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    Parathyroid Hormone Analogs and Modifiers

    BOXED WARNING

    Children, infants, new primary malignancy, osteogenic sarcoma, Paget's disease, radiation therapy

    The use of parathyroid hormone is not recommended in patients at increased risk of osteogenic sarcoma (osteosarcoma), a new primary malignancy, including those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, patients with hereditary disorders predisposing to osteosarcoma, or prior external beam or implant radiation therapy involving the skeleton. Parathyroid hormone has been associated with an increased incidence of osteosarcoma in rat studies. This increased incidence was dependent on dose and duration of treatment; systemic exposure to parathyroid hormone in the rats ranged from 3 to 71 times the exposure given to humans in a 100 mcg dose. The relevance of these animal osteosarcoma findings is uncertain relative to humans; however, the potential risk should be considered. Use is recommended only in patients who cannot be well-controlled on calcium supplements and active forms of vitamin D alone and for whom the potential benefits outweigh the potential risk. Safety and efficacy of parathyroid hormone have not been established in pediatric patients; pediatric patients with open epiphyses (e.g., infants, children, and adolescents) are also considered at risk for osteosarcoma. Patients should report signs or symptoms consistent with osteosarcoma such as persistent localized pain or soft tissue mass tender to palpation. Because of the potential risk of osteosarcoma associated with parathyroid hormone, this medication is available only through a restricted program called the Natpara REMS Program. Under the 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 in the U.S. at 1-800-828-2088.

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant, injectable parathyroid hormone (PTH)
    Adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism

    COMMON BRAND NAMES

    NATPARA

    HOW SUPPLIED

    NATPARA Subcutaneous Inj Pwd F/Sol: 25mcg, 50mcg, 75mcg, 100mcg

    DOSAGE & INDICATIONS

    For the treatment of hypocalcemia in patients with hypoparathyroidism as an adjunct to calcium and vitamin D supplementation.
    NOTE: Parathyroid hormone has not been studied in patients with hypoparathyroidism caused by calcium-sensing receptor mutations nor in patients with acute post-surgical hypoparathyroidism.
    Subcutaneous dosage
    Adults

    Parathyroid hormone is recommended only for patients who cannot be well-controlled on calcium supplements and active forms of vitamin D alone. The dose of parathyroid hormone should be individualized based on total serum calcium (albumin-corrected) and 24-hour urinary calcium excretion. Vitamin D and calcium supplementation will need to be adjusted during parathyroid hormone therapy. The recommended initial dose is 50 mcg once daily administered subcutaneously in the thigh (alternating thighs daily). For dose titration, the following is recommended: for serum calcium less than 8 mg/dL, increase the dose in increments of 25 mcg subcutaneously every 4 weeks. Maximum dose: 100 mcg subcutaneously once daily if serum calcium cannot be maintained above 8 mg/dL without an active form of vitamin D and/or calcium supplementation; for serum calcium more than 9 mg/dL, the dose may be decreased to as low as 25 mcg subcutaneously once daily if total serum calcium is repeatedly more than 9 mg/dL after discontinuation of the active form of vitamin D and the calcium supplement has been decreased sufficiently to meet daily requirements. After any parathyroid dosage change, monitor clinical response and serum calcium; remember to adjust nutritional intake of active vitamin D and calcium supplements. The recommended maintenance dose is the minimum dose required to prevent both hypocalcemia and hypercalciuria. This will generally be the dose that maintains total serum calcium (albumin-corrected) within the lower half of the normal range (8 to 9 mg/dL) without the need for active forms of vitamin D and with calcium supplementation sufficient to meet the patient's daily requirements. If a dose is missed, the next dose should be administered as soon as possible and additional exogenous calcium should be administered in the event of hypocalcemia. Abrupt interruption or discontinuation can result in severe hypocalcemia. Resume treatment with, or increase the dose of, an active form of vitamin D and calcium supplements if indicated.

    MAXIMUM DOSAGE

    Adults

    100 mcg/day subcutaneously.

    Geriatric

    100 mcg/day subcutaneously.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment for parathyroid hormone is recommended in patients with mild to moderate hepatic impairment. No recommendations are available for patients with severe hepatic impairment.

    Renal Impairment

    Clinical studies of parathyroid hormone treatment did not include sufficient numbers of patients with moderate and severe renal impairment to determine whether they respond differently from patients with mild renal impairment or normal renal function. Some of the mechanisms of action of parathyroid hormone (e.g. conversion of 25-OH vitamin D to 1,25-OH2 vitamin D) are dependent on renal function. Parathyroid hormone is eliminated by the kidneys and maximum drug concentrations increase with renal impairment.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Do not abruptly discontinue therapy. Abrupt interruption or discontinuation of parathyroid hormone can result in severe hypocalcemia.
    In the case of a missed dose, the next dose of parathyroid hormone should be administered as soon as possible.

    Subcutaneous Administration

    Patients and caregivers should receive appropriate training and instruction by a trained healthcare provider on the proper technique for administering subcutaneous injections using the mixing device and the Q-Cliq pen.
    The mixing device is designed to enable reconstitution before the first use of each cartridge. The mixing device can be used to reconstitute up to 6 medication cartridges.
    Do NOT shake; discard if shaken.
    Do not transfer the contents of the delivery device to a syringe.
    Discard the needle in a puncture-resistant container after administration.
    Storage of medication: Store in the Q-Cliq pen under refrigeration at 36—46 degrees F (2—8 degrees C) for up to 14 days after reconstitution. Do not freeze; discard if frozen. Store away from heat and light. All reconstituted medication cartridges older than 14 days must be discarded.
    Storage of devices: The mixing device and empty Q-Cliq pen can be stored at room temperature. The Q-Cliq pen can be used for up to 2 years of daily treatment by replacing the reconstituted cartridge every 14 days.

    STORAGE

    NATPARA:
    - Avoid exposure to heat
    - Discard any unused reconstituted product after 14 days
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Do not use if product has been frozen
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Parathyroid hormone injection is contraindicated in patients with a known hypersensitivity to any component of the product. Hypersensitivity reactions (e.g., anaphylaxis, angioedema, and urticaria) have occurred with the use of injectable parathyroid hormone. If signs or symptoms of a serious hypersensitivity reaction occur, discontinue treatment with parathyroid hormone, treat hypersensitivity reaction according to the standard of care, and monitor until signs and symptoms resolve.

    Abrupt discontinuation, hypocalcemia

    Severe hypocalcemia has been reported with the used of parathyroid hormone therapy, including cases of hypocalcemia that have resulted in seizures. The risk is highest when therapy is withheld, missed, or with abrupt discontinuation; however, it can occur at any time. Monitor for signs and symptoms of hypocalcemia and serum calcium concentrations. In some cases, as in acute serious hypersensitivity reactions, discontinuation of parathyroid hormone and treatment of the hypersensitivity is indicated and the clinician should monitor the patient for hypocalcemia. In the case of interrupted or discontinued therapy, resume treatment with, or increase the dose of, an active form of vitamin D and calcium supplements if indicated in order to prevent severe hypocalcemia.

    Hypercalcemia

    Severe hypercalcemia has been reported with parathyroid hormone therapy. The risk is highest when starting or increasing the parathyroid hormone dose. Monitor serum calcium concentrations and patients for signs and symptoms of hypercalcemia. Treat hypercalcemia per standard practice and consider holding and/or lowering the parathyroid hormone dose if severe hypercalcemia occurs.

    Children, infants, new primary malignancy, osteogenic sarcoma, Paget's disease, radiation therapy

    The use of parathyroid hormone is not recommended in patients at increased risk of osteogenic sarcoma (osteosarcoma), a new primary malignancy, including those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, patients with hereditary disorders predisposing to osteosarcoma, or prior external beam or implant radiation therapy involving the skeleton. Parathyroid hormone has been associated with an increased incidence of osteosarcoma in rat studies. This increased incidence was dependent on dose and duration of treatment; systemic exposure to parathyroid hormone in the rats ranged from 3 to 71 times the exposure given to humans in a 100 mcg dose. The relevance of these animal osteosarcoma findings is uncertain relative to humans; however, the potential risk should be considered. Use is recommended only in patients who cannot be well-controlled on calcium supplements and active forms of vitamin D alone and for whom the potential benefits outweigh the potential risk. Safety and efficacy of parathyroid hormone have not been established in pediatric patients; pediatric patients with open epiphyses (e.g., infants, children, and adolescents) are also considered at risk for osteosarcoma. Patients should report signs or symptoms consistent with osteosarcoma such as persistent localized pain or soft tissue mass tender to palpation. Because of the potential risk of osteosarcoma associated with parathyroid hormone, this medication is available only through a restricted program called the Natpara REMS Program. Under the 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 in the U.S. at 1-800-828-2088.

    Neonates, pregnancy

    Available data with parathyroid hormone injection use in pregnant women are insufficient to inform a drug-associated risk of birth defects, miscarriage or adverse maternal or fetal outcomes. The potential effects on the developing fetus if parathyroid hormone is used during pregnancy are not known. Developmental effects of parathyroid hormone exposure, including skeletal alterations, increased morbidity, and stillborn litters were observed in animal studies. There are disease-associated risks to the mother and the fetus related to hypocalcemia in pregnancy. Maternal hypocalcemia can result in an increased rate of spontaneous abortion, premature and dysfunctional labor, and possibly preeclampsia. 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. Neonates 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.

    Breast-feeding

    Because of the potential risk for tumorigenicity (osteosarcoma) shown for parathyroid hormone in animal studies, consideration should be made as to whether to discontinue breast-feeding or whether maternal treatment with parathyroid hormone (PTH) is warranted. It is unknown if parathyroid hormone is excreted in human breast milk. Parathyroid hormone is present in the milk of lactating rats. In animal studies, the parathyroid hormone concentrations in milk were approximately 42-times lower than PTH concentrations observed in plasma. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Infants exposed to parathyroid hormone through breast milk should be monitored for signs and symptoms of hypercalcemia or hypocalcemia. Monitoring of serum calcium in the infant should be considered.

    Hyperparathyroidism

    Parathyroid hormone injection would not be indicated in patients with hyperparathyroidism.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / Incidence not known
    osteogenic sarcoma / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    hypocalcemia / Delayed / 27.0-27.0
    hypercalcemia / Delayed / 19.0-19.0
    hypercalciuria / Delayed / 11.0-11.0
    antibody formation / Delayed / 8.6-8.6
    hypertension / Early / 6.0-6.0
    dyspnea / Early / Incidence not known

    Mild

    paresthesias / Delayed / 31.0-31.0
    headache / Early / 25.0-25.0
    nausea / Early / 18.0-18.0
    hypoesthesia / Delayed / 6.0-14.0
    vomiting / Early / 12.0-12.0
    diarrhea / Early / 12.0-12.0
    arthralgia / Delayed / 11.0-11.0
    musculoskeletal pain / Early / 6.0-10.0
    infection / Delayed / 0-8.0
    abdominal pain / Early / 7.0-7.0
    sinusitis / Delayed / 7.0-7.0
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Alendronate: (Moderate) Coadministration of alendronate with parathyroid hormone (PTH) is not recommended as concomitant use leads to a reduction in the calcium sparing effect, which can interfere with the normalization of serum calcium. The use of PTH alone was superior to use in combination with alendronate in clinical trials. In clinical trials, there was no evidence of synergy between PTH and alendronate. Changes in the volumetric density of trabecular bone, the cortical volume at the hip, and levels of markers of bone turnover suggest that the concurrent use of alendronate may reduce the anabolic effects of PTH. Concurrent use with other bisphosphonates is also controversial. However, sequential use (e.g., PTH followed by anti-resorptive treatment with bisphosphonates) appears to be beneficial and to help maintain beneficial bone effects.
    Alendronate; Cholecalciferol: (Moderate) Coadministration of alendronate with parathyroid hormone (PTH) is not recommended as concomitant use leads to a reduction in the calcium sparing effect, which can interfere with the normalization of serum calcium. The use of PTH alone was superior to use in combination with alendronate in clinical trials. In clinical trials, there was no evidence of synergy between PTH and alendronate. Changes in the volumetric density of trabecular bone, the cortical volume at the hip, and levels of markers of bone turnover suggest that the concurrent use of alendronate may reduce the anabolic effects of PTH. Concurrent use with other bisphosphonates is also controversial. However, sequential use (e.g., PTH followed by anti-resorptive treatment with bisphosphonates) appears to be beneficial and to help maintain beneficial bone effects.
    Digoxin: (Moderate) Caution is warranted in patients receiving digoxin with parathyroid hormone (PTH) therapy. PTH therapy causes transient increases in serum calcium concentrations. Since the inotropic effects of digoxin are affected by serum calcium concentrations, hypercalcemia may predispose patients to digoxin toxicity. Digoxin efficacy is reduced if hypocalcemia is present. Monitor the patient's serum calcium and digoxin concentrations and for signs or symptoms of digitalis toxicity. Adjustment of digoxin and/or parathyroid hormone may be necessary. There has not been a formal drug interaction study of these 2 drugs together.

    PREGNANCY AND LACTATION

    Pregnancy

    Because of the potential risk for tumorigenicity (osteosarcoma) shown for parathyroid hormone in animal studies, consideration should be made as to whether to discontinue breast-feeding or whether maternal treatment with parathyroid hormone (PTH) is warranted. It is unknown if parathyroid hormone is excreted in human breast milk. Parathyroid hormone is present in the milk of lactating rats. In animal studies, the parathyroid hormone concentrations in milk were approximately 42-times lower than PTH concentrations observed in plasma. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Infants exposed to parathyroid hormone through breast milk should be monitored for signs and symptoms of hypercalcemia or hypocalcemia. Monitoring of serum calcium in the infant should be considered.

    MECHANISM OF ACTION

    Parathyroid hormone raises serum calcium by increasing renal tubular calcium reabsorption, increasing intestinal calcium absorption by converting 25-OH vitamin D to 1,25-OH2 vitamin D. Parathyroid hormone also increases bone turnover which releases calcium into the circulation.

    PHARMACOKINETICS

    Parathyroid hormone is administered subcutaneously and has a volume of distribution of 5.35 L at steady state. In vitro and in vivo studies demonstrate that the clearance of parathyroid hormone is primarily a hepatic process with a lesser role played by the kidneys. In the liver, most of the intact parathyroid hormone is cleaved by cathepsins. In the kidney, a small amount of parathyroid hormone binds to physiologic PTH-1 receptors, but most is filtered at the glomerulus. C-terminal fragments are also cleared efficiently by glomerular filtration. The apparent terminal half-life is 3.02 hours for the 50 mcg dose and 2.83 hours for the 100 mcg dose.
     
    After a single subcutaneous injection of either 50 mcg or 100 mcg administered in the thigh, increases in serum calcium concentrations occur in a dose-related manner. Mean peak serum calcium concentrations are reached between 10—12 hours after administration and the increase in serum calcium concentrations above baseline is sustained for more than 24 hours after administration. The maximum mean increase of serum calcium from baseline, occurring at 12 hours, was approximately 0.5 mg/dL with a dose of 50 mcg and 0.7 mg/dL with a dose of 100 mcg. The mean calcium intake for the 50 mcg and 100 mcg doses was 1700 mg.
     
    Affected cytochrome P450 isoenzymes: none

    Subcutaneous Route

    After single subcutaneous injections of parathyroid hormone of 50 mcg and 100 mcg in patients with hypoparathyroidism, peak parathyroid hormone plasma concentrations (mean Tmax) occurs within 5—30 minutes and a second, smaller peak, at 1—2 hours. The plasma AUC increases in a dose proportional manner from 50 mcg to 100 mcg. One 100 mcg subcutaneous dose provides a 24-hour calcemic response in hypoparathyroidism patients. The absolute bioavailability after subcutaneous administration is 53%.