General Information

Natpara is a parathyroid hormone. Parathyroid hormone raises serum calcium which releases calcium into the circulation.

Natpara is specifically indicated as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism. Because of the potential risk of osteosarcoma, Natpara is recommended only for patients who cannot be well-controlled on calcium supplements and active forms of vitamin D alone.

Natpara is supplied as a solution for subcutaneous injection. The dose of Natpara should be individualized based on total serum calcium (albumin-corrected) and 24-hour urinary calcium excretion. The recommended Natpara dose is the minimum dose required to prevent both hypocalcemia and hypercalciuria. This dose will generally be the dose that maintains total serum calcium (albumin-corrected) within the lower half of the normal range (i.e., between 8 and 9 mg/dL) without the need for active forms of vitamin D and with calcium supplementation sufficient and individualized to meet the patient’s daily requirements. For specific dose adjustments, please see the drug label.

Clinical Results

FDA Approval

The FDA approval of Natpara was based on a 24-week, randomized, double-blind, placebo-controlled, multicenter trial. In this trial, patients with established hypoparathyroidism receiving calcium and active forms of vitamin D (vitamin D metabolite or analogs) were randomized to Natpara (n=84) or placebo (n=40). Before randomization, participants entered a 2-16 weeks run-in phase. In this phase calcium supplement and active vitamin D doses were adjusted to target an albumin-corrected serum calcium concentration between 8.0 and 9.0 mg/dL and 25-hydroxyvitamin D was replaced in patients with insufficient stores. At randomization, baseline serum calcium was 8.6 mg and participants were receiving a median (interquartile range) daily oral calcium dose of 2000 (1250, 3000) mg and a median daily oral activevitamin D dose equivalent to 0.75 mcg (0.5, 1) of calcitriol. At randomization, active forms of vitamin D were reduced by 50% and patients were randomized to Natpara 50 mcg daily or placebo. Randomization was followed by a 12-week Natpara titration phase and a 12-week Natpara dose maintenance phase. During the titration phase Natpara was increased by 25 mcg increments every four weeks up to a maximum of 100 mcg. Titration was indicated for patients who could not achieve independence from active vitamin D and who could not reduce oral calcium to 500 mg or less per day. At end of treatment, 56% of subjects randomized to Natpara were receiving 100 mcg of Natpara per day, 26% were receiving 75 mcg of Natpara per day, and 18% were receiving 50 mcg of Natpara per day. Doses of co-administered active forms of vitamin D and calcium were adjusted (reduced or increased) to maintain albumin-corrected serum calcium within a desired target range throughout the trial in both arms. For the efficacy analysis, subjects that fulfilled three components of a three-part response criterion were considered responders. A responder was defined as an individual who had: at least a 50% reduction from baseline in the dose of active vitamin D, at least a 50% reduction from baseline in the dose of oral calcium supplementation and an albumin-corrected total serum calcium concentration between 7.5 mg/dL and 10.6 mg/dL. At the end of treatment, significantly (p-value <0.001) more subjects treated with Natpara [46/84
(54.8%)] compared to placebo [1/40 (2.5%)] met the response criterion. Forty-two percent (35/84) of subjects randomized to Natpara were independent of active forms of vitamin D and were on no more than 500 mg of oral calcium, compared with 2.5% (1/40) of subjects randomized to placebo (p<0.001). There were no differences in the proportion of patients with a calcium level between 7.5 mg and 10.6 mg at end of treatment between subjects randomized to Natpara and placebo.

Side Effects

Adverse effects associated with the use of Natpara may include, but are not limited to, the following:

paresthesia

hypocalcemia

headache

hypercalcemia

nausea

hypoaesthesia

diarrhea

vomiting

arthralgia

hypercalciuria

pain in extremity

Natpara comes with a black box warning about the potential risk of developing osteosarcoma. Natpara is only available through the Risk Evaluation and Mitigation Strategy (REMS) Program.

Mechanism of Action

Natpara is a parathyroid hormone. Parathyroid hormone raises serum calcium by increasing renal tubular calcium reabsorption, increasing intestinal calcium absorption (i.e., by converting 25 OH vitamin D to 1,25 OH2 vitamin D) and by increasing bone turnover which releases calcium into the circulation.