinacalcet group), 75% of patients receiving Sensipar compared with 29% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL and 33% of cinacalcet patients compared with 12% of patients receiving placebo had at least one serum calcium value less than 7.5 mg/dL.

In this trial, 1.1% of patients receiving Sensipar and 0.1% of patients receiving placebo permanently discontinued study drug due to hypocalcemia. During a placebo-controlled part of a 52-week study in patients with primary HPT who met criteria for parathyroidectomy on the basis of corrected total serum calcium (> 11.3 mg/dL and ≤ 12.5 mg/dL ), serum calcium less than 8.4 mg/dL was observed in 6.1% (2/33) of Sensipar-treated patients and 0% (0/34) of placebo-treated patients.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Sensipar. 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. Rash and hypersensitivity reactions (including angioedema and urticaria), and myalgia Isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function Gastrointestinal bleeding Chondrocalcinosis pyrophosphate (acute pseudogout)

Strong CYP3A4 Inhibitors Cinacalcet is partially metabolized by CYP3A4. Dose adjustment of Sensipar may be required if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole). The iPTH and serum calcium concentrations should be closely monitored in these patients.

CYP2D6 Substrates Cinacalcet is a strong inhibitor of CYP2D6

Dose adjustments may be required for concomitant medications that are predominantly metabolized by CYP2D6 (e.g., desipramine, metoprolol, and carvedilol) and particularly those with a narrow therapeutic index (e.g., flecainide and most tricyclic antidepressants).

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. 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. 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.

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. 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.

Sensipar treatment initiation is contraindicated if serum calcium is less than the lower limit of the normal range.

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. Since Sensipar is highly protein bound, hemodialysis is not an effective treatment for overdosage of Sensipar.