Natpar (Parathyroid Hormone rDNA)
Hormone replacement therapy for hypoparathyroidism in adults
Natpar is a recombinant parathyroid hormone (rDNA) used as adjunctive hormone replacement therapy in adults with chronic hypoparathyroidism who cannot be adequately controlled with conventional therapy alone (calcium and active vitamin D supplements). It is the first and only parathyroid hormone replacement therapy approved for this rare endocrine disorder, helping to restore normal calcium and phosphate metabolism.
Quick Facts
Key Takeaways
- Natpar is the first approved parathyroid hormone replacement for chronic hypoparathyroidism in adults who are not adequately controlled with standard calcium and vitamin D supplementation.
- It is given once daily as a subcutaneous injection in the thigh using a reusable pen device, with the dose titrated between 25 and 100 micrograms based on blood calcium levels.
- Blood calcium must be closely monitored, especially during the first week of treatment and after dose changes, as both high and low calcium levels can occur.
- The reconstituted medication must be refrigerated (2–8°C) and used within 14 days; it must never be frozen.
- Natpar holds a conditional marketing authorisation in the EU, meaning additional data is expected as clinical experience grows.
What Is Natpar and What Is It Used For?
Natpar (parathyroid hormone, recombinant DNA origin) is a hormone replacement therapy specifically designed for adults with chronic hypoparathyroidism. This rare endocrine condition occurs when the parathyroid glands, four small glands located behind the thyroid in the neck, produce insufficient amounts of parathyroid hormone (PTH). PTH is essential for regulating calcium and phosphate metabolism throughout the body, and its deficiency can lead to significant clinical consequences.
Hypoparathyroidism most commonly develops as a result of neck surgery (particularly thyroid or parathyroid surgery), but can also be caused by autoimmune destruction of the parathyroid glands, genetic conditions, or rarely, infiltrative diseases. The estimated prevalence is approximately 23 to 37 per 100,000 people in Western countries, making it a rare but clinically important disorder that can significantly impact quality of life.
When parathyroid hormone levels are too low, blood calcium levels drop (hypocalcemia) while phosphate levels may rise (hyperphosphatemia). Low calcium levels can produce symptoms affecting many organ systems, including the skeleton, heart, skin, muscles, kidneys, brain, and nervous system. Chronic hypocalcemia can lead to muscle cramps, tingling in the hands and feet, fatigue, brain fog, seizures, and cardiac arrhythmias.
Traditionally, hypoparathyroidism has been managed with oral calcium supplements and active forms of vitamin D (such as calcitriol or alfacalcidol). However, some patients remain inadequately controlled despite high doses of these supplements, experiencing persistent symptoms, recurrent hypocalcemia, or complications such as kidney calcifications (nephrocalcinosis) and kidney stones. Natpar addresses this unmet need by directly replacing the missing hormone, providing a more physiological approach to calcium homeostasis.
Natpar is administered as a once-daily subcutaneous injection and is intended to be used alongside, not as a replacement for, calcium and vitamin D supplements. The goal of treatment is to maintain blood calcium within the lower part of the normal range while reducing the need for supplemental calcium and active vitamin D, thereby lowering the risk of complications associated with high-dose supplementation.
What Should You Know Before Taking Natpar?
Contraindications
Before starting Natpar, your doctor will assess whether the medication is appropriate for you. There are several important contraindications that must be considered to ensure patient safety. Natpar must not be used if any of the following conditions apply:
- Allergy to parathyroid hormone or any of the other ingredients in Natpar (including sodium chloride, mannitol, citric acid monohydrate, metacresol, or sodium hydroxide).
- Current or prior radiation therapy to the skeleton, as this may increase the risk of bone tumors including osteosarcoma.
- Bone cancer or other cancers that have metastasized to bone, since parathyroid hormone stimulates bone turnover and could theoretically promote tumor growth.
- Increased risk of osteosarcoma, such as in patients with Paget's disease of bone, unexplained elevations in bone-specific alkaline phosphatase, or other pre-existing bone disorders that elevate osteosarcoma risk.
- Pseudohypoparathyroidism, a rare condition in which the body does not respond adequately to parathyroid hormone produced by the body. In these patients, adding exogenous PTH would not provide clinical benefit.
Warnings and Precautions
Patients treated with Natpar require careful monitoring due to the risk of calcium level fluctuations. Both hypercalcemia (high blood calcium) and hypocalcemia (low blood calcium) can occur during treatment, and these fluctuations are most likely to happen in the following situations:
- When starting Natpar for the first time
- When the Natpar dose is changed (increased or decreased)
- When a daily injection is missed
- When Natpar treatment is temporarily or permanently discontinued
Your doctor will monitor your blood calcium levels closely during these critical periods. Within the first 7 days of starting treatment or after any dose adjustment, blood and urine calcium measurements will be performed. Depending on the results, your doctor may adjust your supplemental calcium or vitamin D doses, or modify the Natpar dose itself.
Patients with a history of kidney stones (nephrolithiasis) should inform their doctor before starting Natpar, as changes in calcium and phosphate metabolism may influence stone formation risk. Regular monitoring of urinary calcium excretion is recommended during treatment.
Pregnancy and Breastfeeding
There is limited clinical data on the use of Natpar during pregnancy. Animal studies have shown that parathyroid hormone can cross into breast milk in rats, but it is unknown whether this also occurs in humans. If you are pregnant, breastfeeding, think you may be pregnant, or are planning to have a baby, you should consult your doctor before using Natpar.
Your healthcare provider will carefully weigh the benefits and risks before deciding whether to initiate or continue Natpar treatment during pregnancy or breastfeeding. The effects of Natpar on human fertility are not known. Women of childbearing potential should discuss contraception and family planning with their doctor before starting treatment.
Children and Adolescents
Natpar is not approved for use in children or adolescents under 18 years of age. The safety and efficacy of Natpar in the pediatric population have not been established. Hypoparathyroidism in children is typically managed with calcium and active vitamin D supplementation under the supervision of a pediatric endocrinologist.
Driving and Operating Machinery
Natpar itself does not directly affect the ability to drive or use machines. However, hypoparathyroidism can impair concentration, and fluctuations in blood calcium levels during treatment may also affect alertness. Patients should not drive or operate machinery if their concentration is impaired, and should wait until their condition is stable.
How Does Natpar Interact with Other Drugs?
Drug interactions with Natpar primarily involve medications that affect calcium metabolism or whose effects are influenced by calcium levels. Before starting Natpar, it is essential to inform your healthcare provider about all medications you are currently taking, have recently taken, or might take, including over-the-counter products and dietary supplements.
Major Interactions
The following drug interactions are considered clinically significant and require careful monitoring or dose adjustments when used concurrently with Natpar:
| Drug | Interaction | Clinical Significance |
|---|---|---|
| Digoxin (Digitalis) | Natpar raises blood calcium, which increases sensitivity to digoxin's cardiac effects | Risk of cardiac arrhythmias; digoxin levels and ECG may need closer monitoring |
| Lithium | Lithium can affect parathyroid hormone secretion and calcium metabolism | Combined use may lead to unpredictable calcium levels; frequent monitoring required |
Minor Interactions
The following interactions are generally manageable but should be discussed with your healthcare provider:
| Drug | Interaction | Clinical Significance |
|---|---|---|
| Bisphosphonates (e.g. alendronic acid) | Bisphosphonates inhibit bone resorption, which may partially counteract PTH effects on bone | May reduce the bone-related effects of Natpar; clinical response should be monitored |
| Thiazide diuretics | Thiazides reduce urinary calcium excretion, potentially amplifying the hypercalcemic effect of Natpar | Increased risk of hypercalcemia; calcium levels should be monitored more frequently |
| Calcium supplements | Natpar reduces the need for supplemental calcium; doses typically require downward adjustment | Dose of calcium supplements usually reduced during Natpar therapy; guided by blood calcium levels |
| Active Vitamin D (calcitriol, alfacalcidol) | Natpar may reduce the need for active vitamin D; combined use can increase hypercalcemia risk | Active vitamin D dose typically reduced or discontinued under medical supervision |
What Is the Correct Dosage of Natpar?
Natpar dosing is highly individualized and based on regular monitoring of blood calcium levels. The medication is administered as a once-daily subcutaneous injection using a reusable pen device. Your doctor and nurse will provide detailed training on how to prepare and inject the medication before you begin self-administration at home.
Adults
Standard Adult Dosing
Starting dose: 50 micrograms once daily subcutaneously. However, your doctor may start you at 25 micrograms per day based on your baseline blood calcium levels and clinical assessment.
Dose titration: After 2 to 4 weeks, your doctor may adjust the dose upward or downward in increments of 25 micrograms based on your blood calcium response.
Maintenance dose range: 25 to 100 micrograms once daily. The optimal dose varies from patient to patient and is determined by achieving stable blood calcium levels within the target range.
Administration site: Inject subcutaneously in the thigh. Alternate between left and right thigh each day.
| Strength | Cartridge Color | Doses per Cartridge | Volume per Dose |
|---|---|---|---|
| 25 micrograms/dose | Purple | 14 doses | 71.4 microlitres |
| 50 micrograms/dose | Red | 14 doses | 71.4 microlitres |
| 75 micrograms/dose | Grey | 14 doses | 71.4 microlitres |
| 100 micrograms/dose | Blue | 14 doses | 71.4 microlitres |
Children
Natpar is not approved for use in children or adolescents under 18 years of age. There are no established pediatric dosing recommendations. Hypoparathyroidism in children should be managed by a pediatric endocrinologist using conventional calcium and active vitamin D supplementation.
Elderly
No specific dose adjustments are recommended for elderly patients. However, as older adults may have reduced renal function and be more susceptible to calcium fluctuations, closer monitoring may be warranted. Dose titration should proceed cautiously, with frequent assessment of blood calcium, renal function, and overall clinical status.
Missed Dose
Take the injection as soon as you remember, but do not inject more than one dose on the same day. Take your next dose at the usual time the following day. You may need to take additional calcium supplements if you develop signs of low blood calcium (such as tingling, numbness, or muscle cramps). Never inject a double dose to compensate for a missed dose.
Overdose
If you accidentally inject more than one dose of Natpar in a day, contact your doctor or pharmacist immediately. Overdose may lead to hypercalcemia (high blood calcium), which can cause symptoms such as nausea, vomiting, dizziness, confusion, irregular heartbeat, and excessive thirst. Seek urgent medical attention if you experience these symptoms.
How to Use the Natpar Pen
Natpar is supplied as a powder in a cartridge that must be reconstituted (mixed) with a solvent before use. The reconstitution is performed using a mixing device provided with the medication. Once mixed, the cartridge is loaded into the reusable Natpar pen and can provide up to 14 daily doses. Key points for pen use include:
- Reconstitution: Mix the powder and solvent using the provided mixing device. Gently rock the cartridge side to side approximately 10 times — do not shake. Wait 5 minutes for the powder to dissolve completely.
- Inspection: Before each injection, check that the solution is clear, colorless, and free of visible particles. Small bubbles are normal. Do not use if the solution is cloudy, discolored, or contains particles.
- New needle daily: Attach a new disposable pen needle before each injection. Never reuse needles.
- Injection technique: Inject into the thigh, alternating between left and right thigh each day. After inserting the needle, press the injection button and hold the needle in place for at least 10 seconds to ensure the full dose is delivered.
- After injection: Carefully recap the needle using the scoop technique, remove and dispose of it in a sharps container. Replace the pen cap and store in the refrigerator.
What Are the Side Effects of Natpar?
Like all medicines, Natpar can cause side effects, although not everybody gets them. The most clinically significant side effects are related to changes in blood calcium levels, which require close medical supervision. Your doctor will monitor your calcium levels regularly to detect and manage these effects early.
Very common: High blood calcium (hypercalcemia) — more frequent when starting treatment. Symptoms may include nausea, vomiting, thirst, confusion, rapid heartbeat, and fatigue.
Very common: Low blood calcium (hypocalcemia) — more frequent if treatment is suddenly stopped. Symptoms may include tingling, numbness, muscle spasms, cramping, and seizures.
Very Common
- Headache
- Tingling and numbness in the skin (paresthesia)
- Diarrhea
- Nausea and vomiting
- Joint pain (arthralgia)
- Muscle spasms
- High blood calcium levels (hypercalcemia)
- Low blood calcium levels (hypocalcemia)
Common
- Feeling nervous or anxious
- Sleep problems (daytime drowsiness or difficulty sleeping at night)
- Rapid or irregular heartbeat (palpitations)
- High blood pressure (hypertension)
- Cough
- Abdominal (stomach) pain
- Muscle twitching or cramping
- Muscle pain (myalgia)
- Neck pain
- Pain in arms and legs
- Increased calcium in urine (hypercalciuria)
- Frequent urination
- Tiredness and lack of energy (fatigue)
- Chest pain
- Redness and pain at the injection site
- Excessive thirst
- Antibodies against Natpar (detected in blood tests)
- Decreased vitamin D and magnesium levels (seen in blood tests)
Reported (Unknown Frequency)
- Allergic reactions (hypersensitivity) — may include facial swelling, lip or tongue swelling, shortness of breath, itching, rash, or hives
- Seizures due to low blood calcium levels
In clinical studies, some side effects were associated with high calcium levels (such as headache, diarrhea, nausea, vomiting, rapid heartbeat, high blood pressure, stomach pain, tiredness, thirst, and chest pain) while others were associated with low calcium levels (such as tingling, numbness, muscle spasms, twitching, cough, anxiety, frequent urination, neck pain, arm and leg pain, decreased vitamin D and magnesium, and seizures). Your doctor will use blood tests to determine whether symptoms are related to calcium fluctuations.
If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed above. You can also report suspected side effects directly to your national medicines regulatory authority, which helps enable continuous monitoring of the benefit-risk balance of the medication.
How Should You Store Natpar?
Proper storage of Natpar is critical to maintaining the effectiveness and safety of the medication. Incorrect storage can degrade the parathyroid hormone, rendering the medication ineffective or potentially harmful. Follow these guidelines carefully:
Before Reconstitution (Unmixed)
- Store in a refrigerator at 2°C to 8°C.
- Do not freeze. Do not use a cartridge that has been frozen.
- Keep the cartridge in its holder inside the outer carton to protect from light.
- Check the expiry date (EXP) on the cartridge and carton before use. The expiry date refers to the last day of the stated month.
After Reconstitution (Mixed)
- Continue to store in a refrigerator at 2°C to 8°C.
- Do not freeze.
- Keep the pen containing the reconstituted cartridge properly closed and protected from light.
- Use within 14 days of reconstitution. Discard the cartridge after 14 days even if medication remains.
- Do not use the medication if it has not been stored correctly.
Check that the solution is clear, colorless, and free from visible particles before attaching a new needle. Small bubbles are normal. If the solution appears cloudy, colored, or contains particles, do not use it and contact your doctor, pharmacist, or nurse.
Keep this medicine out of the sight and reach of children. Do not dispose of medicines via household waste. Ask your pharmacist about how to properly dispose of medicines that are no longer needed, as these measures help to protect the environment.
What Does Natpar Contain?
Natpar is supplied as a two-component system within a single glass cartridge: a freeze-dried powder containing the active ingredient and a liquid solvent. These must be mixed together (reconstituted) before the medication can be injected. Understanding the composition helps patients identify potential allergens and ensures informed consent for treatment.
Active Ingredient
The active substance is parathyroid hormone (rDNA), a synthetic version of the full-length 84-amino-acid human parathyroid hormone produced using recombinant DNA technology in Escherichia coli. It is biologically identical to the natural hormone produced by the parathyroid glands.
Inactive Ingredients
In the powder:
- Sodium chloride (stabilizer)
- Mannitol (bulking agent)
- Citric acid monohydrate (buffering agent)
- Sodium hydroxide (for pH adjustment)
In the solvent:
- Metacresol (preservative)
- Water for injections
Natpar contains less than 1 mmol (23 mg) sodium per dose, meaning it is essentially sodium-free. This is relevant for patients on sodium-restricted diets.
Packaging and Appearance
Each Natpar cartridge contains a white to off-white powder and a clear solvent within a glass cartridge sealed with a rubber closure. The cartridge is enclosed in a plastic holder. Natpar is available in packs containing 2 cartridges in holders. The cartridge color indicates the strength:
- Purple cartridge — 25 micrograms per dose
- Red cartridge — 50 micrograms per dose
- Grey cartridge — 75 micrograms per dose
- Blue cartridge — 100 micrograms per dose
The reusable Natpar pen can be used for up to 2 years. Pen needles, alcohol swabs, and sharps disposal containers are not included in the Natpar packaging and must be obtained separately. Always use the pen needles recommended by your healthcare provider.
Frequently Asked Questions About Natpar
Medical References
This article is based on the following peer-reviewed sources and international guidelines:
- European Medicines Agency (EMA). Natpar Summary of Product Characteristics. Last updated December 2023. Available at: EMA — Natpar EPAR.
- 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(4):275-283. doi:10.1016/S2213-8587(13)70106-2.
- Brandi ML, Bilezikian JP, Shoback D, et al. Management of Hypoparathyroidism: Summary Statement and Guidelines. J Clin Endocrinol Metab. 2016;101(6):2273-2283. doi:10.1210/jc.2015-3907.
- Bollerslev J, Rejnmark L, Marcocci C, et al. European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults. Eur J Endocrinol. 2015;173(2):G1-G20. doi:10.1530/EJE-15-0628.
- Khan AA, Koch CA, Van Uum S, et al. Standards of care for hypoparathyroidism in adults: a Canadian and international consensus. Eur J Endocrinol. 2019;180(3):P1-P22. doi:10.1530/EJE-18-0609.
- Shoback DM, Bilezikian JP, Costa AG, et al. Presentation of Hypoparathyroidism: Etiologies and Clinical Features. J Clin Endocrinol Metab. 2016;101(6):2300-2312. doi:10.1210/jc.2015-3909.
- World Health Organization (WHO). WHO Model List of Essential Medicines. 23rd list, 2023.
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