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NATPARA® (parathyroid hormone) for injection

The active ingredient in NATPARA, parathyroid hormone, is produced by recombinant DNA technology using a modified strain of Escherichia coli. Parathyroid hormone has 84 amino acids and a molecular weight of 9425 daltons.

NATPARA (parathyroid hormone) for injection for subcutaneous use is supplied as a medication cartridge, which is comprised of a multiple-dose, dual-chamber glass cartridge containing a sterile lyophilized powder and a sterile diluent, within a plastic cartridge holder. The sterile lyophilized powder contains either 0.4 mg or 0.8 mg or 1.21 mg or 1.61 mg of parathyroid hormone, depending on dosage strength, and 4.5 mg sodium chloride, 30 mg mannitol, and 1.26 mg citric acid monohydrate. The volume of the sterile diluent is 1.13 mL and the diluent contains a 3.2 mg/mL aqueous solution of m-cresol.

The disposable NATPARA medication cartridge is designed for use with a reusable mixing device for product reconstitution and a reusable Q-Cliq pen for drug delivery. The Q-Cliq pen delivers a fixed volumetric dose of 71.4 μL. Using the Q-Cliq pen, each NATPARA dual chamber cartridge delivers 14 doses of NATPARA

INDICATIONS AND USAGE

NATPARA is a parathyroid hormone indicated as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism.

Limitations of Use

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 was not studied in patients with hypoparathyroidism caused by calcium-sensing receptor mutations.
NATPARA was not studied in patients with acute post-surgical hypoparathyroidism.

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.

DOSAGE AND ADMINISTRATION

Dosing Guidelines: 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.

Doses of active forms of vitamin D and calcium supplements will need to be adjusted when using NATPARA.

Before Initiating NATPARA and During Therapy with NATPARA

Confirm 25-hydroxyvitamin D stores are sufficient. If insufficient, replace to sufficient levels per standard of care.
Confirm serum calcium is above 7.5 mg/dL before starting NATPARA.
The goal of NATPARA treatment is to achieve serum calcium within the lower half of the normal range.

Initiating NATPARA

Initiate NATPARA 50 mcg once daily as a subcutaneous injection in the thigh (alternate thigh every day).

In patients using active forms of vitamin D, decrease the dose of active vitamin D by 50%, if serum calcium is above 7.5 mg/dL.
In patients using calcium supplements, maintain calcium supplement dose.
Measure serum calcium concentration within 3 to 7 days.
Adjust dose of active vitamin D or calcium supplement or both based on serum calcium value and clinical assessment (i.e., signs and symptoms of hypocalcemia or hypercalcemia). Suggested adjustments to active vitamin D and calcium supplement based on serum calcium levels are provided below (see Table 1).

Table 1: Recommended Dosage Adjustments for NATPARA

	Adjust First	Adjust Second
Serum Calcium	Active Vitamin D Forms	Calcium Supplement
Above the Upper Limit of Normal (10.6 mg/dL)	Decrease or Discontinue*	Decrease
Greater than 9 mg/dL and below the Upper Limit of Normal (10.6 mg/dL)	Decrease or Discontiinue*	No change or decrease if active vitamin D has been discontinued
Less than or equal to 9 mg/dL and above 8 mg/dL	No change	No change
Lower than 8 mg/dL	Increase	Increase

Repeat steps 4 and 5 until target serum calcium levels are within the lower half of the normal range, active vitamin D has been discontinued and calcium supplementation is sufficient to meet daily requirements.

NATPARA Dose Adjustments: The dose of NATPARA may be increased in increments of 25 mcg every four weeks up to a maximum daily dose of 100 mcg if serum calcium cannot be maintained above 8 mg/dL without an active form of vitamin D and/or oral calcium supplementation.

The dose of NATPARA may be decreased to as low as 25 mcg per day if total serum calcium is repeatedly above 9 mg/dL after the active form of vitamin D has been discontinued and calcium supplement has been decreased to a dose sufficient to meet daily requirements.

After a NATPARA dose change monitor clinical response as well as serum calcium. Adjust active vitamin D and calcium supplements per steps 4-6 above if indicated.

NATPARA Maintenance Dose: The maintenance dose should be the lowest dose that achieves a total serum calcium (albumin-corrected) within the lower half of the normal total serum calcium range (i.e., approximately 8 and 9 mg/dL), without the need for active forms of vitamin D and with calcium supplementation sufficient to meet daily requirements. Monitor serum calcium and 24-hour urinary calcium per standard of care once a maintenance dose is achieved.

NATPARA Dose Interruption or Discontinuation: Abrupt interruption or discontinuation of NATPARA can result in severe hypocalcemia. Resume treatment with, or increase the dose of, an active form of vitamin D and calcium supplements if indicated inpatients interrupting or discontinuing NATPARA, monitor for signs and symptoms of hypocalcemia and serum calcium levels.

In the case of a missed dose, the next NATPARA dose should be administered as soon as reasonably feasible and additional exogenous calcium should be taken in the event of hypocalcemia.

Reconstitution and Administration Instructions

Patients and caregivers who will administer NATPARA should receive appropriate training and instruction by a trained healthcare professional prior to first use of NATPARA.
Follow the Instructions for Use to reconstitute NATPARA using the mixing device for reconstitution and to administer NATPARA using the pen delivery device (i.e., Q-Cliq™ pen).
Inspect NATPARA visually for particulate matter and discoloration prior to administration.
Discard the needle in a puncture-resistant container following administration.
Store the Q-Cliq pen containing the remaining doses of NATPARA in a refrigerator.
All reconstituted NATPARA medication cartridges older than 14 days must be discarded.

CONTRAINDICATIONS

NATPARA is contraindicated in patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions (e.g., anaphylaxis, angioedema, and urticaria) have occurred with NATPARA.

WARNINGS AND PRECAUTIONS

Potential Risk of Osteosarcoma: In male and female rats, parathyroid hormone caused an increase in the incidence of osteosarcoma(a malignant bone tumor). The occurrence of osteosarcoma was observed to be dependent on parathyroid hormone dose and treatment duration. This effect was observed at parathyroid hormone exposure levels ranging from 3 to 71 times the exposure levels for humans receiving a 100 mcg dose of NATPARA. These data could not exclude a risk to humans.

Because of a potential risk of osteosarcoma, use NATPARA only in patients who cannot be well-controlled on calcium supplements and active forms of vitamin D alone and for whom the potential benefits are considered to outweigh this potential risk.

To further mitigate the potential risk of osteosarcoma, avoid use of NATPARA in patients who are at increased risk for osteosarcoma, such as patients with Paget’s disease of bone or unexplained elevations of alkaline phosphatase, pediatric and young adult patients with open epiphyses, patients with hereditary disorders predisposing to osteosarcoma, or patients with a prior history of external beam or implant radiation therapy involving the skeleton. Instruct patients to promptly report clinical symptoms (e.g., persistent localized pain) and signs (e.g., soft tissue mass tender to palpation) that could be consistent with osteosarcoma.

NATPARA is available only through a restricted program under a REMS.

Hypercalcemia: Severe hypercalcemia has been reported with NATPARA. In the pivotal trial, 3 patients randomized to NATPARA required administration of IV fluids to correct hypercalcemia during treatment with NATPARA. The risk is highest when starting or increasing the dose of NATPARA, but can occur at any time. Monitor serum calcium and patients for signs and symptoms of hypercalcemia. Treat hypercalcemia per standard practice and consider holding and/or lowering the dose of NATPARA if severe hypercalcemia occurs.

Hypocalcemia: Severe hypocalcemia has been reported in patients taking NATPARA, including cases of

hypocalcemia that resulted in seizures. The risk is highest when NATPARA is withheld, missed or abruptly discontinued, but can occur at any time. Monitor serum calcium and patients for signs and symptoms of hypocalcemia. Resume treatment with, or increase the dose of, an active form of vitamin D or calcium supplements or both if indicated in patients interrupting or discontinuing NATPARA to prevent severe hypocalcemia.

Risk of Digoxin Toxicity with Concomitant Use of Digitalis Compounds: The inotropic effects of digoxin are affected by serum calcium levels. Hypercalcemia of any cause may predispose to digoxin toxicity. In patients using NATPARA concomitantly with digitalis compounds, monitor serum calcium and digoxin levels and patients for signs and symptoms of digitalis toxicity. Adjustment of digoxin and/or NATPARA may be needed. No drug-drug interaction study has been conducted with digoxin and NATPARA.

Hypersensitivity: There have been reports of hypersensitivity reactions in patients taking NATPARA. Reactions included anaphylaxis, dyspnea, angioedema, urticaria, and rash. If signs or symptoms of a serious hypersensitivity reaction occur, discontinue treatment with NATPARA, treat hypersensitivity reaction according to the standard of care, and monitor until signs and symptoms resolve. Monitor for hypocalcemia if NATPARA is discontinued.

Adverse drug reactions

The following adverse reactions have been identified during post-approval use of NATPARA.

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.

Hypersensitivity reactions (e.g., anaphylaxis, dyspnea, angioedema, urticaria, and rash).
Seizures due to hypocalcemia

DRUG INTERACTIONS

Alendronate: Co-administration of alendronate and NATPARA leads to reduction in the calcium-sparing effect, which can interfere with the normalization of serum calcium. Concomitant use of NATPARA with alendronate is not recommended.

Digoxin: NATPARA causes transient increase in calcium and therefore, concomitant use of NATPARA andcardiac glycosides (e.g., digoxin) may predispose patients to digitalis toxicity if hypercalcemia develops.

Digoxin efficacy is reduced if hypocalcemia is present. In patients using NATPARA concomitantly with digoxin, carefully monitor serum calcium and digoxin levels, and patients for signs and symptoms of digoxin toxicity. Adjustment of digoxin and/or NATPARA may be needed. No drug-drug interaction study has been conducted with digoxin and NATPARA.

USE IN SPECIFIC POPULATIONS

Pregnancy: Available data with NATPARA Injection use in pregnant women are insufficient to inform a drug associated risk of birth defects, miscarriage or adverse maternal or fetal outcomes. There are disease associated risks to the mother and the fetus related to hypocalcemia in pregnancy.

Maternal hypocalcemia can result in an increased rate of spontaneous abortion, premature and dysfunctional labor, and possibly preeclampsia.

Fetal/Neonatal adverse reactions: Infants born to mothers with hypocalcemia can have associated fetal and neonatal hyperparathyroidism, which in turn can cause fetal and neonatal skeletal demineralization, subperiosteal bone resorption, osteitisfibrosa cystica and neonatal seizures. Infants born to mothers with hypocalcemia should be carefully monitored for signs of hypocalcemia or hypercalcemia, including neuromuscular irritability (ranging from myotonic jerks to seizures), apnea, cyanosis and cardiac rhythm disorders.

Lactation: There are no data available on the presence of parathyroid hormone in the breast milk, the effects on the breastfed infant or the effects on milk production. Parathyroid hormone is present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present inhuman milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NATPARA and any potential adverse effects on the breastfed child from NATPARA or from the underlying maternal condition.

Infants exposed to parathyroid hormone through breast milk should be monitored for signs and symptoms of hypercalcemia or hypocalcemia. Monitoring of serum calcium in the infant should be considered.

Pediatric Use: Safety and efficacy in patients less than 18 years of age has not been established. Avoid use of NATPARA in patients who are at increased baseline risk for osteosarcoma including pediatric and young adult patients with open epiphyses.

Geriatric Use: Clinical studies of NATPARA did not include sufficient numbers of subjects aged 65 and over to determine whether response in these subjects is different from younger subjects. In general, dose selection for elderly individuals should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment: Clinical studies of NATPARA did not include sufficient numbers of subjects with moderate and severe renal impairment to determine whether they respond differently from subjects with mild renal impairment or normal renal function. Some of the mechanisms of action of NATPARA (e.g., conversion of 25-OH vitamin D to 1,25-OH2 vitamin D) are dependent on renal function. NATPARA is eliminated by the kidney and maximum drug levels increased with renal impairment.

OVERDOSAGE

Accidental overdose in studies in hypoparathyroidism occurred in 1 subject who received a 150 mcg dose and experienced mild palpitations. Serum calcium 24 hours later was 10.3 mg/dL. In the event of overdose, the patient should be carefully monitored for hypercalcemia by a medical professional.

NATPARA® (parathyroid hormone) for injection

NATPARA® (parathyroid hormone) for injection