Clinical and Economic Implications of Restrictions on Calcitonin Utilization in a Health System

Abstract

Background: Hypercalcemia is a relatively common problem that may require hospital admission based on severity. A treatment option for hypercalcemia is calcitonin given intramuscularly or subcutaneously. Purpose: In 2015, calcitonin was on our health system formulary, but due to a sharp rise in cost, restrictions were placed to ensure appropriate utilization. Intervention: These restrictions reserved calcitonin for patients with symptomatic hypercalcemia or severe hypercalcemia, which was defined as an ionized calcium of greater than 1.5 mmol/L and/or total/corrected calcium (Ca) of greater than 13 mg/dL. In addition to providing criteria for its use, calcitonin orders also had an automatic stop date of 24 hours to ensure no more than 2 doses were provided in a 24-hour period. After the initial 24 hours, a patient would have to be reviewed again before any further doses were ordered and administered. If the patient met criteria, an additional 2 doses could be given in the next 24 hours for a total maximum treatment of 4 doses over a 48-hour time frame. Results: An evaluation to assess health system–wide compliance of the usage of calcitonin restrictions regarding utilization, effectiveness, and cost was conducted. In the 2-month study time frame that was examined, there was a decrease in 66 vials of calcitonin that were dispensed. This represents a 43% reduction in usage and an estimated US $450,000 reduction in the total money spent for calcitonin annually. No notable differences in Ca reduction were identified between the groups. Conclusion: This evaluation revealed that putting health system–wide restrictions in use for a high-cost medication can have a major financial impact without compromising clinical efficacy.

Introduction

Hypercalcemia is a relatively common clinical issue that may require hospital admission based on severity. The 2 most common causes of hypercalcemia are malignancy and hyperparathyroidism, accounting for about 90% of cases.^1-3 Hypercalcemia can be classified into 3 different severities based on serum calcium (Ca) or ionized calcium (iCa) levels, including mild, moderate, and severe. Mild and moderate hypercalcemic patients are often asymptomatic, whereas severe hypercalcemia is considered a crisis that is accompanied by symptoms. Severe hypercalcemia typically presents with a serum Ca level greater than 13.0 mg/dL or iCa ≥1.5 mmol/L.² Although the causes of hypercalcemia may vary, the process for development of hypercalcemia can be explained by 3 different mechanisms: increased bone resorption, increased gastrointestinal absorption, and increased tubular reabsorption.²

Treatment of hypercalcemia is based on the degree of hypercalcemia, acuity of hypercalcemia, and the presence of symptoms. The goals of treatment are to resolve the signs and symptoms and to normalize the levels of Ca in the patient.² As hypercalcemia is usually due to an underlying disease state, it is important to treat the root cause of the problem. Clinically, patients are often asymptomatic unless the hypercalcemia is moderate to severe. Some signs and symptoms of hypercalcemia include lethargy, muscle weakness, shortened QT interval, tachyarrhythmias, muscle weakness, and hypertension. Severe hypercalcemia is treated as an emergency and is treated with hemodialysis, hydration with normal saline (NS), diuresis, or calcitonin.^1-3 Additional treatments include bisphosphonates and denosumab, which are usually used for treatment of hypercalcemia associated with malignancy. Allium nitrate, mithramycin, and glucocorticoids have also been used for the treatment of hypercalcemia.^1-3 Unlike dialysis, hydration/urinary excretion, and calcitonin, the other treatment options for hypercalcemia resolve the hypercalcemia at a slower onset and have many additional side effects. Treatment with calcitonin also has its limitations. While calcitonin has a quicker onset of action, tachyphylaxis with calcitonin is a known phenomenon that has been described to occur after 48 hours of usage.^4,5 Studies have shown that the effect that calcitonin has on Ca levels is not a permanent effect, but a transient one, and that additional measures, such as hydration and usage of pamidronate, are essential.⁶

At our health system, calcitonin injection is on formulary, but due to increased cost, restrictions were placed to ensure that it was used appropriately. After the restrictions were placed, calcitonin was reserved for patients with symptomatic hypercalcemia (as determined by ordering provider) or severe hypercalcemia (iCa of greater than 1.5 mmol/L and/or total/corrected Ca of greater than 13 mg/dL). In addition to restricting calcitonin for patients who meet these criteria, an automatic stop date was placed to all calcitonin orders. The initial order would enable the provider to order 2 doses, requiring them to reassess the need for additional dosing. As previously stated, the utilization of calcitonin greater than 48 hours does not provide additional benefit due to the development of tachyphylaxis.^4,5 Therefore, the last restriction placed was providing a maximum of 4 doses over a 48-hour period, given the standard dosing is every 12 hours. An example order sentence would be “calcitonin 400 units every 12 hours for 2 doses.” The provider could then order “calcitonin 400 units every 12 hours for 2 doses” the next day to meet the maximum of 4 doses over 48 hours. This evaluation assessed health system–wide compliance of the usage of calcitonin restrictions regarding utilization, effectiveness, and cost.

Methods

Evaluation of Calcitonin Usage

A retrospective chart review of adult patients admitted to our health system that received calcitonin intramuscularly or subcutaneously was performed. The 2 groups were delineated based on the time frame of the restrictions. The first group received doses between January 1, 2015 to February 28, 2015 and was defined as the pre-implementation group. The second group received doses between January 1, 2016 to February 29, 2016 and was defined as the post-implementation group. All orders for calcitonin placed during the specified time frame were evaluated. Patients were excluded if an order of calcitonin was placed, but not administered. Our primary outcome was to review utilization pre and post. Secondary outcomes included changes in Ca levels, utilization of concomitant therapy, and adherence to restrictions. Serum Ca levels were corrected for hypoalbuminemia using the following formula: Corrected Calcium = (0.8 * [Normal Albumin − Pt’s Albumin]) + Serum Ca.^7,8

To assess compliance with the aforementioned restrictions, an electronic form was created to capture indications for use (Figure 1). This form automatically alerts after a prescriber orders calcitonin to select one of the indications that would qualify the patient for therapy. After implementation of the form, data were collected during the same 2 months in the post-implementation time frame to determine the clinical and cost savings impact that restrictions could have throughout our health system.

Figure 1.

Calcitonin injection inclusion criteria form.

Cost Savings

Cost savings were calculated using a weighted price from purchase data. Calcitonin was purchased in 200 units per vial and 400 units per vial package sizes in 2015 and was only purchased in 400 units per vial package size in 2016. Vials were purchased using multiple accounts, and the weighted price represents the associated split between inpatient group purchasing organization (GPO) prices and outpatient 340B/Non-GPO prices. The annual savings are calculated through the difference in total purchase of calcitonin products for the health system from 2015 to 2016. The 2015 prices and costs have been adjusted to reflect the 1.3% inflation rate in the consumer price index.⁹

Results

Evaluation of Calcitonin Usage

A total of 35 patients were identified in the pre-implementation group and 30 patients were identified in the post-implementation group. Thirty patients in each group met inclusion criteria. Five patients in the pre-implementation group were excluded due to having an order for calcitonin placed, but not administered. Baseline demographics can be found in Table 1.

Table 1.

Patient Demographics.

Patients	Pre-implementation (n = 30)	Post-implementation (n = 30)
Female, No. (%)	18 (60)	24 (80)
Mean age, y	62.6 ± 18.1	67.3 ± 11.4
Mean weight, kg	80 ± 21.3	79.6 ± 18.3
Mean length of stay, d	20.9 ± 29.1	10 ± 5.9
Average serum calcium level, mg/dL	13.4 ± 1.5	13.7 ± 1.2
Average ionized calcium level, mg/dL	1.7 ± 0.2	1.8 ± 0.3

The recommended dosing of calcitonin for hypercalcemia is 4 units/kg per dose based on actual body weight every 12 hours.⁴ Based on the data provided, the average dose of calcitonin for the pre-implementation and post-implementation groups was 3.4 units/kg per dose. Only 15 patients (50%) were started on the appropriate dose in pre-implementation group, and that the number only slightly increased to 19 patients (63%) in the post-implementation group. The average number of doses given per order was 6.3 in the pre-implementation group compared with 2.4 in the post-implementation group (Table 2). There were 17 patients (57%) who received more than 4 doses before implementation of the form compared with 4 patients (13%) after implementation.

Table 2.

Usage of Calcitonin.

	Pre-implementation (n = 30)	Post-implementation (n = 30)
Total doses	189a	73
Total units	46 669	20 267
Vials used	117	51
Average dosage given (units)	268.3 ± 124.3	270.8 ± 113
Average units, kg	3.42 ± 1.26	3.37 ± 1.04
Average no. of doses given	6.3 ± 5.3	2.4 ± 1.74

^aOne patient with 30 doses administered.

Secondary outcomes reviewed included concomitant therapy and average change in serum Ca. Similar rates of Ca reduction after 24 hours of treatment were seen between the varying treatment modalities. The average serum Ca at time of therapy initiation was 13.39 mg/dL and it was reduced to 1.48 mg/dL in pre-implementation group (Table 3). In the post-implementation group, the average serum Ca at the time of therapy initiation was 13.68 mg/dL and it was reduced to 1.24 mg/dL (Table 4).

Table 3.

Decrease in Serum Ca in the Pre-implementation Group.

Therapies	Pre-implementation (n = 30)
	Average Ca before treatment, mg/dL	Average Ca after treatment, mg/dL	Average change in Ca, mg/dL
Calcitonin monotherapy (n = 4)	13.66 ± 1.37	12.03 ± 1.23	1.63
Calcitonin + NS hydration (n = 11)	13.50 ± 1.39	12.01 ± 1.30	1.5
Calcitonin + Pamidronate (n = 3)	13.82 ± 1.22	12.18 ± 1.12	1.63
Calcitonin + NS hydration + Pamidronate (n = 12)	13.42 ± 1.53	11.99 ± 1.34	1.47
Overall (n = 30)	13.39 ± 1.49	11.91 ± 1.75	1.48

Note. Serum Ca levels adjusted for hypoalbuminemia.^7,8 Ca = Calcium; NS = normal saline.

Table 4.

Decrease in Serum Ca in the Post-implementation Group.

Therapies	Post-implementation (n = 30)
	Average Ca before treatment, mg/dL	Average Ca after treatment, mg/dL	Average change in Ca, mg/dL
Calcitonin monotherapy (n = 2)	13.66 ± 1.31	12.03 ± 1.41	1.63
Calcitonin + NS hydration (n = 12)	13.9 ± 1.54	12.689 ± 1.56	1.23
Calcitonin + pamidronate (n = 0)	N/A	N/A	N/A
Calcitonin + NS hydration + pamidronate (n = 16)	13.68 ± 1.6	12.44 ± 1.57	1.24
Overall (n = 30)	13.68 ± 1.6	12.44 ± 1.57	1.24

Note. Serum Ca levels adjusted for hypoalbuminemia.^7,8 Ca = Calcium; NS = normal saline.

Appropriateness of the criteria checked on the form was approximately 85%. The iCa criteria box was not checked 11 (36%) times, but prescribers missed checking the box 5 times when this criterion was met based on chart review for laboratory value. There was a similar trend for serum Ca being greater than 13 mg/dL. There was one instance in which the form did not populate—when a pharmacist placed the order as a phone order. The symptoms that were most selected on the form were lethargy, fatigue, and bone pain. While the number of orders did not change after restrictions were placed, the volume of doses dispensed decreased due to the restrictions. No clinical differences were noted between the groups using pamidronate, NS hydration, or combination therapy.

Of patients evaluated, 93% of patients met at least one of the criteria based on current prescribing restrictions compared with 90% in the previous year (Table 5). The number of doses reduced due to the maximum 4 dose limits within a 48-hour time frame had a substantial impact on the overall decrease in utilization. Due to implementation of the form, we reduced the number of units dispensed from 46,669 to 20,267 during the study months (2015 and 2016). This prescribing reduction led to a decrease from using 117 vials in the pre-implementation group to 51 vials in post-implementation group for this 2-month time frame comparison.

Table 5.

Comparison Between Pre-implementation and Post-implementation.

Patients meeting criteria	Pre-implementation (n = 30)	Post-implementation (n = 30)
ICa ≥ 1.5 mmol/L	13 (43%)	21 (70%)
Ca ≥ 13 mg/dL	17 (57%)	21 (70%)
Symptoms	18 (60%)	14 (47%)
Patients with at least 1 criteria met	27 (90%)	28 (93%)
Patients with at least 4a units/kg	15 (50%)	19 (63%)
Patients receiving >4 doses	17 (57%)	4 (13%)

Note. ICa = ionized calcium; Ca = calcium.

^a>3.8 rounded up to 4 units.

Cost Savings

After the form was implemented, there was a 56.4% decrease in the total vials of calcitonin dispensed that were used for the patients evaluated in this study for the health system. In the 2-month study time frame that was examined, there was a decrease in 66 vials of calcitonin used. The average price paid for 400 units per vial of calcitonin was US $1777.40 in 2015 and US $1807.33 in 2016. The total money spent on calcitonin for the health system was US $1 105 466.31 for 247 800 units in 2015 and US $645 215.18 for 142 800 units in 2016, reflecting purchase data. After the implementation of this form, annual cost for calcitonin decreased by US $460 251.13 or approximately 41.6% (Table 6).

Table 6.

Purchase and Pricing Data Between Pre-implementation and Post-Implementation.

	Pre-implementationa	Post-implementation	Difference, %
Total calcitonin units purchased	247 800	142 800	−105 000 (−42.4)
Total calcitonin spent	US $1 105 466.31	US $645 215.08	−US $460 251.13 (−41.6)
Weighted price per 400-unit vial	US $1777.40	US $1807.33	US $29.93 (1.7)

^aPurchased both 200-unit and 400-unit vial size.

Discussion

Implications

The implementation of the restrictions and calcitonin criteria form both have proven valuable through decreasing usage of calcitonin with no impact on quality of care to patients. Because both components were implemented concurrently, it is difficult to determine whether the restriction to calcitonin prescribing or the form led to the substantial decrease in calcitonin utilization. We believe that the restrictions affected the decrease in utilization to a greater extent compared with the form. However, the form played an important role in treating patients with symptomatic hypercalcemia who may not have met specified laboratory criteria. Unrestricted calcitonin guidelines allow for the product to be used on patients that may not benefit from receiving it. The final recommendation was made to continue utilization of the form for prescribing restrictions for calcitonin. Approximately 9 months into the post-implementation period, a change was made to apply a standardized dosing of 4 units/kg per dose (with dose rounding) due to underdosing of patients identified in both groups on completion of the evaluation (Table 7).

Table 7.

Standardized Dose Rounding for Calcitonin.

Range	Range 1	Range 2	Dose units	Standardized dose	Dose unit
Between	100	215	Units	200	Units
Between	215	265	Units	250	Units
Between	265	315	Units	300	Units
Between	315	365	Units	350	Units
≥	365		Units	400	Units

Limitations

There are a few limitations to our study. The 2-month time frame from which the data were obtained was narrow and only represents a sample. In addition, the 2 vial sizes that were purchased in 2015 add an additional variable to the cost savings that were reported. Finally, the data collected were dependent on accurate documentation and charting in the electronic medical record. Despite these limitations, the financial impact seen for our health system was substantial.

Conclusions

The financial impact of the utilization of the calcitonin form and restrictions was substantial for our health system. The total money spent on calcitonin was less in the post-implementation despite an increase in cost per vial after accounting for inflation. Not only was calcitonin being ordered inappropriately, but it also was being wasted without standardized dosage rounding for the product. Finally, product standardization for purchasing the 400 units per vial package size led to an overall lower cost per unit of calcitonin due to the high per unit cost for the 200 units per vial package size. Overall, our health system was able to receive substantial cost savings through these changes without compromising the effects on Ca level reduction.