- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1.NAME OF THE MEDICINAL PRODUCT
Natpar 25 micrograms/dose powder and solvent for solution for injection
Natpar 50 micrograms/dose powder and solvent for solution for injection
Natpar 75 micrograms/dose powder and solvent for solution for injection
Natpar 100 micrograms/dose powder and solvent for solution for injection
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Natpar 25 micrograms
Each dose contains 25 micrograms parathyroid hormone (rDNA)* in 71.4 microlitre solution following reconstitution.
Each cartridge contains 350 micrograms parathyroid hormone (rDNA).
Natpar 50 micrograms
Each dose contains 50 micrograms parathyroid hormone (rDNA) in 71.4 microlitre solution following reconstitution.
Each cartridge contains 700 micrograms parathyroid hormone (rDNA).
Natpar 75 micrograms
Each dose contains 75 micrograms parathyroid hormone (rDNA) in 71.4 microlitre solution following reconstitution.
Each cartridge contains 1050 micrograms parathyroid hormone (rDNA).
Natpar 100 micrograms
Each dose contains 100 micrograms parathyroid hormone (rDNA) in 71.4 microlitre solution following reconstitution.
Each cartridge contains 1400 micrograms parathyroid hormone (rDNA).
*Parathyroid hormone (rDNA), produced in E. coli using recombinant DNA technology, is identical to the 84 amino acid sequence of endogenous human parathyroid hormone.
Excipient(s) with known effect
Each dose contains 0.32 mg of sodium.
For the full list of excipients, see section 6.1.
Powder and solvent for solution for injection.
The powder is white and the solvent is a clear, colourless solution.
Natpar is indicated as adjunctive treatment of adult patients with chronic hypoparathyroidism who cannot be adequately controlled with standard therapy alone.
4.2Posology and method of administration
Treatment should be supervised by a physician or other qualified healthcare professional experienced in the management of patients with hypoparathyroidism.
The goal of treatment with Natpar is to achieve calcaemic control and to reduce symptoms (see also section 4.4). The optimisation of parameters of
Prior to initiating and during treatment with Natpar:
•Confirm serum magnesium is within the reference range.
1.Initiate treatment with 50 micrograms once daily as a subcutaneous injection in the thigh (alternate thigh every day). If
2.In patients using active vitamin D, decrease the dose of active vitamin D by 50%, if
3.In patients using calcium supplements, maintain calcium supplement dose.
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 hypocalcaemia or hypercalcaemia). Suggested adjustments to Natpar, active vitamin D and calcium supplements based on serum calcium levels are provided below:
Active vitamin D
Above the upper limit
Consider reducing or
stopping Natpar and
of normal (ULN)
No change, or decrease
2.25 mmol/L and
if active vitamin D was
below the upper limit of
normal (2.55 mmol/L)*
before this titration step
Less than or equal to
2.25 mmol/L and
above 2 mmol/L
Consider increase after
Lower than 2 mmol/L
*The value of ULN may vary by laboratory
**Discontinue in patients receiving the lowest available dose
6.Repeat steps 4 and 5 until target
Natpar dosage adjustments after the initiation period
Serum calcium concentration must be monitored during titration (see section 4.4).
The dose of Natpar may be increased by 25 microgram increments approximately every 2 to 4 weeks, up to a maximum daily dose of 100 micrograms. Downward titration to a minimum of 25 micrograms can occur at any time.
It is recommended to measure the
At any dose level of Natpar, if
In the case of a missed dose, Natpar must be administered as soon as reasonably feasible and additional exogenous sources of calcium and/or active vitamin D must be taken based on symptoms of hypocalcaemia.
Interruption or discontinuation of treatment
Abrupt interruption or discontinuation of Natpar can result in severe hypocalcaemia. Temporary or permanent discontinuation of Natpar treatment must be accompanied by monitoring of serum calcium levels and adjustment, as necessary, of exogenous calcium and/or active vitamin D (see section 4.4).
See section 5.2.
No dose adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance 30 to 80 mL/min). There are no data available in patients with severe renal impairment (see section 4.4).
No dose adjustment is necessary for patients with mild or moderate hepatic impairment (total score of 7 to 9 on the
The safety and efficacy of Natpar in children less than 18 years of age have not yet been established. No data are available.
Method of administration
Natpar is suitable for patient
Each dose must be administered as a subcutaneous injection once a day in alternating thighs.
- Preotact - parathyroid hormone (rdna)
Prescription drugs listed. Substance: "Parathyroid hormone"
For instructions on reconstitution of the medicinal product before administration and for using the pen injector, see section 6.6 and the instructions included with the package leaflet.
Natpar must not be administered intravenously or intramuscularly.
Natpar is contraindicated in patients:
-with hypersensitivity to the active substance or to any of the excipients listed in section 6.1
-who are receiving or who have previously received radiation therapy to the skeleton
-with skeletal malignancies or bone metastases
-who are at increased baseline risk for osteosarcoma such as patients with Paget’s disease of bone or hereditary disorders
-with unexplained elevations of
4.4Special warnings and precautions for use
It is strongly recommended that every time Natpar is administered to a patient, the name and lot number of the product are recorded in order to maintain a link between the patient and the lot of the product.
The aim of treatment with Natpar is to achieve a
Monitoring of patients during treatment
Hypercalcaemia was reported in clinical trials with Natpar. Hypercalcaemia commonly occurred during the titration period, during which doses of oral calcium, active vitamin D, and Natpar were being adjusted. Hypercalcaemia may be minimised by following the recommended dosing, the monitoring information, and asking patients about any symptoms of hypercalcaemia. If severe hypercalcaemia (>3.0 mmol/L or above upper limit of normal with symptoms) develops, hydration and temporarily stopping Natpar, calcium and active vitamin D should be considered until serum calcium returns to the normal range. Then consider resuming Natpar, calcium and active vitamin D at lower doses (see sections 4.2 and 4.8).
Hypocalcaemia, a common clinical manifestation of hypoparathyroidism, was reported in clinical trials with Natpar. Most of the hypocalcaemic events occurring in the clinical trials were mild to moderate in severity. The risk for serious hypocalcaemia was greatest after the withdrawal of Natpar. Temporary or permanent discontinuation of Natpar must be accompanied by monitoring of serum calcium levels and increase of exogenous calcium and/or active vitamin D sources as necessary. Hypocalcaemia may be minimised by following the recommended dosing, the monitoring information, and asking patients about any symptoms of hypocalcaemia (see sections 4.2 and 4.8).
Concomitant use with cardiac glycosides
Hypercalcaemia of any cause may predispose to digitalis toxicity. In patients using Natpar concomitantly with cardiac glycosides (such as digoxin or digitoxin), monitor serum calcium and cardiac glycoside levels and patients for signs and symptoms of digitalis toxicity (see section 4.5).
Severe renal or hepatic disease
Natpar should be used with caution in patients with severe renal or hepatic disease because they have not been evaluated in clinical trials.
Use in young adults
Natpar should be used with caution in young adult patients with open epiphyses as these patients may be at increased risk for osteosarcoma (see section 4.3).
Use in elderly patients
Clinical studies of Natpar did not include sufficient numbers of subjects aged 65 and over to determine whether response in these subjects is different from younger subjects.
If serum concentration of
4.5Interaction with other medicinal products and other forms of interaction
The inotropic effects of cardiac glycosides are affected by serum calcium levels. Combined use of Natpar and cardiac glycosides (e.g., digoxin or digitoxin) may predispose patients to digitalis toxicity if hypercalcaemia develops. No
For any drug that affects serum calcium levels (e.g., lithium, thiazides), patients’ serum calcium levels should be monitored.
Natpar is a protein that is not metabolised by and does not inhibit hepatic microsomal
4.6Fertility, pregnancy and lactation
There are no data from the use of Natpar in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
A risk to the pregnant woman or developing foetus cannot be excluded. A decision must be made whether to initiate or discontinue treatment with Natpar during pregnancy taking into account the known risks of therapy versus the benefit for the woman.
It is unknown whether Natpar is excreted in human milk.
Available pharmacology data in animals have shown excretion of Natpar in milk (see section 5.3).
A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue
There are no data on the effects of Natpar on human fertility. Animal data do not indicate any impairment of fertility.
4.7Effects on ability to drive and use machines
Natpar has no or negligible influence on the ability to drive and use machines. Since neurologic symptoms may be a sign of uncontrolled hypoparathyroidism, patients with disturbances in cognition or attention should be advised to refrain from driving or using machines until symptoms have subsided.
Summary of the safety profile
The most frequent adverse reactions among patients treated with Natpar were hypercalcaemia, hypocalcaemia, and their associated clinical manifestations including headache, diarrhoea, vomiting, paraesthesia, hypoaesthesia and hypercalciuria. In the clinical studies, these reactions were generally mild to moderate in severity and transient, and were managed with adjustments of Natpar, calcium and/or active vitamin D doses (see sections 4.4 and 5.1).
Tabulated list of adverse reactions
Adverse reactions for
System organ class
Very common (≥1/10)
Common (≥1/100 to <1/10)
Metabolism and nutrition
Nervous system disorders
Respiratory, thoracic and
diarrhoea*,†, nausea*, vomiting*
abdominal pain upper*
Musculoskeletal and connective
arthralgia*, muscle spasms†
musculoskeletal pain†, myalgia†,
neck pain†, pain in extremity
Renal and urinary disorders
General disorders and
asthenia*, chest pain†, fatigue,
administration site conditions
injection site reactions, thirst*
decreased†, vitamin D decreased
*Signs and symptoms potentially associated with hypercalcaemia that were observed in the clinical trials.
†Signs and symptoms potentially associated with hypocalcaemia that were observed in the clinical trials.
Description of selected adverse reactions
Hypercalcaemia and hypocalcaemia were commonly encountered during the dose titration period. The risk for serious hypocalcaemia was greatest after the withdrawal of Natpar (see section 4.4).
Injection site reactions
Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of Natpar may trigger the development of antibodies. In the
8.8% (3/34) and 5.9% (1/17) in patients who received subcutaneous administration of 50 to 100 micrograms Natpar or placebo once daily for 24 weeks, respectively.
Across all clinical studies in patients with hypoparathyroidism following treatment with Natpar for up to 4 years, the immunogenicity incidence rate was 17/87 (19.5%) and did not appear to increase over time. These 17 patients had low titre
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Overdose can cause hypercalcaemia, the symptoms of which may include heart palpitations, ECG changes, hypotension, nausea, vomiting, dizziness and headache. Severe hypercalcaemia may be a
Pharmacotherapeutic group: Calcium homeostasis, parathyroid hormones and analogues, ATC code: H05AA03
Mechanism of action
Endogenous parathyroid hormone (PTH) is secreted by the parathyroid glands as a polypeptide of
84 amino acids. PTH exerts its action via
PTH has a variety of critical physiological functions that include its central role in modulating serum calcium and phosphate levels within tightly regulated levels, regulating renal calcium and phosphate excretion, activating vitamin D, and maintaining normal bone turnover.
Natpar is produced in E. coli using recombinant DNA technology, and is identical to the 84 amino acid sequence of endogenous human parathyroid hormone.
The overall effect of PTH is to increase serum calcium concentration, to reduce urinary excretion of calcium and to lower serum phosphate concentration.
Natpar has the same primary amino acid sequence as endogenous parathyroid hormone and may be anticipated to have the same physiological actions.
Clinical efficacy and safety
The safety and clinical efficacy of Natpar in adults with hypoparathyroidism is derived from
Study 1 – REPLACE
The objective of this trial was to maintain serum calcium with Natpar while reducing or replacing oral calcium and active vitamin D. The study was a
At randomisation, active forms of vitamin D were reduced by 50% and patients were allocated to Natpar 50 micrograms daily or placebo. Randomisation was followed by a
Ninety percent of patients who were randomised completed 24 weeks of treatment.
For the efficacy analysis, subjects that fulfilled three components of a
At the end of treatment, 46/84 (54.8%) patients treated with Natpar achieved the primary endpoint versus 1/40 (2.5%) with placebo (p<0.001).
At Week 24, for patients who completed the study, 34/79 (43%) Natpar patients were independent of active vitamin D treatment and were receiving no more than 500 mg of calcium citrate, compared with 2/33 (6.1%) placebo patients (p<0.001).
6.5% (SD 38.5) in the placebo group (p<0.001). In addition, 87% (73/84) of patients treated with
Natpar showed a ≥50% reduction in oral active vitamin D versus 45% (18/40) in the placebo group.
Study 2 – RACE
Study 2 is a
A total of 49 patients were enrolled in the study. Patients received doses of 25 micrograms,
50 micrograms, 75 micrograms or 100 micrograms/day for up to approximately 40 months (mean 1067 days, range 41 to 1287 days).
The results demonstrate durability of the physiological effects of Natpar over 36 months including maintenance of mean
The European Medicines Agency has deferred the obligation to submit the results of studies with Natpar in one or more subsets of the paediatric population in hypoparathyroidism (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a
The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
The pharmacokinetics of Natpar following subcutaneous administration in the thigh of hypoparathyroidism subjects was consistent with that observed in healthy
Natpar administered subcutaneously had an absolute bioavailability of 53%.
Following intravenous administration, Natpar has a volume of distribution of 5.35 L at steady state.
In vitro and in vivo studies demonstrated that the clearance of Natpar is primarily a hepatic process with a lesser role played by the kidneys.
In the liver, parathyroid hormone is cleaved by cathepsins. In the kidney, parathyroid hormone and
Parathyroid hormone (rDNA) was evaluated in an
Peak plasma concentrations (mean Tmax) of Natpar occur within 5 to 30 minutes and a second usually smaller peak at 1 to 2 hours. The apparent terminal
50 and 100 micrograms dose, respectively. The maximum mean increases of serum calcium, which occurred at 12 hours, were approximately 0.125 mmol/L and 0.175 mmol/L with the 50 micrograms and 100 micrograms dose, respectively.
Effect on mineral metabolism
Treatment with Natpar increases serum calcium concentration in hypoparathyroidism patients, and this increase occurs in a
Urinary calcium excretion
Treatment with Natpar produces a decrease in urinary calcium excretion by 13 and 23% (50 and
100 microgram dose, respectively) to a nadir in the 3 to 6 hour time point, which returns to
Following injection with Natpar, serum phosphate levels decrease proportionally to
Active vitamin D
A pharmacokinetic study in
Pharmacokinetics following a single 100 micrograms subcutaneous dose of Natpar was evaluated in 16
impairment. The mean maximum concentration (Cmax) of PTH following 100 micrograms parathyroid hormone (rDNA) in subjects with
as measured by
Based on these results, no dose adjustment is necessary in patients with
Pharmacokinetic data in paediatric patients are not available.
- Preotact - H05AA03
Prescription drugs listed. ATC Code: "H05AA03"
Clinical studies with Natpar did not include sufficient numbers of subjects aged 65 and over to determine whether response in these subjects is different from younger subjects.
No clinically relevant gender differences were observed in the REPLACE study.
No dose adjustment is necessary based on weight.
5.3Preclinical safety data
Rats treated with daily injections of Natpar for 2 years had
Natpar did not adversely affect fertility or early embryonic development in rats,
In monkeys receiving daily subcutaneous doses for 6 months, there was an increased occurrence of renal tubular mineralisation at exposure levels 2.7 times the clinical exposure levels at the highest dose.
6.1List of excipients
Citric acid monohydrate
Sodium hydroxide (for pH adjustment)
Water for injections
This medicinal product must not be mixed with other medicinal products.
After reconstitution, chemical and physical
Keep the pen containing a reconstituted cartridge tightly closed in order to protect from light.
6.4Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze.
Keep the cartridge within its cartridge holder in the outer carton in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5Nature and contents of container
Natpar 25 micrograms
Each cartridge in the purple cartridge holder contains 350 micrograms of parathyroid hormone (rDNA) as powder in the first chamber and 1000 microlitres of solvent in the second chamber (corresponding to 14 doses).
Natpar 50 micrograms
Each cartridge in the red cartridge holder contains 700 micrograms of parathyroid hormone (rDNA) as powder in the first chamber and 1000 microlitres of solvent in the second chamber (corresponding to 14 doses).
Natpar 75 micrograms
Each cartridge in the grey cartridge holder contains 1050 micrograms of parathyroid hormone (rDNA) as powder in the first chamber and 1000 microlitres of solvent in the second chamber (corresponding to 14 doses).
Natpar 100 micrograms
Each cartridge in the blue cartridge holder contains 1400 micrograms of parathyroid hormone (rDNA) as powder in the first chamber and 1000 microlitres of solvent in the second chamber (corresponding to 14 doses).
Pack size: Carton containing 2 cartridges.
Carton/cartridge colours are used to indicate the different strengths:
25 micrograms – Purple
50 micrograms – Red
75 micrograms – Grey
100 micrograms – Blue
6.6Special precautions for disposal and other handling
Parathyroid hormone (rDNA) is injected using the cartridge with a reusable pen. Each pen must be used by only one patient. A new sterile needle must be used for every injection. Use 31 G x 8 mm pen needles. After reconstitution, the liquid must be colourless and practically free of foreign particles; parathyroid hormone (rDNA) must not be used if the reconstituted solution is cloudy, coloured, or contains visible particles.
DO NOT SHAKE during or after reconstitution; shaking may cause denaturation of the active substance.
Read the instructions for use provided in the package leaflet before using the reusable pen.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.MARKETING AUTHORISATION HOLDER
Shire Pharmaceuticals Ireland Limited
Citywest Business Campus
8.MARKETING AUTHORISATION NUMBER(S)
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 24 April 2017