Natpara is indicated only as adjunctive therapy to calcium and vitamin D supplementation and is available only through a restricted REMS program.
In January, FDA gave its approval to Natpara (parathyroid hormone for injection; NPS Pharmaceuticals) for treatment of hypoparathyroidism in patients who cannot be controlled with calcium and active vitamin D supplementation alone.
Natpara is a recombinant human parathyroid hormone (rhPTH) derived from modified strains of E. coli using recombinant DNA technology. It raises plasma calcium levels by increasing intestinal absorption and renal reabsorption of calcium and increasing bone-turnover rates, which releases calcium from bone into the blood. It is indicated only as adjunctive therapy to calcium and vitamin D supplementation. Natpara’s boxed warning highlights the potential risk for osteosarcoma associated with its use. It is available only through a restricted REMS program.
Approval of Natpara was based primarily on the findings of a randomized, double-blind, placebo-controlled, multicenter trial (REPLACE). Patients with established hypoparathyroidism who were receiving calcium and active vitamin D supplementation were included in the trial. Patients with calcium-sensing receptor mutations resulting in hypoparathyroidism were excluded. Prior to randomization, each participant’s dosing of calcium and vitamin D supplementation was optimized to achieve albumin-corrected serum calcium levels between 8.0 and 9.0 mg/dL.
Participants were randomized to receive either 50 mcg of Natpara or placebo daily. Both groups received a 50% dose reduction of vitamin D. The dose of Natpara was increased by 25 mcg every four weeks up to a maximum dose of 100 mcg, which was continued for 12 weeks of maintenance therapy. Doses of calcium and vitamin D were adjusted during the study.
The primary endpoint of the study is the proportion of patients at week 24 who received at least a 50% dose reduction from baseline daily doses of calcium and vitamin D and maintained serum calcium concentrations ≥ the baseline concentration but within normal limits. Of patients receiving rhPTH, 53% met the primary endpoint of the study, compared to 2% of patients receiving placebo.
An equal proportion of patients who received rhPTH and who received placebo reported at least one adverse event. Among patients taking Natpara, adverse effects reported to occur with a frequency greater than 10% included paraesthesias, muscle spasms, headache, nausea and hypocalcemia hypercalcemia, hypoaesthesia, diarrhea, vomiting, arthralgia, extremity pain, and hypercalciuria.
Severe hypercalcemia is most common when initiating or adjusting Natpara doses or other medications known to increase plasma calcium concentrations. Severe hypocalcemia may occur with abrupt discontinuation or disruption of Natpara therapy. Patients must be counseled to call their prescriber immediately when Natpara therapy is interrupted or when symptoms associated with hypercalcemia or hypocalcemia are present.
Studies in rats demonstrated an increased risk of osteosarcoma at doses comparable to those within the upper therapeutic range for humans. Although no increased risk has been demonstrated in humans, the potential benefits associated with use of Natpara must outweigh the potential risk of use for an individual. The patient brochure for the drug must be used to counsel patients about the risks and benefits of Natpara therapy, and patients must sign a Natpara REMS patient-prescriber acknowledgment form before the drug is dispensed. Only certified pharmacies may dispense Natpara.
Natpara is initiated at 50 mcg daily as a subcutaneous injection. The recommended maintenance dose of Natpara is the individualized minimum dose required to maintain the patient’s albumin-corrected serum calcium concentration within the lower half of the normal range (i.e. 8-9 mg/dL) without causing hypercalciuria. Serum calcium concentrations and 24-hour urinary calcium excretion results are required for monitoring and dose adjustment.
The dose may be increased every four weeks in 25 mcg increments up to a maximum dose of 100 mcg daily. The dose may be decreased to 25 mcg daily, if necessary, to maintain appropriate levels. Doses of coadministered supplemental calcium and vitamin D should be adjusted as needed during therapy.
Natpara is supplied as a 14-dose medication cartridge. A reusable mixing device and a specialized Q-Cliq pen is designed for proper use of this medication.
1. Natpara [package insert]. Bedminster, NJ: NPS Pharmaceuticals, Inc.; Issued January 2015.
2. Mannstadt M, Clarke BL, Vokes T, et al. Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): A double-blind, placebo-controlled, randomized, phase 5 study. Lancet Diab Endocrinol. 2013. Dec;1:275–283.
Kathryn Wheeler is associate clinical professor of pharmacy practice at the University of Connecticut School of Pharmacy, Storrs, Conn.