Parathyroid Hormone

FDA Drug Information • Also known as: Natpara (Parathyroid Hormone)

Brand Names: Natpara (Parathyroid Hormone)
Drug Class: Parathyroid Hormone [EPC]
Route: SUBCUTANEOUS
Dosage Form: INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

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 )

Description

11 DESCRIPTION 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

What Is Parathyroid Hormone Used For?

1 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 [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.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION 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...

Side Effects (Adverse Reactions)

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...

Drug Interactions

7 DRUG INTERACTIONS 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.

Contraindications

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

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary 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. (see Clinical Considerations ). In animal reproduction studies, no adverse developmental effects were observed when pregnant rats and rabbits were administered parathyroid hormone subcutaneously during the period of organogenesis at doses resulting in 123 times and 8 times, respectively, the human exposure at the 100 mcg/day clinical dose. When female rats were administered parathyroid hormone subcutaneously prior to birth and continuing to weaning at doses resulting in 10 times the human exposure at the 100 mcg/day clinical dose, increased incidence of dehydration, broken palate and palate injuries related to incisor misalignment and mortality were observed in offspring (see Data ) . All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes.In the U.S. general population, the estimated major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and Embryo/Fetal Risk 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, osteitis fibrosa 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....

Overdosage

10 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 [see Adverse Reactions (6.1) ] .

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 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...

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.