WARNING: 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 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 in humans receiving a 100 mcg dose of NATPARA. These data could not exclude a risk to humans [see Warnings and Precautions (5.1) , Nonclinical Toxicology (13.1) ]. Because of a potential risk of osteosarcoma, use NATPARA only in patients who cannot be well-controlled on calcium and active forms of vitamin D alone and for whom the potential benefits are considered to outweigh this potential risk [see Indications and Usage (1) , Warnings and Precautions (5.1) ]. Avoid use of NATPARA in patients who are at increased baseline 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 [see Warnings and Precautions (5.1) ]. Because of the risk of osteosarcoma, NATPARA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the NATPARA REMS Program [see Warnings and Precautions (5.2) ] . WARNING: POTENTIAL RISK OF OSTEOSARCOMA See full prescribing information for complete boxed warning. In male and female rats, parathyroid hormone caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on dose and treatment duration. A risk to humans could not be excluded ( 5.1 , 13.1 ) Because of the potential risk of osteosarcoma, prescribe NATPARA only to patients who cannot be well-controlled on calcium and active forms of vitamin D and for whom the potential benefits are considered to outweigh the potential risk. ( 1 , 5.1 ) Avoid use of NATPARA in patients who are at increased baseline risk for osteosarcoma (including those 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 history of prior external beam or implant radiation therapy involving the skeleton) ( 5.1 ) NATPARA is available only through a restricted program called the NATPARA REMS Program ( 5.2 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Potential Risk of Osteosarcoma: Prescribe NATPARA only to patients who cannot be well-controlled on calcium and active vitamin D. Avoid use of NATPARA in patients who are at increased risk for osteosarcoma. ( 5.1 ) Severe Hypercalcemia : Monitor serum calcium when starting or adjusting NATPARA dose and when making changes to co-administered drugs known to raise serum calcium. ( 2.4 , 5.3 , 6.1 ) Severe Hypocalcemia: Can occur with interruption or discontinuation of NATPARA treatment. Monitor serum calcium and replace calcium and vitamin D. ( 2.4 , 5.4 , 6.1 ) Digoxin Toxicity: Hypercalcemia increases the risk of digoxin toxicity. In patients using NATPARA concomitantly with digoxin, monitor serum calcium more frequently and increase monitoring when initiating or adjusting NATPARA dose. ( 5.5 ) Hypersensitivity: Hypersensitivity reactions (anaphylaxis, dyspnea, angioedema, urticaria, rash) have been reported. If signs or symptoms of a serious hypersensitivity reaction occur, discontinue treatment with NATPARA and treat patient according to the standard of care ( 2.6 , 4 , 5.6 , 6.3 ) 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 ADVERSE REACTIONS 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