2.1 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.

2.2 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.

2.3 Initiating NATPARA

1.

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

2.

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.

3.

In patients using calcium supplements, maintain calcium supplement dose.

4.

Measure serum calcium concentration within 3 to 7 days.

5.

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).

6.

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.

2.4 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 [see Dosage and Administration (2.3)].

2.5 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.

2.6 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 in patients interrupting or discontinuing NATPARA, monitor for signs and symptoms of hypocalcemia and serum calcium levels [see Warnings and Precautions (5.4)].

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.

2.7 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 [see How Supplied/Storage and Handling (16.2)].

5.1 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 [see Nonclinical Toxicology (13.1)].

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 [see Limitations of Use (1)].

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 [see Warnings and Precautions (5.2)].

5.2 NATPARA REMS Program

Because of the potential risk of osteosarcoma associated with NATPARA therapy, NATPARA is available only through a restricted REMS program called the NATPARA REMS Program. Under the NATPARA REMS Program, only certified healthcare providers can prescribe and only certified pharmacies can dispense NATPARA. Further information is available at www.NATPARAREMS.com or by telephone at 1-855-NATPARA (1-855-628-7272).

5.3 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 [see Dosage and Administration (2), Adverse Reactions (6.1)].

5.4 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 [see Dosage and Administration (2.6), Adverse Reactions (6.1)].

5.5 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 [see Drug Interactions (7), Adverse Reactions (6.1)].

5.6 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 [see Contraindications (4), Adverse Reactions (6.3)]. Monitor for hypocalcemia if NATPARA is discontinued [see Dosage and Administration (2.6)].

6.1 Adverse Reactions in Clinical Trials for Hypoparathyroidism

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

NATPARA was studied in a placebo-controlled trial [see Clinical Studies (14)].

The data described in Table 2 below reflect exposure to NATPARA in 84 patients, including 78 exposed for 24 weeks. The mean age of the trial population was 47 years and ranged from 19 to 74 years old. Seventy-nine percent (79%) were females. Ninety-six percent (96%) were Caucasian, 0.8% were Black, and 1.6% were Asian. Patients had had hypoparathyroidism for on average 15 years and hypoparathyroidism was caused by post-surgical complications in 71% of cases, idiopathic hypoparathyroidism in 25% of cases, DiGeorge Syndrome in 3% of cases, and auto-immune hypoparathyroidism in 1% of cases. Prior to trial enrollment, participants were receiving a median (interquartile range) daily oral calcium dose of 2000 (1250, 3000) mg and a median daily oral active vitamin D dose equivalent to 0.75 (0.5, 1) mcg of calcitriol. The mean eGFR at baseline was 97.4 mL/min/1.73 m2 and 45%, 10% and 0% had mild, moderate and severe renal impairment, respectively, at baseline. During the trial, most patients received 100 mcg and the dose range was 50 to 100 mcg administered subcutaneously once daily in the thigh.

Table 2 lists common adverse reactions associated with NATPARA use in the clinical trial. Common adverse reactions were reactions that occurred in ≥5% of subjects and occurred more commonly on NATPARA than on placebo.

6.2 Immunogenicity

NATPARA may trigger the development of antibodies. In the placebo-controlled study in adults with hypoparathyroidism, the incidence of anti-PTH antibodies was 8.6% (3/35) and 5.9% (1/17) in subjects who received subcutaneous administration of 50 to 100 mcg NATPARA or placebo once daily for 24 weeks, respectively.

Across all clinical studies in subjects with hypoparathyroidism following treatment with NATPARA for up to 2.6 years, the immunogenicity incidence rate was 16.1% (14/87). These 14 subjects had low titer anti-PTH antibodies and, of these, 3 subjects subsequently became antibody negative. One of these subjects had antibodies with neutralizing activity; this subject maintained a clinical response with no evidence of immune-related adverse reactions. Anti-PTH antibodies did not appear to affect efficacy or safety during the clinical trials but their longer-term impact is unknown.

Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying diseases. For these reasons, comparison of the incidence of antibodies to NATPARA with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience

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

7.1 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.

7.2 Digoxin

NATPARA causes transient increase in calcium and therefore, concomitant use of NATPARA and cardiac 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.

8.1 Pregnancy

8.2 Lactation

8.4 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 [see Boxed Warning, Warnings and Precautions (5.1)].

8.5 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 [see Clinical Pharmacology (12.3)].

8.6 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 [see Clinical Pharmacology (12.3)].

12.1 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.

12.2 Pharmacodynamics

The pharmacodynamics in subjects with hypoparathyroidism after single subcutaneous administration of 50 and 100 mcg dose of NATPARA in the thigh were evaluated.

Treatment with NATPARA increases serum calcium levels (Figure 2). The increase in serum calcium levels in hypoparathyroidism subjects occurs in a dose-related manner. Mean peak serum calcium levels are reached between 10 and 12 hours following a single subcutaneous injection and the increase in serum calcium above baseline is sustained for more than 24 hours after administration. The maximum mean increases of serum calcium, which occurred at 12 hours, were approximately 0.5 mg/dL and 0.7 mg/dL from baseline with the 50 mcg and 100 mcg doses, respectively. The mean calcium intake for the 50 and 100 mcg doses was 1700 mg [see Clinical Pharmacology (12.3)].

12.3 Pharmacokinetics

Following single subcutaneous(SC) injections of NATPARA at 50 mcg and 100 mcg in subjects with hypoparathyroidism, peak plasma concentrations (mean Tmax) of NATPARA occurs within 5 to 30 minutes and a second usually smaller peak at 1 to 2 hours. The plasma AUC increased in a dose-proportional manner from 50 mcg to 100 mcg. The apparent terminal half-life (t1/2) was 3.02 and 2.83 hours for the 50 and 100 mcg dose, respectively.

Mean unadjusted concentration-time profiles of parathyroid hormone in plasma following SC administration of 100 mcg of NATPARA are presented in Figure 2. One 100 mcg dose of NATPARA provides a 24-hour calcemic response in hypoparathyroidism subjects.

Figure 2 Mean (±SE) Unadjusted Plasma Parathyroid Hormone and Albumin-Corrected Serum Calcium Concentration Following 100 mcg SC Administration in Subjects with Hypoparathyroidism

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study in rats, parathyroid hormone was given subcutaneously at doses of 10, 50 and 150 mcg/kg/day. These doses resulted in systemic exposures that were, respectively 3 to 71 times higher than systemic exposure observed in humans following a subcutaneous dose of 100 mcg/day based on AUC. Systemic exposure at the 10 mcg/kg/day dose of parathyroid hormone was 3-5 times greater AUC than the exposure observed in hypoparathyroidism subjects at the clinical dose of 100 mcg/day. This is the lowest dose at which a parathyroid hormone-related increase in bone tumors was observed in rats. Higher exposures resulted in a marked dose-related increase in all bone tumors including osteoma, osteoblastoma and osteosarcomas in both sexes. The bone tumors in rats occurred in association with a large increase in bone mass and focal osteoblast hyperplasia. However, since bone metabolism in the rat differs from that in humans, the relevance of these animal findings to humans is uncertain.

Parathyroid hormone is not genotoxic in any of the following test systems: the bacterial reverse mutation (Ames) assay or the in vitro mammalian cell forward-gene mutation (AS52/XPRT) assay study with and without metabolic activation.

No effect on fertility was observed in male and female rats given parathyroid hormone at doses up to 1000 mcg/kg/day (120 times systemic exposure after a clinical dose of 100 mcg/day).

13.2 Animal Toxicology and/or Pharmacology

In pregnant rats given subcutaneous doses up to 1000 mcg/kg/day during organogenesis there were no findings observed at 123 times the 100 mcg/day clinical dose based on AUC. In pregnant rabbits given subcutaneous doses of 5, 10 and 50 mcg/kg/day during organogenesis, various skeletal alterations including in complete ossification in <35% of litters given 10 mcg/kg/day which were statistically significant but within historical control range at exposures 8 times the 100 mcg/kg/day clinical dose. There was a fetus with spina bifida in the 50 mcg/kg/day dose group at 72 times the 100 mcg/day clinical dose based on AUC. Given the association of folic acid deficiency and neural tube defects this finding may be related to decreased body weight and food consumption in the pregnant rabbits.

Developmental effects were observed in a peri-/post-natal study in pregnant rats given subcutaneous doses of 100, 300, 1000 mcg/kg/day from organogenesis through lactation while an entire litter was stillborn in the 300 mcg/kg/day group (34 times the 100 mcg/day clinical dose based on AUC) and an entire litter from the 1000 mcg/kg/day (123 times the 100 mcg/day clinical dose based on AUC) was dead by postnatal day 4. Increased incidence of morbidity associated with dehydration, broken palate and palate injuries related to incisor misalignment and mortality were found in pups from litters given 100 mcg/kg/day (10 times the 100 mcg/day clinical dose based on AUC). At 300 mcg/kg/day there was a litter with kidney dilatation and another with an extra liver lobe. There was a single pup with a diaphragmatic hernia from a litter exposed to 1000 mcg/kg/day.

Study in Patients with Established Hypoparathyroidism

The efficacy of NATPARA was evaluated in 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 (2:1) to NATPARA (n=84) or placebo (n=40). The mean age was 47 years (range, 19 to 74 years), 79.0% were females and 96.0% were Caucasian, 0.8% were Black, and 1.6% were Asian. Patients had hypoparathyroidism for on average 15 years and hypoparathyroidism was caused by post-surgical complications in 71% of cases, idiopathic hypoparathyroidism in 25%, DiGeorge Syndrome in 3%, and auto-immune hypoparathyroidism in 1%. Patients with hypoparathyroidism due to calcium-sensing receptor mutations were excluded from the trial. The mean eGFR at baseline was 97.4 mL/min/1.73 m2 and 45%, 10% and 0% had mild, moderate and severe renal impairment, respectively, at baseline.

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 active vitamin 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.

Table 5 shows the proportion of individuals who, at the end of treatment, fulfilled the 3-part response criterion. Table 6 provides results on individual components of the response criterion.

16.1 How Supplied

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 medication cartridge is available in 4 dosage strengths (25, 50, 75, and 100 mcg/dose). The 25 mcg/dose cartridge contains 0.4 mg parathyroid hormone; the 50 mcg/dose cartridge contains 0.8 mg parathyroid hormone; the 75 mcg/dose cartridge contains 1.21 mg parathyroid hormone; the 100 mcg/dose cartridge contains 1.61 mg parathyroid hormone.

NATPARA is supplied in the following packages:

 

• 2 cartridges of 25 mcg/dose strength (NDC 68875-0202-2)
• 2 cartridges of 50 mcg/dose strength (NDC 68875-0203-2)
• 2 cartridges of 75 mcg/dose strength (NDC 68875-0204-2)
• 2 cartridges of 100 mcg/dose strength (NDC 68875-0205-2)

The disposable NATPARA medication cartridge is designed for use with a reusable mixing device for product reconstitution and a reusable Q-Cliq pen injector for drug delivery. The Q-Cliq pen is designed to deliver a fixed volumetric dose of 71.4 µL. Using the Q-Cliq pen, each NATPARA medication cartridge delivers 14 doses; each dose contains 25, 50, 75, or 100 mcg of NATPARA depending on the product dosage strength.

Designed for use with 31G × 8 mm BD Ultra-Fine™ Pen Needles.

The mixing device, provided in a separate carton, is designed to enable reconstitution of the product before the first use of each cartridge. The mixing device can be used to reconstitute up to 6 NATPARA medication cartridges.

The Q-Cliq pen, packaged in a separate carton, can be used for up to 2 years of daily treatment by replacing the reconstituted cartridge every two weeks (14 days).

Instructions for use of the mixing device and the Q-Cliq pen are provided with the NATPARA medication cartridges.

16.2 Storage and Handling

Prior to reconstitution, the dual-chamber NATPARA medication cartridge should be stored in the package provided at refrigerated temperature, 36 to 46°F (2 to 8°C). After reconstitution, the medication cartridge should be stored in the Q-Cliq pen under refrigeration at 36 to 46°F (2 to 8°C). The reconstituted product can be used for up to 14 days under these conditions. Store away from heat and light. Avoid exposure to elevated temperatures. Discard reconstituted NATPARA medication cartridges after 14 days.

Do not freeze or shake. Do not use NATPARA if it has been frozen or shaken.

The mixing device and empty Q-Cliq pen can be stored at room temperature.

Safely discard needles.

Potential Risk of Osteosarcoma

[see Warnings and Precautions (5.1)]

Advise patients that the active ingredient in NATPARA, parathyroid hormone, caused an increase in the incidence of osteosarcoma (a malignant bone tumor) in male and female rats in dedicated lifelong carcinogenicity studies and that the risk of osteosarcoma in rats was dependent on parathyroid hormone dose administered, on treatment duration and occurred at exposure levels close to the clinical exposure range. Based on these findings NATPARA may carry a potential risk to humans.

Patients should be advised that because of a potential risk of osteosarcoma, NATPARA is only recommended for patients who cannot be well-controlled on oral calcium supplementation and on active forms of vitamin D. In addition, use of NATPARA should be avoided in patients who have risk factors for osteosarcoma unless the benefits of using NATPARA in these patients are determined to outweigh this potential risk.

Instruct patients to promptly report signs and symptoms of possible osteosarcoma such as persistent localized pain or occurrence of a new soft tissue mass that is tender to palpation.

NATPARA REMS

[see Warnings and Precautions (5.1, 5.2)]

• NATPARA is available only through a restricted program called the NATPARA REMS Program, because of the potential risk of osteosarcoma.
• Counsel patients on the benefits and risks of NATPARA using the NATPARA Patient Brochure.
• Patients must sign the NATPARA REMS Patient-Prescriber Acknowledgment Form.
• Provide patient with a copy of the NATPARA Patient Brochure and NATPARA REMS Patient-Prescriber Acknowledgment Form.
• NATPARA is only available through certified pharmacies, provide information to your patients about how they will receive prescriptions:
  • Submit the NATPARA prescription to the NATPARA REMS Program Coordinating Center (by fax or email).
  • The REMS Program Coordinating Center will send the prescription to a certified pharmacy to fill after verifying that the prescriber is certified and a Patient-Prescriber Acknowledgment Form is on record.
  • The REMS Program Coordinating Center will call the patient and provide the name and phone number of the certified pharmacy that will be dispensing NATPARA.
  • The certified pharmacy will contact the patient to arrange the date to ship NATPARA once the prescription is filled.

Severe Hypercalcemia

[see Warnings and Precautions (5.3)]

Instruct patients that severe hypercalcemia can occur when starting or adjusting NATPARA dose and/or when making changes to co-administered drugs known to raise serum calcium. Instruct patients to: report symptoms of hypercalcemia promptly, report any changes to co-administered drug(s) known to influence calcium levels and follow recommended serum calcium monitoring.

Severe Hypocalcemia

[see Warnings and Precautions (5.4)]

Instruct patients that severe hypocalcemia can occur if NATPARA dosing is abruptly interrupted or discontinued. Instruct patients to report symptoms of hypocalcemia promptly, report interruption in NATPARA dosing and follow recommended serum calcium monitoring. In the event of NATPARA dose interruption, patients should contact their healthcare provider, as their doses of active vitamin D and calcium supplementation may need adjustment.

Digoxin Toxicity

[see Warnings and Precautions (5.5)]

Instruct patients to report use of digoxin containing medication, and follow recommended serum calcium monitoring.

Hypersensitivity

[see Warnings and Precautions (5.6)]

Instruct patients that serious hypersensitivity reactions (anaphylaxis, dyspnea, angioedema, urticaria, rash) can occur with NATPARA. Instruct patients to immediately report symptoms of serious hypersensitivity reactions and to seek medical attention if a reaction occurs.

Lactation

Advise women that infants exposed to parathyroid hormone through breast milk should be monitored for symptoms of hypercalcemia or hypocalcemia.

Dosing Instructions

Instruct patients to read the Instructions for Use document carefully. The patient or caregiver should be instructed by a physician or an appropriately qualified healthcare professional in the proper technique for administering subcutaneous injections using the mixing device and the Q-Cliq pen, including the use of aseptic technique. The patient and caregiver should be cautioned that needles must not be re-used and instructed in safe disposal procedures. A puncture-resistant container for disposal of used needles should be supplied to the patient along with instructions for safe disposal of the full container. Instruct patients to never share their devices with other patients. Advise patients to never transfer the contents of the delivery device to a syringe.

After reconstitution, each NATPARA medication cartridge can be used for 14 subcutaneous injections. After the use period, only the cartridge should be discarded. The Q-Cliq pen can be used for up to 2 years by replacing the reconstituted medication cartridge every two weeks (14 days).

Common Adverse Reactions

[see Adverse Reactions (6.1)]

Inform patients that the most common adverse reactions occurring in patients on NATPARA were paresthesia, hypocalcemia, headache, hypercalcemia, nausea, hypoaesthesia, diarrhea, vomiting, arthralgia, hypercalciuria and pain in extremity.