human parathyroid hormone, recombinant (Rx)

Brand and Other Names:Natpara
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

SC injection cartridge

  • 25 mcg/dose
  • 50 mcg/dose
  • 75 mcg/dose
  • 100 mcg/dose

Hypocalcemia

Indicated as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism

Dosing guidelines

  • Individualize dose based on total serum calcium (albumin-corrected) and 24-hr urinary calcium excretion
  • The recommended dose is the minimum 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 (ie, 8-9 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 recombinant human parathyroid hormone (rhPTH)

Before initiating rhPTH

  • Confirm 25-hydroxyvitamin D stores are sufficient; if insufficient, replace to sufficient levels per standard of care
  • Confirm serum calcium is >7.5 mg/dL

Initiating rhPTH

  • Initial: 50 mcg SC qDay; administer in the thigh (alternate thigh each day)
  • In patients using active forms of vitamin D, decrease the dose of active vitamin D by 50%, if serum calcium is >7.5 mg/dL
  • In patients using calcium supplements, maintain calcium supplement dose
  • Measure serum calcium concentration within 3-7 days
  • Adjust dose of active vitamin D or calcium supplement or both based on serum calcium value and clinical assessment (ie, signs and symptoms of hypocalcemia or hypercalcemia)
  • Suggested adjustments to active vitamin D and calcium supplement based on serum calcium levels are provided below; repeat steps 4 and 5 until target serum calcium levels are within the lower half of the normal range (ie, 8-9 mg/dL), active vitamin D has been discontinued, and calcium supplementation is sufficient to meet daily requirements
  • Vitamin D and calcium dose adjustment
    • Adjust active vitamin D forms first and calcium supplement second
    • Serum calcium >ULN (10.6 mg/dL): Decrease or discontinue vitamin D; decrease calcium supplement
    • Serum calcium >9 mg/dL and
    • Serum calcium ≤9 mg/dL and >8 mg/dL: No change for vitamin D and calcium supplements
    • Serum calcium <8 mg/dL: Increase vitamin D and calcium supplements

rhPTH dose adjustment

  • May increase dose in increments of 25 mcg q4wk; not to exceed 100 mcg/day if serum calcium cannot be maintained >8 mg/dL without an active form of vitamin D and/or oral calcium supplementation
  • May decrease dose to as low as 25 mcg/day if total serum calcium is repeatedly >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
  • Monitor clinical response and serum calcium levels after a dosage change
  • Adjust active vitamin D and calcium supplements (as described above) if indicated

rhPTH maintenance dose

  • 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 (ie, ~8-9 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

rhPTH dose interruption or discontinuation

  • Abrupt interruption or discontinuation of rhPTH 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 rhPTH
  • Monitor for signs and symptoms of hypocalcemia and serum calcium levels
  • In the case of a missed dose, the next rhPTH dose should be administered as soon as reasonably feasible and additional exogenous calcium should be taken in the event of hypocalcemia

Dosage Modifications

Hepatic impairment

  • Mild-to-moderate (Child-Pugh A or B): No dose adjustment required
  • Severe (Child-Pugh C): Data are not available

Renal impairment

  • Mild-to-moderate (CrCl 30-90 mL/min): No dose adjustment required
  • Severe (CrCl <30 mL/min), ESRD, dialysis: Data are not available

Dosing Considerations

Because of the potential risk of osteosarcoma, recommended only for patients who cannot be well-controlled on calcium supplements and active forms of vitamin D alone

Not studied in patients with hypoparathyroidism caused by surgery or calcium-sensing receptor mutations

<18 years: Safety and efficacy not established

Avoid use in patients who are at increased baseline risk for osteosarcoma, including pediatric and young adult patients with open epiphyses

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Interactions

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            Adverse Effects

            >10%

            Paraesthesia (31%)

            Hypocalcemia (27%)

            Headache (25%)

            Hypercalcemia (19%)

            Nausea (18%)

            Hypoaesthesia (14%)

            Diarrhea (12%)

            Vomiting (12%)

            Arthralgia (11%)

            Hypercalciuria (11%)

            1-10%

            Pain in extremity (10%)

            Upper respiratory tract infection (8%)

            Abdominal pain upper (7%)

            Sinusitis (7%)

            Blood 25-hydroxycholecalciferol decreased (6%)

            Hypertension (6%)

            Hypoaesthesia facial (6%)

            Neck pain (6%)

            Postmarketing Reports

            Hypersensitivity reactions

            Seizures (due to hypocalcemia)

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            Warnings

            Black Box Warnings

            Because of the potential risk of osteosarcoma, prescribe 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

            Available only through a restricted program called the NATPARA REMS Program

            Avoid with increased osteosarcoma risk

            • Paget disease of bone or unexplained elevations of alkaline phosphatase
            • Pediatric and young adult patients with open epiphyses
            • Hereditary disorders predisposing to osteosarcoma
            • History of prior external beam or implant radiation therapy involving the skeleton

            Contraindications

            Hypersensitivity to drug or excipients

            Cautions

            Potential increased risk of osteosarcoma (see Black Box Warnings)

            Hypersensitivity reactions, including anaphylaxis, dyspnea, angioedema, urticaria, and rash reported; if signs or symptoms of serious hypersensitivity reaction occur, discontinue treatment and treat hypersensitivity reaction according to standard of care; monitor until signs and symptoms resolve; monitor for hypocalcemia if therapy discontinued

            Severe hypercalcemia reported; the risk is highest when starting or increasing the dose; monitor serum calcium and patients for signs and symptoms of hypercalcemia; monitor serum calcium when starting or adjusting dose and when making changes to co-administered drugs known to raise serum calcium

            Severe hypocalcemia that resulted in seizures reported; the risk is highest when a rhPTH dose is withheld, missed, or abruptly discontinued, but can occur at any time; monitor for signs and symptoms of hypocalcemia

            Monitor digoxin levels if coadministered; the inotropic effects of digoxin are affected by serum calcium levels; hypercalcemia of any cause may predispose to digoxin toxicity; monitor serum calcium more frequently and increase monitoring when initiating or adjusting dose

            Coadministration with alendronate leads to reduction in the calcium-sparing effect, which can interfere with the normalization of serum calcium; concomitant use with alendronate is not recommended

            REMS Program

            • Because of potential risk of osteosarcoma associated with therapy, drug is available only through restricted REMS program; under the program, only certified healthcare providers can prescribe and only certified pharmacies can dispense the drug; further information is available at www.NATPARAREMS.com or by telephone at 1-800-828-2088
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            Pregnancy & Lactation

            Pregnancy

            There are no adequate and well-controlled studies in pregnant women

            Animal Data

            • Because animal reproduction studies are not always predictive of human response, use during pregnancy only if the potential benefit justifies the potential risk to the fetus
            • Developmental effects were observed in a perinatal/postnatal study in pregnant rats given SC doses of 100, 300, 1000 mcg/kg/day from organogenesis through lactation, entire stillborn litters were observed in the 300-mcg/kg/day group (34 times the 100-mcg/day clinical dose based on AUC)
            • 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)

            Lactation

            Unknown if distributed in human breast milk

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Bioengineered replica of human parathyroid hormone 1-84 (rhPTH 1-84)

            Parathyroid hormone raises serum calcium by increasing renal tubular calcium reabsorption, increasing intestinal calcium absorption (ie, by converting 25 OH vitamin D to 1,25 OH2 vitamin D), and increasing bone turnover, which releases calcium into the circulation

            Absorption

            Bioavailability: 53%

            Peak plasma concentration: 5-30 min; second small peak at 1-2 hr

            Distribution

            Vd: 5.35 L (steady state)

            Metabolism

            Primarily via hepatic clearance; most of the intact PTH is cleaved by cathepsins

            Elimination

            Half-life: ~3 hr

            Excretion: A small amount of PTH binds to physiologic PTH-1 receptors, but most is filtered at the glomerulus; C-terminal fragments are also cleared efficiently by glomerular filtration

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            Administration

            SC Preparation

            Supplied as a multiple dose, dual-chamber glass cartridge containing a sterile powder and diluent in 4 dosage strengths

            Reconstitute each cartridge using the mixing device for reconstitution Inspect visually for particulate matter and discoloration prior to administration

            Discard the needle in a puncture-resistant container following administration

            After reconstitution, each medication cartridge can be used for 14 SC injections

            SC Administration

            Administer SC by using the pen delivery device (ie, Q-Cliq pen)

            Administer in thigh, rotating between thighs for each dose

            Storage

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

            Store away from heat and light; avoid exposure to elevated temperatures

            Do not freeze or shake; do not use if it has been frozen or shaken

            Unreconstituted cartridges

            • Refrigerate at 36-46°F (2-8°C)
            • Store away from heat and light; avoid exposure to elevated temperatures
            • Do not freeze or shake
            • Do not use if it has been frozen or shaken

            Reconstituted cartridge

            • Refrigerate (36-46°F [2-8°C]) the remaining reconstituted doses in the Q-Cliq pen for up to 14 days
            • After the 2-wk use period, only the cartridge should be discarded (ie, do not discard Q-Cliq pen)
            • The Q-Cliq pen can be used for up to 2 years by replacing the reconstituted medication cartridges q2wk
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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.