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Drug Criteria & Outcomes
Cinacalcet HCl (Sensipar) Formulary Evaluation
Part 2 of 2: Availability and Cost, Clinical Studies, Critique of Studies, Recommendations/Conclusion
By April H. Eubanks,
Harrison School of Pharmacy
Auburn (AL) University
Availability and cost
Cinacalcet was approved for release on March 8, 2004. It is made available by Amgen Pharmaceuticals as Sensipar.
Wholesale cost of Sensipar:
Daily cost of traditional medications:
Oral — $1.29 to $6.44
IV— $88.65 to $405
Study 1: The calcimimetic AMG 073 [name given to cinacalcet in preclinical studies] as a potential treatment for secondary hyperparathyroidism of end-stage renal disease.
This was a placebo-controlled, double-blind, randomized study consisting of two phases: a 12-week dose-titration phase, during which four possible doses were evaluated sequentially (25, 50, 75, and 100 mg AMG 073 or placebo) and a maintenance phase, in which the final dose from the end of the dose-titration phase was maintained for six weeks. During the dose-titration phase, dose increases were permitted at weeks 3, 6, and 9 of the study, based on the mean PTH of the two previous study weeks. Patients were allowed to continue receiving prescribed vitamin D sterols and phosphate-binders during the study.
Efficacy was assessed using PTH values obtained at the end of each dosing interval. During the maintenance phase, PTH concentrations in the AMG 073 group were reduced by 33% 24 hours after dosing, compared with an increase of 3% in the placebo group (P < 0.001). In addition, the study showed that 44% of the AMG 073 patients had reductions in PTH to < 250 pg/mL during the maintenance phase, compared to only 20% in the placebo patient group (P = 0.029). Mean serum calcium decreased in the AMG 073 group (-4.6%), compared with a slight increase in the placebo group (2.6%) (P < 0.001). There was no significant difference in the mean change from baseline of serum phosphorus levels between the groups. Mean Ca × P decreased 7.9% in the AMG 073 group compared with an increase of 11.0% in the placebo group, but this was not statistically significant (P = 0.013).
The safety profiles were similar between treatment groups (see Table 1, below), with only vomiting occurring more often in the AMG 073 group.
Study 2: The calcimimetic AMG 073 reduces parathyroid hormone and calcium ´ phosphorus in secondary hyperparathyroidism.
This was a placebo-controlled, double-blind, randomized, multicenter study consisting of two phases: a 12-week dose-titration phase, followed by a maintenance phase in which the final dose from the end of the dose-titration phase was maintained for six weeks. Patients were randomized to receive either AMG 073 or placebo. Those in the AMG 073 group began on 20 mg AMG 073 once daily, which could then be titrated up to 30, 40, or 50 mg, or down to 10 mg, every three weeks until they had achieved a reduction in PTH values of > 30% from baseline and < 250 pg/mL. In addition to AMG 073 or placebo, patients were allowed to continue receiving prescribed vitamin D sterols or phosphate binders during the study.
Baseline PTH levels were similar between treatment groups. The mean PTH level in the maintenance phase decreased by an average of 26% below baseline in the AMG 073 group, while it increased by an average of 22% in the placebo group (P < 0.001). The mean PTH over the maintenance phase was 460 ± 47.4 pg/mL in the AMG 073 group, compared with 701 ± 70.3 pg/mL in the placebo group. The mean serum calcium level over the maintenance phase decreased in the AMG 073-treated patients by 4.7%, while there was no change in the placebo group (P < 0.001). Patients receiving AMG 073 had an average reduction of 7.5% in their serum phosphorus levels during the maintenance phase, while the placebo group experienced a 10.9% increase (P = 0.003). In patients given AMG 073, Ca × P levels decreased by 11.9% over the maintenance phase, while placebo patients had an increase of 10.9% (P < 0.001).
The safety profile was similar between the study groups with respect to the incidence and severity of adverse events. The most frequent adverse events included nausea and dyspnea. Transient, asymptomatic hypocalcemia occurred in three out of 38 patients treated with AMG 073 (serum calcium < 7.5 mg/dL).
Study 3: Phase III experience with cinacalcet HCl in hemodialysis and peritoneal dialysis patients with secondary hyperparathyroidism.
This was a randomized, double-blind, placebo-controlled, multicenter, Phase III study in end-stage renal disease patients with poorly controlled secondary hyperparathyroidism. The study consisted of two phases: a 16-week dose-titration phase in which five possible doses (30-180 mg once daily) were evaluated sequentially, followed by a 10-week efficacy assessment phase. Doses were evaluated and could be increased every four weeks if the PTH value was > 200 pg/mL. Dose titration continued into the efficacy-assessment phase if necessary. Patients were allowed to continue prescribed vitamin D sterols and phosphate binders during the study.
Three hundred ninety-five hemodialysis and peritoneal dialysis patients were enrolled in this study. Mean PTH decreased by 40% in the cinacalcet group, compared to an increase of 4% in the placebo group (P < 0.001). Cinacalcet reduced Ca × P by 13%, whereas only a 1% reduction was seen in the placebo group (P < 0.001). Serum calcium was reduced by 6% in the cinacalcet group, while the placebo group had a 1% increase (P < 0.001). Serum phosphorus was decreased 7% in the cinacalcet group, compared to a 2% decrease in the placebo group (P = 0.039).
Nausea and vomiting occurred more frequently in the cinacalcet group, but these events tended to be only mild to moderate in severity and infrequently led to withdrawal. Hypocalcemia (serum calcium < 7.5 mg/dL) was seen in about 5% of cinacalcet-treated patients, whereas only 1% of placebo-treated patients experienced this adverse event. Episodes were transient and were rarely associated with symptoms. The occurrence of serious adverse events was similar between treatment groups.
Study 4: Phase III study results demonstrate efficacy and safety of the calcimimetic cinacalcet HCl in hemodialysis patients with secondary hyperparathyroidism.
This was a randomized, double-blind, placebo-controlled, multicenter, Phase III study in end-stage renal disease patients with inadequately controlled secondary hyperparathyroidism. The study lasted six months and consisted of two phases: a 12-week dose-titration phase, in which five possible doses (30-180 mg daily) of cinacalcet were evaluated sequentially, followed by an efficacy-assessment phase lasting 14 weeks, in which dosage adjustments were allowed. Patients were allowed to continue prescribed vitamin D and phosphate binder therapies during the study.
Four hundred ten patients enrolled in the study (205 were placed in the cinacalcet group and 205 were placed in the placebo group). PTH decreased by 38% in the cinacalcet group, compared with a 10% increase in the placebo group (P < 0.001). Ca × P decreased by 13% in the cinacalcet group, compared with a 1% increase in the control group (P < 0.001). Serum calcium decreased by 6% in the cinacalcet group, compared with a 1% increase in the control group (P < 0.001). Finally, serum phosphorus decreased by 7% in the cinacalcet group, compared with a 1% increase in the control group (P < 0.001).
The most frequent adverse events were nausea and vomiting, which occurred more frequently in the cinacalcet group than in the placebo group. These events infrequently led to withdrawal and were generally transient and mild to moderate in severity. The occurrence of serious adverse events was similar between treatment groups.
Study 5: Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl.
This was an open-label extension study designed to assess the long-term efficacy and safety of cina-calcet for the treatment of secondary hyperparathyroidism in patients receiving hemodialysis. Data from 59 patients who completed two years of therapy were presented. In this study, cinacalcet was initiated at a dose of 30 mg once daily and was titrated at three-week intervals during a 12-week titration phase, up to a maximum dose of 100 mg daily. During the maintenance phase, doses could be increased up to 180 mg daily at the discretion of the investigator. Patients were allowed to continue use of prescribed vitamin D sterols and phosphate binders during the study.
Cinacalcet was shown to reduce PTH concentrations in the study patients, and these reductions were maintained throughout the two-year study. Fifty percent of patients achieved a PTH value < 300 pg/mL, which was greater than that seen in the three lead-in studies. This was due to higher doses used in this extension study. Also due to the higher doses, the percent of patients who achieved > 30% reduction in PTH was approximately 60% and was greater than that seen in the lead-in studies. Serum Ca × P, calcium, and phosphorus levels did not increase during the study.
Adverse events were generally mild to moderate and the most common included vomiting, hypertension, nausea, thrombosis of the vascular access, and headache.
Critique of studies
Four of the five studies included here were randomized, controlled, double-blinded clinical trials and were fairly well designed. In addition, they all tried to control for the effects of vitamin D sterols on the results by setting specific guidelines for dosing adjustments.
The extension two-year safety trial was open-label, which could have introduced some bias and may have helped to give better results than those seen in previous studies.
Only two of the studies mentioned enrolled more than 100 people, so in general, the studies were small and may not have had sufficient power to produce reliable results. In addition, these trials were short in duration and only the extension study included patients who had been previously treated with the drug. There is an obvious need for additional studies enrolling larger numbers of people who are followed for an extended period of time (longer than the average six months of these studies) to get a better understanding of the drug’s long-term safety and efficacy.
All of the studies to date have listed results from the trial in relative numbers. This makes clinical interpretation of the data difficult and may cause confusion when trying to apply the results to the rest of the population.
Cinacalcet has performed well against placebo in all studies performed to date, and all indicators point to the fact that this is a very promising agent for management of secondary hyperpara-thyroidism. However, these studies do have weaknesses (listed above) that reduce the reliability of the results produced. In addition, the cost of cinacalcet far outweighs that of traditional therapy. For these reasons, it should be recommended that patients be started on traditional therapy initially and cinacalcet should be reserved for those who have not had success with the vitamin D sterols and phosphate binders.
It is recommended that cinacalcet be made available on formulary at this time. It will be prescribed in the outpatient arena, and thus patients will enter the hospital already taking the medication. Due to the high cost of the agent, and potential low use, it is recommended that only the 30 mg tablets be stocked, since these could be used to meet the dosing needs of all patients. If higher strengths are needed, they can be ordered on a case-to-case basis.