NATPARA (PARATHYROID HORMONE)

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; the amino acid sequence for parathyroid hormone is shown below in Figure 1. Figure 1: Amino Acid Sequence of Parathyroid Hormone 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 [see Dosage Forms and Strengths (3) ] . Figure 1

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 [see Warnings and Precautions (5.1) ] . 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. NATPARA is a parathyroid hormone indicated as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism. ( 1 ) 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. ( 5.1 ) 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.

The dose of NATPARA should be individualized to achieve a serum calcium level in the lower half of the normal range. ( 2.1 ) Confirm vitamin D stores are sufficient and serum calcium is above 7.5 mg/dL before starting NATPARA. ( 2.2 ) The starting dose of NATPARA is 50 mcg injected once daily in the thigh. When starting NATPARA, decrease dose of active vitamin D by 50%, if serum calcium is above 7.5 mg/dL. ( 2.3 ) Monitor serum calcium levels every 3 to 7 days after starting or adjusting NATPARA dose and when adjusting either active vitamin D or calcium supplements dose while using NATPARA. ( 2.1 , 5.3 , 5.4 ) 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 ). 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 Discontinue in patients receiving the lowest available dose Decrease Greater than 9 mg/dL and below the Upper Limit of Normal (10.6 mg/dL) Decrease or Discontinue 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 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) ] .

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 [see Warnings and Precautions (5.6) , Adverse Reactions (6.3) ] . Hypersensitivity to any component of this product. ( 4 )

The following serious adverse reactions are described in greater detail in other sections of the label: Osteosarcoma [see Boxed Warning , Warnings and Precautions (5.1) ] Hypercalcemia [see Warnings and Precautions (5.3) ] Hypocalcemia [see Warnings and Precautions (5.4) ] Hypersensitivity [see Contraindications (4) , Warnings and Precautions (5.6) ] The most common adverse reactions associated with NATPARA and occurring in greater than 10% of individuals were: paresthesia, hypocalcemia, headache, hypercalcemia, nausea, hypoesthesia, diarrhea, vomiting, arthralgia, hypercalciuria and pain in extremity ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-800-828-2088 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 m 2 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. Table 2: Common Adverse Reactions associated with NATPARA use in Subjects with Hypoparathyroidism Adverse Reaction Placebo (N=40) % NATPARA (N=84) % Paresthesia 25 31 Hypocalcemia Hypocalcemia combines reported events of hypocalcemia and blood calcium decreased; hypercalciuria combines reported events of hypercalciuria and urine calcium increased; and hypercalcemia combines reported events of hypercalcemia and blood calcium increased. 23 27 Headache 23 25 Hypercalcemia 3 19 Nausea 18 18 Hypoesthesia 10 14 Diarrhea 3 12 Vomiting 0 12 Arthralgia 10 11 Hypercalciuria 8 11 Pain in extremity 8 10 Upper respiratory tract infection 5 8 Abdominal pain upper 3 7 Sinusitis 5 7 Blood 25-hydroxycholecalciferol decreased 3 6 Hypertension 5 6 Hypoesthesia facial 3 6 Neck pain 3 6 Hypercalcemia In the overall pivotal trial, a greater proportion of patients on NATPARA had albumin-corrected serum calcium above the normal range (8.4 to 10.6 mg/dL). During the entire trial duration 3 patients on NATPARA and 1 patient on placebo had a calcium level above 12 mg/dL. Table 3 displays the number of subjects who had albumin-corrected serum calcium levels above the normal range (8.4 to 10.6 mg/dL) by study treatment period in the placebo-controlled study based on routine monitoring at each trial visit. More patients randomized to NATPARA had hypercalcemia in both phases of the study (note: all trial participants underwent a 50% reduction in active vitamin D dose at randomization). Table 3: Proportion of Subjects with Albumin-Corrected Serum Calcium Greater Than Upper Limit of Normal (10.6 mg/dL) During the Treatment Period Titration Period (Weeks 0-12) NATPARA was only titrated upwards for up to Week 6 Maintenance Period (Weeks 12-24) Albumin-corrected serum calcium Placebo N=40 NATPARA N=84 Placebo N=40 NATPARA N=84 >10.6 to ≤12 mg/dL 0% 30% 0% 10% >12 to ≤13 mg/dL 0% 2% 3% 0% Hypocalcemia Table 4 displays the number of subjects who had albumin-corrected serum calcium levels below 8.4 mg/dL by treatment period in the placebo-controlled study based on routine monitoring at each trial visit. More patients randomized to placebo had hypocalcemia of less than 7 mg/dL in the titration phase (note: all trial participants underwent a 50% reduction in active vitamin D dose at randomization). More patients randomized to NATPARA had hypocalcemia of less than 7 mg/dL in the dose maintenance phase. Table 4: Proportion of Subjects with Albumin-Corrected Serum Calcium Below the Lower Limit of Normal (8.4 mg/dL) During the Treatment Period Titration Period (Weeks 0-12) Maintenance Period (Weeks 12-24) Albumin-corrected serum calcium Placebo N=40 NATPARA N=84 Placebo N=40 NATPARA N=84 ≥7 to <8.4 mg/dL 98% 79% 75% 71% <7 mg/dL 18% 6% 0% 12% The risk of hypocalcemia increases when NATPARA is withdrawn. At the end of the trial, NATPARA and placebo were withdrawn, calcium and active vitamin D were returned to baseline doses and subjects were followed for 4 weeks. During this withdrawal phase, more patients previously randomized to NATPARA experienced an albumin-corrected serum calcium value of less than 7 mg/dL (5.0% versus 17% for previous treatment with placebo and NATPARA, respectively). Twenty subjects (24%) previously randomized to NATPARA experienced adverse reactions of hypocalcemia in the post-treatment phase compared to three subjects (8%) previously randomized to placebo. Five subjects previously randomized to NATPARA with albumin-corrected serum calcium below 7 mg/dL required treatment with IV calcium gluconate to correct hypocalcemia. Hypercalciuria Treatment with NATPARA did not lower 24-hour urinary calcium excretion in the placebo-controlled trial. The proportion of subjects with hypercalciuria (defined as urine calcium levels of >300 mg/24 hours) was similar at baseline and trial end in the NATPARA and placebo groups. The median (IQR) 24-hour Urine Calcium at trial end was similar between NATPARA [231 (168-351) mg/24 hours], and placebo [232 (139-342) mg/24 hours]. At trial end, serum calcium values between NATPARA and placebo were also similar. Risk of hypercalciuria throughout the trial was related to serum calcium levels. To minimize the risk of hypercalciuria, NATPARA should be dosed to a target albumin-corrected total serum calcium within the lower half of the normal range (i.e., between 8 and 9 mg/dL) [see Dosage and Administration (2.1) ] . 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

Digoxin: Monitor serum calcium more frequently when using NATPARA in patients receiving digoxin. ( 5.5 , 7.2 ) 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.

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.