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Natpara

Generic Name: Parathyroid Hormone
Class: Parathyroid
Chemical Name: Parathormone (human recombinant)
Molecular Formula: C408H674N126O126S2
CAS Number: 9002-64-6

Warning(s)

  • Potential Risk of Osteosarcoma
  • Increased incidence of osteosarcoma observed in rats.1 Relevance to humans not known.1 (See Osteosarcoma under Cautions.)

  • Use only in patients who cannot be well controlled on calcium and activated forms of vitamin D alone and for whom potential benefits outweigh such potential risk.1

  • Do not use in patients with an increased baseline risk of osteosarcoma (e.g., patients with Paget's disease of the bone or unexplained increases in serum alkaline phosphatase concentrations, pediatric or young adult patients with open epiphyses, patients with hereditary disorders predisposing them to osteosarcoma, patients who have received prior external beam or implant radiation therapy involving the skeleton).1

  • Restricted Distribution Program
  • Available only through the Natpara REMS program.1 (See Restricted Distribution Program under Dosage and Administration.)

REMS:

FDA approved a REMS for parathyroid hormone to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of parathyroid hormone and consists of the following: elements to assure safe use and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Biosynthetic (recombinant DNA origin) preparation of human parathyroid hormone (parathormone, PTH);1 3 7 9 14 structurally identical to the full-length (84-amino acid) endogenous hormone.3 9 14

Uses for Natpara

Hypoparathyroidism

Adjunct to calcium and vitamin D for management of hypocalcemia in patients with hypoparathyroidism;1 3 14 designated an orphan drug by FDA for this use.2

Has been shown to maintain serum calcium concentrations within the normal physiologic range, while substantially reducing (sometimes even eliminating) supplemental calcium and activated vitamin D requirements.1 3 11 12 13

Because of potential risk of osteosarcoma (see Boxed Warning), recommended only in patients who cannot be well controlled with calcium and activated vitamin D supplementation alone and for whom potential benefits are considered to outweigh such potential risk.1

Safety and efficacy not established in patients with hypoparathyroidism caused by calcium-sensing receptor mutations or in patients with acute postsurgical hypoparathyroidism.1

Natpara Dosage and Administration

General

  • Prior to initiating therapy, evaluate 25-hydroxyvitamin D stores, and replace to sufficient levels if deficient; also ensure serum calcium concentration >7.5 mg/dL.1

  • Adjust vitamin D and calcium supplementation during therapy; goal is to reduce or completely discontinue the supplements.1 (See Calcium and Vitamin D Supplementation under Dosage and Administration.) Abrupt interruption or discontinuance of parathyroid hormone therapy may cause severe hypocalcemia; resume or increase dosage of calcium and/or activated vitamin D, if necessary, in these situations.1 (See Hypocalcemia under Cautions.)

  • Routinely monitor serum calcium concentrations to assess therapeutic response and adverse effects (e.g., hyper- or hypocalcemia).1

Restricted Distribution Program

  • Available only through a restricted distribution program (Natpara REMS program) because of potential risk of osteosarcoma.1 (See Osteosarcoma under Cautions.)

  • Clinicians and pharmacies must be certified with the program before they can prescribe or dispense the drug.1 4

  • Additional information available at 855-628-7272 or .1

Administration

Sub-Q Administration

Administer by sub-Q injection; using Q-Cliq pen delivery device (supplied by manufacturer).1

Administer once daily.1

Inject sub-Q into thigh; alternate thighs daily.1

If dose is missed, administer missed dose as soon as reasonably possible.1 In the event of hypocalcemia resulting from a missed dose, administer additional calcium supplementation.1

May be self-administered after patient and/or caregiver is properly trained.1 6

Commercially available as a dual-chambered cartridge containing lyophilized drug and sterile diluent; when used as directed, each cartridge delivers 14 doses of parathyroid hormone.1

Never transfer contents of delivery device to syringe.1

Reconstitution

Reconstitute directly in cartridge by using mixing device supplied by manufacturer.1 6

Mix contents by slowly moving cartridge back and forth about 10 times;6 do not shake.1

The reconstituted solution should be colorless;5 however, it is normal for small particles to be present.1

Each cartridge containing reconstituted drug may be used for up to 14 days if stored under recommended conditions.1 (See Storage under Stability.)

Mixing device may be used up to 6 times (i.e., to reconstitute 6 medication cartridges).1

Dosage

Individualize dosage according to albumin-corrected serum calcium concentration and 24-hour urinary calcium excretion.1 Goal is to administer lowest dosage that will prevent both hypocalcemia and hypercalciuria.1 To minimize risk of hypercalciuria, target serum calcium concentrations should be in the lower half (i.e., 8–9 mg/dL) of normal range.1 15

Adults

Hypoparathyroidism
Initial Dosage
Sub-Q

Initially, 50 mcg once daily in conjunction with activated vitamin D and calcium supplementation.1

If baseline serum calcium concentration >7.5 mg/dL, reduce dosage of activated vitamin D by 50% upon initiation of parathyroid hormone therapy.1 Maintain current calcium dosage.1

Measure serum calcium concentrations within 3–7 days of initiating parathyroid hormone therapy and adjust vitamin D and calcium supplementation accordingly (see Calcium and Vitamin D Supplementation under Dosage and Administration).1

Maintenance Dosage
Sub-Q

Titrate dosage based on total albumin-corrected serum calcium concentrations.1 Goal is to achieve the minimum dosage that will maintain total albumin-corrected serum calcium concentrations at 8–9 mg/dL without the need for activated vitamin D and with only the minimum amount of calcium supplementation necessary to meet daily requirements.1

Increase by 25 mcg every 4 weeks up to 100 mcg once daily if serum calcium concentration cannot be maintained above 8 mg/dL without activated vitamin D and/or calcium supplementation.1

May reduce to as low as 25 mcg once daily if total serum calcium concentration is repeatedly >9 mg/dL after activated vitamin D has been discontinued and calcium supplementation has been reduced to a dosage sufficient to meet daily requirements.1

Monitor serum calcium concentrations and clinical response after each dosage adjustment.1 Adjust daily dosages of activated vitamin D and calcium accordingly.1 (See Calcium and Vitamin D Supplementation under Dosage and Administration.)

Once a maintenance dosage of parathyroid hormone has been achieved, monitor serum calcium concentrations and 24-hour urinary calcium excretion according to the standard of care.1

Calcium and Vitamin D Supplementation

During parathyroid hormone therapy, adjust vitamin D and calcium supplementation based on serum calcium concentrations and clinical response (i.e., manifestations of hypo- or hypercalcemia).1 Monitor serum calcium concentrations within 3–7 days of initiating parathyroid hormone therapy, and adjust dosage of the supplements accordingly (see Table 1).1 Repeat process until serum calcium concentration is 8–9 mg/dL, activated vitamin D is discontinued, and calcium supplementation is sufficient to meet patient's daily requirements.1

Discontinue in patients receiving the lowest available dose of vitamin D.

Table 1. Recommended Dosage Adjustments for Activated Vitamin D and Calcium Supplementation1

Serum Calcium Concentration (mg/dL)

Dosage of Activated Vitamin D (adjust first)

Dosage of Calcium Supplement (adjust second)

>10.6

Decrease or discontinue

Decrease

>9 and <10.6

Decrease or discontinue

No change or decrease if active vitamin D has been discontinued

>8 and ≤9

No change

No change

<8

Increase

Increase

Prescribing Limits

Adults

Hypoparathyroidism
Sub-Q

Maximum 100 mcg daily.1

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: Dosage adjustments not needed.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment: Dosage adjustments not needed.1 (See Renal Impairment under Cautions.)

Severe renal impairment and patients receiving dialysis: Dosage recommendations not available; safety and efficacy not established.1

Geriatric Patients

Select dosage with caution (at low end of dosage range) because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1

Cautions for Natpara

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Warnings

Osteosarcoma

In rat carcinogenicity studies, a dose- and duration-dependent increase in osteosarcoma observed; occurred at systemic exposures ranging from 3–71 times those achieved in humans at recommended doses.1

Use of parathyroid hormone recommended only in selected patients.1 (See Boxed Warning.)

Avoid use in patients with increased baseline risk of osteosarcoma.1

Other Warnings and Precautions

Hypercalcemia

Risk of severe hypercalcemia, particularly when drug is initiated or dosage is increased.1

Monitor serum calcium concentrations and patients for hypercalcemia; symptoms may include nausea, vomiting, constipation, fatigue, and muscle weakness.1 5

If hypercalcemia occurs, manage according to standard practice; consider withholding and/or decreasing dosage of parathyroid hormone.1

Hypocalcemia

Risk of severe hypocalcemia, particularly when drug is withheld, missed, or abruptly discontinued.1

Monitor serum calcium concentrations and patients for hypocalcemia; symptoms may include tingling, cramping or twitching of muscles, seizures, depression, and cognitive impairment.1 5

Resume or increase dosage of calcium and/or vitamin D supplements, if indicated.1

Concomitant Use of Digoxin

Risk of digoxin toxicity in patients with hypercalcemia.1

In patients receiving concomitant digoxin and parathyroid hormone therapy, monitor serum calcium and digoxin concentrations more frequently, particularly when initiating or adjusting dosage of parathyroid hormone.1 Monitor for signs and symptoms of digoxin toxicity and adjust dosage of the drugs, if necessary.1 (See Specific Drugs under Interactions.)

Immunogenicity

Antibodies to parathyroid hormone (including neutralizing antibodies) detected.1 Such antibodies do not appear to affect efficacy and safety; however, long-term implications unknown.1

Specific Populations

Pregnancy

Category C.1

Developmental toxicity observed in animal reproduction studies; no adequate and well-controlled studies in pregnant women.1 Use during pregnancy only if potential benefits justify potential risk to fetus.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1 Avoid use in individuals at increased risk of osteosarcoma, including pediatric and young adult patients with open epiphyses.1 (See Osteosarcoma under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Increased plasma concentrations observed in patients with moderate hepatic impairment (Child-Pugh class B).1 (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Renal Impairment

Since parathyroid hormone is eliminated by the kidneys, plasma concentrations may be increased in patients with renal impairment.1 (See Renal Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Not evaluated in patients with severe renal impairment or in patients undergoing dialysis.1

Common Adverse Effects

Paresthesia,1 3 hypocalcemia,1 3 headache,1 hypercalcemia,1 3 nausea,1 3 hypoesthesia,1 3 diarrhea,1 3 vomiting,1 3 arthralgia,1 hypercalciuria,1 3 extremity pain,1 3 upper respiratory tract infection,1 3 upper abdominal pain,1 3 sinusitis,1 3 decreased 25-hydroxycholecalciferol concentration,1 3 hypertension,1 3 facial hypoesthesia,1 3 neck pain.1 3

Interactions for Natpara

Specific Drugs

Drug

Interaction

Comments

Alendronate

Possible reduction in calcium-sparing effect, which can interfere with normalization of serum calcium concentrations1

Concomitant use not recommended1

Digoxin

Hypercalcemia may predispose patients to digoxin toxicity; hypocalcemia may reduce digoxin efficacy1

Monitor serum calcium and digoxin concentrations; monitor patients for signs and symptoms of digoxin toxicity1

Dosage adjustment of either or both drugs may be required1

Natpara Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability approximately 53% after sub-Q injection.1

Peak plasma concentrations generally attained in a biphasic manner;1 9 10 initial peak within 5–30 minutes and second (usually smaller) peak at 1–2 hours.1

Dose-proportional increases in exposure observed with usual dosages.1

Duration

Longer duration of calcemic effect compared with teriparatide;3 8 10 duration of calcemic response is 24 hours in patients with hypoparathyroidism following a 100-mcg dose.1 3

Special Populations

In patients with moderate hepatic impairment (Child-Pugh class B), peak plasma concentrations increased by approximately 18–20% compared with individuals with normal hepatic function.1

In patients with mild (Clcr 60–90 ml/minute) or moderate (Clcr 30–60 mL/minute) renal impairment, peak plasma concentrations and systemic exposure increased by 22 and 3.9%, respectively, compared with individuals with normal renal function.1

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Elimination

Metabolism

Cleaved in liver by cathepsins into N- and C-terminal fragments.1 15 N-terminal fragments are further degraded, while C-terminal fragments are released into the circulation and eliminated by the kidneys.1 15

Elimination Route

Any intact parathyroid hormone mostly cleared through glomerular filtration; small amounts bind to parathyroid hormone receptors.1 15 C-terminal fragments are filtered at the glomerulus.1 15

Half-life

Following sub-Q administration of 50 or 100 mcg, apparent half-life approximately 3 hours.1 9 10

Stability

Storage

Parenteral

Powder for Injection

Store cartridges containing lyophilized drug and sterile diluent at 2–8°C; do not freeze or shake.1 Store in original package.1 Store mixing device and empty Q-Cliq pen delivery device at room temperature.1

Store reconstituted cartridge in the Q-Cliq pen at 2–8°C for up to 14 days.1 Protect from light and heat; avoid exposure to elevated temperatures.1

Actions

  • Structurally identical to full-length, 84-amino acid endogenous human parathyroid hormone.1 3 7 8

  • Binds and activates parathyroid hormone receptors in the kidney and bone.1 7

  • Responsible for calcium and phosphate homeostasis and maintenance of bone health.7 8

  • Increases serum calcium concentrations through reabsorption of calcium in the distal renal tubules, stimulation of renal 1-α-hydroxylase (to facilitate conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D and increase intestinal calcium absorption), and release of calcium from bone into circulation from increased bone turnover.1 7

  • Also promotes phosphate excretion.7

Advice to Patients

  • Importance of providing patients with a copy of the manufacturer's patient information (medication guide and instructions for use) prior to initiating parathyroid hormone therapy, and of ensuring that patients fully understand the risks and benefits of therapy.1 5 6

  • Potential risk of osteosarcoma; importance of informing patients that parathyroid hormone caused a dose- and duration-dependent increase in osteosarcoma in rats and that a potential risk also may exist in humans.1 Advise patients to promptly report manifestations of possible osteosarcoma (e.g., persistent localized pain, new soft tissue mass that is tender to palpation).1

  • Importance of advising patients that parathyroid hormone is available only through a restricted distribution program (Natpara REMS Program).1 Inform patients of the requirements of the program and provide them with information on how they can obtain the drug (e.g., through certified pharmacies).1

  • Importance of informing patients that severe hypercalcemia can occur when initiating or adjusting parathyroid hormone therapy.1 Advise patients to promptly report any symptoms of hypercalcemia or changes in concurrently administered medications known to influence serum calcium concentration.1 Importance of informing patients that severe hypocalcemia can occur if parathyroid hormone therapy is abruptly discontinued or interrupted.1 Advise patients to promptly report any symptoms of hypocalcemia or interruptions in therapy, including missed doses.1 Recommendations for monitoring serum calcium concentration should be followed.1

  • Importance of instructing patients and/or their caregivers regarding proper preparation and administration of parathyroid hormone, including use of aseptic technique, and proper storage and disposal of the delivery device (Q-Cliq pen) and related supplies (e.g., used needles).1 Importance of not sharing the Q-Cliq pen with other patients.1

  • Importance of advising patients of common adverse effects (e.g., paresthesia, hypocalcemia, headache, hypercalcemia, nausea, hypoesthesia, diarrhea, vomiting, arthralgia, hypercalciuria, extremity pain).1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., digoxin) and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of parathyroid hormone is restricted.1 4 (See Restricted Distribution Program under Dosage and Administration.)

Parathyroid Hormone (Recombinant DNA Origin)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for subcutaneous use

0.4 mg (25 mcg per dose/pen device)

Natpara (available as prefilled disposable dual-chamber multiple-dose cartridge with sterile diluent)

NPS Pharmaceuticals

0.8 mg (50 mcg per dose/pen device)

Natpara (available as prefilled disposable dual-chamber multiple-dose cartridge with sterile diluent)

NPS Pharmaceuticals

1.21 mg (75 mcg per dose/pen device)

Natpara (available as prefilled disposable dual-chamber multiple-dose cartridge with sterile diluent)

NPS Pharmaceuticals

1.61 mg (100 mcg per dose/pen device)

Natpara (available as prefilled disposable dual-chamber multiple-dose cartridge with sterile diluent)

NPS Pharmaceuticals

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: December 07, 2015
Last reviewed: December 07, 2015
Date modified: February 08, 2016

References

1. NPS Pharmaceuticals. Natpara (parathyroid hormone) for injection for subcutaneous use prescribing information. Bedminster, NJ; 2015 Jan.

2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. Accessed 2015 Jun 2.

3. Mannstadt M, Clarke BL, Vokes T et al. Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study. Lancet Diabetes Endocrinol. 2013; 1:275-83. [PubMed 24622413]

4. Natpara (parathyroid hormone) risk evaluation and mitigation strategy (REMS). From FDA website. Accessed 2015 Jun 2.

5. NPS Pharmaceuticals. Natpara (parathyroid hormone) for injection medication guide. Bedminster, NJ; 2015 Jan.

6. NPS Pharmaceuticals. Instructions for use. From Natpara website. Accessed 2015 Jun 15.

7. Monis EL, Mannstadt M. Hypoparathyroidism - disease update and emerging treatments. Ann Endocrinol (Paris). 2015; 76:84-8. [PubMed 25882889]

8. Cusano NE, Rubin MR, Bilezikian JP. PTH(1-84) replacement therapy for the treatment of hypoparathyroidism. Expert Rev Endocrinol Metab. 2015; 10:5-13. [PubMed 25705243]

9. Clarke BL, Kay Berg J, Fox J et al. Pharmacokinetics and pharmacodynamics of subcutaneous recombinant parathyroid hormone (1-84) in patients with hypoparathyroidism: an open-label, single-dose, phase I study. Clin Ther. 2014; 36:722-36. [PubMed 24802860]

10. Sikjaer T, Amstrup AK, Rolighed L et al. PTH(1-84) replacement therapy in hypoparathyroidism: a randomized controlled trial on pharmacokinetic and dynamic effects after 6 months of treatment. J Bone Miner Res. 2013; 28:2232-43. [PubMed 23649554]

11. Rubin MR, Sliney J, McMahon DJ et al. Therapy of hypoparathyroidism with intact parathyroid hormone. Osteoporos Int. 2010; 21:1927-34. [PubMed 20094706]

12. Sikjaer T, Rejnmark L, Rolighed L et al. The effect of adding PTH(1-84) to conventional treatment of hypoparathyroidism: a randomized, placebo-controlled study. J Bone Miner Res. 2011; 26:2358-70. [PubMed 21773992]

13. Cusano NE, Rubin MR, McMahon DJ et al. Therapy of hypoparathyroidism with PTH(1-84): a prospective four-year investigation of efficacy and safety. J Clin Endocrinol Metab. 2013; 98:137-44. [PubMed 23162103]

14. Kim ES, Keating GM. Recombinant Human Parathyroid Hormone (1-84): A Review in Hypoparathyroidism. Drugs. 2015; 75:1293-303. [PubMed 26177893]

15. . Recombinant human parathyroid hormone (Natpara). Med Lett Drugs Ther. 2015; 57:87-8. [PubMed 26035748]

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