Natpar

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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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. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for solution for injection. 
 
The powder is white and the solvent is a clear, colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Natpar is indicated as adjunctive treatment of adult patients with chronic hypoparathyroidism who 
cannot be adequately controlled with standard therapy alone. 
 



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4.2 Posology and method of administration 
 
General 
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 calcium-phosphate metabolism should be in line with 
current therapeutic guidelines for the treatment of hypoparathyroidism. 
 
Prior to initiating and during treatment with Natpar: 

• Confirm 25-OH vitamin D stores are sufficient. 
• Confirm serum magnesium is within the reference range. 

 
Posology 
 
Initiating Natpar 
1. Initiate treatment with 50 micrograms once daily as a subcutaneous injection in the thigh 

(alternate thigh every day). If pre-dose serum calcium is >2.25 mmol/L, a starting dose of 
25 micrograms can be considered. 

2. In patients using active vitamin D, decrease the dose of active vitamin D by 50%, if pre-dose 
serum calcium is above 1.87 mmol/L. 

3. In patients using calcium supplements, maintain calcium supplement dose. 
4. Measure pre-dose serum calcium concentration within 2 to 5 days. If pre-dose serum calcium is 

below 1.87 mmol/L or above 2.55 mmol/L, this measurement should be repeated the following 
day. 

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: 

 

 
6. Repeat steps 4 and 5 until target pre-dose serum calcium concentration is within the range of 

2.0-2.25 mmol/L, active vitamin D has been discontinued and calcium supplementation is 
sufficient to meet daily requirements. 

 

 Adjust first Adjust second Adjust third 
Pre-dose serum 
calcium 

Natpar Active vitamin D 
forms 

Calcium supplement 

Above the upper limit 
of normal (ULN) 
(2.55 mmol/L)* 

Consider reducing or 
stopping Natpar and 
re-assess by means of 

serum calcium 
measurement 

Decrease or 
discontinue** Decrease 

Greater than 
2.25 mmol/L and 
below the upper limit of 
normal (2.55 mmol/L)* 

Consider reduction 
Decrease or 

discontinue** 

No change, or decrease 
if active vitamin D was 
already discontinued 

before this titration step 
Less than or equal to 
2.25 mmol/L and 
above 2 mmol/L  

No change 
No change No change 

Lower than 2 mmol/L 
Consider increase after 
at least 2-4 weeks at a 

stable dose 
Increase Increase 

 *The value of ULN may vary by laboratory 
**Discontinue in patients receiving the lowest available dose 



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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 albumin-corrected serum calcium 8-12 hours after dosing Natpar. If 
post-dose serum calcium is >ULN, then first reduce active vitamin D and calcium supplements and 
monitor progress. Measurements of pre- and post-dose serum calcium should be repeated and 
confirmed to be within an acceptable range before titration to a higher dose of Natpar is considered. If 
post-dose serum calcium remains >ULN, oral calcium supplementation should be further reduced or 
discontinued (see also adjustment table under Initiating Natpar). 
 
At any dose level of Natpar, if post-dose albumin-corrected serum calcium exceeds the ULN and all 
active vitamin D and oral calcium have been withheld, or symptoms suggesting hypercalcaemia are 
present, the dose of Natpar should be reduced (see section 4.4). 
 
Missed dose 
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). 
 
Special populations 
Elderly 
See section 5.2. 
 
Renal impairment 
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). 
 
Hepatic impairment 
No dose adjustment is necessary for patients with mild or moderate hepatic impairment (total score 
of 7 to 9 on the Child-Pugh scale). There are no data available in patients with severe hepatic 
impairment (see section 4.4). 
 
Paediatric population 
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 self-administration. Patients must be trained on the proper injection 
techniques by the prescriber or nurse, in particular during initial use. 
 
Each dose must be administered as a subcutaneous injection once a day in alternating thighs. 
 
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. 
 



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4.3 Contraindications 
 
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 bone-specific alkaline phosphatase 
- with pseudohypoparathyroidism. 
 
4.4 Special warnings and precautions for use 
 
Traceability 
In order to improve the traceability of biological medicinal products, the name and batch number of 
the administered product should be clearly recorded. 
 
The aim of treatment with Natpar is to achieve a pre-dose serum calcium concentration of 
2.0-2.25 mmol/L and an 8-12 hour post-dose serum calcium concentration <2.55 mmol/L. 
 
Monitoring of patients during treatment 
Pre-dose and in some cases post-dose serum calcium levels must be monitored during treatment with 
Natpar (see section 4.2). In a multi-centre clinical trial, albumin-corrected serum calcium (ACSC) 
values 6-10 hours post-dose were on average 0.25 mmol/L higher than the pre-dose values, with a 
maximum increase observed of 0.7 mmol/L. Calcium, vitamin D, or Natpar doses may need to be 
reduced if post-dose hypercalcaemia is observed, even if pre-dose calcium concentrations are 
acceptable (see section 4.2). 
 
Hypercalcaemia 
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 
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. In the post-marketing setting, cases of symptomatic hypocalcaemia, including 
cases that resulted in seizures, have been reported in patients being treated with Natpar. The risk for 
serious hypocalcaemia is highest after Natpar is withheld, missed or abruptly discontinued, but can 
occur at any time. 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). 
 



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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. 
 
Tachyphylaxis 
The calcium-raising effect of Natpar may diminish over time in some patients. The response of serum 
calcium concentration to administration of Natpar should be monitored at intervals to detect this and 
the diagnosis of tachyphylaxis considered. 
 
If serum concentration of 25-OH vitamin D is low then appropriate supplementation may restore 
serum calcium response to Natpar (see section 4.2). 
 
Urolithiasis 
Natpar has not been studied in patients with urolithiasis. Natpar should be used with caution in 
patients with active or recent urolithiasis because of the potential to exacerbate this condition. 
 
Hypersensitivity 
There have been post-marketing reports of hypersensitivity reactions in patients taking Natpar. 
Hypersensitivity reactions can include anaphylaxis, dyspnoea, angioedema, urticaria, rash, etc. If signs 
or symptoms of a serious hypersensitivity reaction occur, treatment with Natpar should be 
discontinued and hypersensitivity reaction should be treated according to the standard of care. Patients 
should be monitored until signs and symptoms resolve (see sections 4.3 and 4.8). If Natpar is to be 
discontinued, monitoring for hypocalcaemia is necessary (see section 4.2). 
 
4.5 Interaction 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 drug-drug interaction study has been conducted with cardiac 
glycosides and Natpar (see section 4.4). 
 
For any drug that affects serum calcium levels (e.g., lithium, thiazides), patients’ serum calcium levels 
should be monitored. 
 
Co-administration of alendronic acid and Natpar may lead to a reduction in the calcium sparing effect, 
which can interfere with the normalisation of serum calcium. Concomitant use of Natpar with 
bisphosphonates is not recommended. 
 
Natpar is a protein that is not metabolised by and does not inhibit hepatic microsomal 
drug-metabolising enzymes (e.g., cytochrome P450 isoenzymes). Natpar is not protein bound and has 
a low volume of distribution. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
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). 
 



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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. 
 
Breast-feeding 
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 
breast-feeding or to discontinue therapy with Natpar, taking into account the benefit of breast-feeding 
for the child and the benefit of therapy for the woman. 
 
Fertility 
There are no data on the effects of Natpar on human fertility. Animal data do not indicate any 
impairment of fertility. 
 
4.7 Effects 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. 
 
4.8 Undesirable effects 
 
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 Natpar-treated patients in the placebo-controlled study and in post-marketing 
experience are listed below by MedDRA system organ class and frequency. Frequencies are defined as 
very common (≥1/10), common (≥1/100 to <1/10), and not known (cannot be estimated from the 
available data). All adverse reactions identified in post-marketing experience are italicised. 
 
System organ class Very common (≥1/10) Common (≥1/100 to 

<1/10) 
Not known (cannot be 
estimated from the 
available data) 

Immune system 
dysorders 

  Hypersensitivity 
reactions, (dyspnoea, 
angioedema, urticaria, 
rash) 

Metabolism and 
nutrition disorders 

hypercalcaemia, 
hypocalcaemia 

hypomagnesaemia†, 
tetany† 

 

Psychiatric disorders  anxiety†, insomnia*  
Nervous system 
disorders 

headache*,†, 
hypoaesthesia†, 
paraesthesia† 

somnolence*  

Cardiac disorders  palpitations*,†  
Vascular disorders  hypertension*  
Respiratory, thoracic 
and mediastinal 

 cough†  



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disorders 
Gastrointestinal 
disorders 

diarrhoea*,†, nausea*, 
vomiting* 

abdominal pain upper*  

Musculoskeletal and 
connective tissue 
disorders 

arthralgia*, muscle 
spasms† 

muscle twitching†, 
musculoskeletal pain†, 
myalgia†, neck pain†, 
pain in extremity 

 

Renal and urinary 
disorders 

 hypercalciuria*, 
pollakiuria† 

 

General disorders and 
administration site 
conditions 

 asthenia*, chest pain†, 
fatigue, injection site 
reactions, thirst* 

 

Investigations  anti-PTH antibody 
positive, blood 
25-hydroxycholecalcif
erol 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. Cases of hypocalcaemia 
resulting in seizures have been reported post-marketing (see section 4.4). 
 
Injection site reactions 
In the placebo-controlled study, 9.5% (8/84) Natpar-treated patients and 15% (6/40) placebo-treated 
patients experienced an injection site reaction, all of which were mild or moderate in severity. 
 
Immunogenicity 
Consistent with the potentially immunogenic properties of medicinal products containing peptides, 
administration of Natpar may trigger the development of antibodies. In the placebo-controlled study in 
adults with hypoparathyroidism, the incidence of anti-parathyroid hormone (PTH) antibodies was 
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 anti-PTH antibodies and, of these, 3 subsequently became 
antibody negative. The apparent transient nature of antibodies to PTH is likely due to the low titre. 
Three of these patients had antibodies with neutralising activity; these patients maintained a clinical 
response with no evidence of immune-related adverse reactions. 
 
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. 
 
4.9 Overdose 
 
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 
life-threatening condition requiring urgent medical care and careful monitoring (see section 4.4). 
 
 



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5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
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 cell-surface parathyroid hormone receptors, present in bone, 
kidney and nerve tissue. Parathyroid hormone receptors belong to the family of G-coupled protein 
receptors. 
 
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. 
 
Pharmacodynamic effects 
PTH (1-84) is the principal regulator of plasma calcium homeostasis. In the kidney, PTH (1-84) 
increases renal tubular reabsorption of calcium and promotes phosphate excretion. 
 
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 
1 randomised, placebo-controlled study and an open-label extension study. In these studies, Natpar 
was self-administered, with daily doses ranging from 25 to 100 micrograms per subcutaneous 
injection. 
 
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 24-week, randomised, double-blind, 
placebo-controlled, multicentre trial. In this trial, patients with chronic hypoparathyroidism receiving 
calcium and active forms of vitamin D (vitamin D metabolite or analogues) were randomised to 
Natpar (n=84) or placebo (n=40). The mean age was 47.3 years (range 19 to 74 years); 79% were 
females. Patients had hypoparathyroidism for an average of 13.6 years. 
 
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 12-week Natpar titration 
phase and a 12-week Natpar dose maintenance phase. 
 
Ninety percent of patients who were randomised completed 24 weeks of treatment. 
 
For the efficacy analysis, subjects that fulfilled three components of a three-part response criterion 
were considered responders. A responder was defined using a composite primary efficacy endpoint of 
at least a 50% reduction from the baseline active vitamin D dose AND at least a 50% reduction from 
the baseline oral calcium AND an albumin-corrected total serum calcium concentration maintained or 
normalised compared with the baseline value (≥1.875 mmol/L) and did not exceed the upper limit of 
the laboratory normal range. 
 



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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). 
 
Sixty-nine percent (58/84) of subjects randomised to Natpar showed a reduction in oral calcium of 
≥50% compared to 7.5% (3/40) of subjects randomised to placebo. The mean percent change from 
baseline in oral calcium was -51.8% (SD 44.6) in subjects receiving Natpar compared to 
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 long-term, open-label extension study of daily subcutaneous dosing of Natpar in 
hypoparathyroidism patients who completed prior studies with Natpar. 
 
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 60 months (mean 
1161 days, range 41 to 1820 days). 
 
The results demonstrate durability of the physiological effects of Natpar over 60 months including 
maintenance of mean albumin-corrected serum calcium levels (n=49, 2.11 ±0.19 mmol/L), a decrease 
from baseline in urinary calcium excretion (n=47, -2.23 ±5.9 mmol/24 h), a decrease in serum 
phosphate (n=49, -0.29 ±0.28 mmol/L) and the maintenance of normal calcium phosphate product 
(n=49, <4.4mmol2/L2). 
 
Paediatric population 
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 so-called ‘conditional approval’ scheme. This 
means that further evidence on this medicinal product is awaited. 
 
The European Medicines Agency will review new information on this medicinal product at least every 
year and this SmPC will be updated as necessary. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of Natpar following subcutaneous administration in the thigh of 
hypoparathyroidism subjects was consistent with that observed in healthy post-menopausal women 
who received parathyroid hormone in the thigh and abdomen. 
 
Absorption 
Natpar administered subcutaneously had an absolute bioavailability of 53%. 
 
Distribution 
Following intravenous administration, Natpar has a volume of distribution of 5.35 L at steady state. 
 
Biotransformation 
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. 
 
Elimination 
In the liver, parathyroid hormone is cleaved by cathepsins. In the kidney, parathyroid hormone and 
C-terminal fragments are cleared by glomerular filtration. 



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Pharmacokinetic/pharmacodynamic relationship 
Parathyroid hormone (rDNA) was evaluated in an open-label PK/PD study in which 7 patients with 
hypoparathyroidism received single subcutaneous doses of 50 and 100 micrograms with a 7-day 
washout interval between doses. 
 
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 half-life (t1/2) was 3.02 and 2.83 hours for the 
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 dose-related manner. After a single injection of parathyroid hormone (rDNA), the 
mean serum total calcium reached its peak level between 10 and 12 hours. The calcaemic response is 
sustained for more than 24 hours after administration. 
 
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 pre-dosing 
levels by 16 to 24 hours. 
 
Phosphate 
Following injection with Natpar, serum phosphate levels decrease proportionally to PTH(1-84) levels 
over the first 4 hours and persist over 24 hours post-injection. 
 
Active vitamin D 
Serum 1,25-(OH)2D increases following a single dose of Natpar to maximum levels at about 12 hours 
with a return to near baseline levels by 24 hours. A greater increase in the levels of 1,25-(OH)2D in 
serum were observed with the 50 micrograms dose than with the 100 micrograms dose, likely due to 
direct inhibition of the renal 25-hydroxyvitamin D-1-hydroxylase enzyme by serum calcium. 
 
Special populations 
 
Hepatic impairment 
A pharmacokinetic study in non-hypoparathyroidism subjects was conducted in 6 men and 6 women 
with moderate hepatic impairment (Child-Pugh Classification of 7-9 [Grade B]) as compared with a 
matched group of 12 subjects with normal hepatic function. Following a single 100 micrograms 
subcutaneous dose, the mean Cmax and baseline-corrected Cmax values were 18% to 20% greater in the 
moderately impaired subjects than in those with normal function. There were no apparent differences 
in the serum total calcium concentration-time profiles between the 2 hepatic function groups. No dose 
adjustment for Natpar is recommended in patients with mild to moderate hepatic impairment. There 
are no data in patients with severe hepatic impairment. 
 
Renal impairment 
Pharmacokinetics following a single 100 micrograms subcutaneous dose of Natpar was evaluated 
in 16 non-impaired subjects (creatinine clearance (CLcr) >80 mL/min) and 16 subjects with renal 
impairment. The mean maximum concentration (Cmax) of PTH following 100 micrograms parathyroid 
hormone (rDNA) in subjects with mild-to-moderate renal impairment (CLcr 30 to 80 mL/min) was 
approximately 23% higher than that observed in subjects with normal renal function. Exposure to PTH 
as measured by AUC0-last and baseline-corrected AUC0-last was approximately 3.9% and 2.5%, 
respectively, higher than that observed for subjects with normal renal function. 
 
Based on these results, no dose adjustment is necessary in patients with mild-to-moderate renal 
impairment (CLcr 30 to 80 mL/min). No studies were conducted in patients on renal dialysis. There are 
no data in patients with severe renal impairment. 



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Paediatric population 
Pharmacokinetic data in paediatric patients are not available. 
 
Elderly 
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. 
 
Gender 
No clinically relevant gender differences were observed in the REPLACE study. 
 
Weight 
No dose adjustment is necessary based on weight. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, mutagenicity, toxicity to fertility and general reproduction, and local tolerance. 
 
Rats treated with daily injections of Natpar for 2 years had dose-dependent exaggerated bone 
formation and an increased incidence of bone tumours, including osteosarcoma, most probably due to 
a non-genotoxic mechanism. Due to the differences in bone physiology in rats and humans, the 
clinical relevance of these findings is unknown. No osteosarcomas have been observed in clinical 
trials. 
 
Natpar did not adversely affect fertility or early embryonic development in rats, embryo-foetal 
development in rats and rabbits, or pre/post-natal development in rats. A minimal amount of Natpar is 
excreted in the milk of lactating 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. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Powder 
Sodium chloride 
Mannitol 
Citric acid monohydrate 
Sodium hydroxide (for pH adjustment) 
 
Solvent 
Metacresol 
Water for injections 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products. 
 
6.3 Shelf life 
 
3 years. 
 



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Reconstituted solution 
After reconstitution, chemical and physical in-use stability of the solution has been demonstrated for 
up to 14 days when stored in a refrigerator (2°C – 8°C) and for up to 3 days when stored outside the 
refrigerator not above 25°C during the 14-day use period. 
 
Keep the pen containing a reconstituted cartridge tightly closed in order to protect from light. 
 
6.4 Special 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. 
 
6.5 Nature and contents of container 
 
The glass dual-chamber cartridge inside the cartridge holder is made from type I glass with 
2 bromobutyl rubber stoppers and a crimp cap (aluminium) with a bromobutyl rubber seal. 
 
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 
 
6.6 Special 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. 
 



14 

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 
Block 2 & 3 Miesian Plaza 
50 – 58 Baggot Street Lower 
Dublin 2 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1078/001 
EU/1/15/1078/002 
EU/1/15/1078/003 
EU/1/15/1078/004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 24 April 2017 
Date of latest renewal: 29 April 2019 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 



15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE 
SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE 
FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
E. SPECIFIC OBLIGATION TO COMPLETE POST-

AUTHORISATION MEASURES FOR THE CONDITIONAL 
MARKETING AUTHORISATION 



16 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer(s) of the biological active substance(s) 
 
Boehringer Ingelheim RCV GmbH & Co KG 
Dr.-Boehringer-Gasse 5-11 
A-1121 Vienna 
Austria 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Shire Pharmaceuticals Ireland Limited 
Block 2 & 3 Miesian Plaza 
50 – 58 Baggot Street Lower 
Dublin 2 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 
6 months following authorisation. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
• Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measures: 
 



17 

Description Due date 
Non-interventional post-authorisation safety study (PASS): In order to 
collect long-term data on clinical efficacy and safety, the MAH should 
submit the results of a study based on data deriving from a registry of 
patients with hypoparathyroidism and who are treated with NATPAR. The 
MAH should collect data on clinical hard endpoints (bone, soft tissue 
calcifications and renal function), together with data on hypercalciuria and 
quality of life. 
 
The final clinical study report should be submitted by: 
 

The MAH shall 
plan to include 
regular progress 
reports of the 
registry in the 
PSUR. 
 
 
31 December 2035. 

 
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE CONDITIONAL MARKETING AUTHORISATION 
 
This being a conditional marketing authorisation and pursuant to Article 14a(4) of Regulation (EC) No 
726/2004, the MAH shall complete, within the stated timeframe, the following measures: 
 
Description Due date 
In order to further confirm the efficacy and safety of NATPAR in the 
treatment of patients with chronic hypoparathyroidism who cannot be 
adequately controlled with standard therapy alone, the MAH should 
conduct a randomised controlled trial comparing NATPAR to Standard of 
Care and to alternative dosing according to an agreed protocol. 
 
The clinical study report should be submitted by: 
 

 
 
 
 
 
 
30 June 2023 



18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



20 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
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 
Parathyroid hormone (rDNA) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each dose contains 25 micrograms parathyroid hormone (rDNA) in 71.4 microlitre solution following 
reconstitution. 
Each cartridge contains 350 micrograms parathyroid hormone (rDNA). 
 
Each dose contains 50 micrograms parathyroid hormone (rDNA) in 71.4 microlitre solution following 
reconstitution. 
Each cartridge contains 700 micrograms parathyroid hormone (rDNA). 
 
Each dose contains 75 micrograms parathyroid hormone (rDNA) in 71.4 microlitre solution following 
reconstitution. 
Each cartridge contains 1050 micrograms parathyroid hormone (rDNA). 
 
Each dose contains 100 micrograms parathyroid hormone (rDNA) in 71.4 microlitre solution 
following reconstitution. 
Each cartridge contains 1400 micrograms parathyroid hormone (rDNA). 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium chloride, mannitol, citric acid monohydrate, metacresol, sodium hydroxide (for pH 
adjustment), water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
2 cartridges in their cartridge holders 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Subcutaneous use. 
 
Use with mixing device, Natpar pen, pen needles 
 
 



21 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
Discard mixed cartridge after 14 days. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Keep the cartridge within its cartridge holder in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Shire Pharmaceuticals Ireland Limited, Block 2 & 3 Miesian Plaza, 50 – 58 Baggot Street Lower, 
Dublin 2, Ireland. 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1078/001 
EU/1/15/1078/002 
EU/1/15/1078/003 
EU/1/15/1078/004 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 



22 

16. INFORMATION IN BRAILLE 
 
Natpar 25 
Natpar 50 
Natpar 75 
Natpar 100 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 



23 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
CARTRIDGE HOLDER LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Natpar 25 mcg/dose powder for solution for injection 
Natpar 50 mcg/dose powder for solution for injection 
Natpar 75 mcg/dose powder for solution for injection 
Natpar 100 mcg/dose powder for solution for injection 
Parathyroid hormone (rDNA) 
SC 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



24 

REMINDER TAB TEXT (included in the pack) 
 
 
Attach needle before mixing 
See Instructions for Use 
 
 



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



26 

Package leaflet: Information for the patient 
 

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 
Parathyroid hormone 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
 
What is in this leaflet 
 
1. What Natpar is and what it is used for 
2. What you need to know before you use Natpar 
3. How to use Natpar 
4. Possible side effects 
5. How to store Natpar 
6. Contents of the pack and other information 
7 Instructions for use 
 
 
1. What Natpar is and what it is used for 
 
What is Natpar? 
 
Natpar is a hormone replacement for adults with under-active parathyroid glands, a condition known 
as ‘hypoparathyroidism’. 
 
Hypoparathyroidism is a disease caused by low levels of parathyroid hormone, which is produced by 
the parathyroid glands in the neck. This hormone controls the amount of calcium and phosphate in the 
blood and urine. 
 
If your levels of parathyroid hormone are too low, you can have low blood calcium. Low calcium can 
cause symptoms in many parts of your body, including the bones, heart, skin, muscles, kidneys, brain 
and nerves. For a list of symptoms of low calcium, see section 4. 
 
Natpar is a synthetic form of parathyroid hormone that helps you keep calcium and phosphate levels in 
your blood and urine at a normal level. 
 
 
2. What you need to know before you use Natpar 
 
Do not use Natpar 
- if you are allergic to parathyroid hormone or any of the other ingredients of this medicine (listed 

in section 6) 



27 

- if you are having or have had radiation therapy to the skeleton 
- if you have cancer of the bones or other cancer that has spread to your bones 
- if you are at increased risk of developing a bone cancer called osteosarcoma (for instance, if you 

have Paget’s disease or other bone diseases) 
- if a blood test shows you have unexplained increases in bone alkaline phosphatase 
- if you have pseudohypoparathyroidism, a rare condition where the body does not respond 

adequately to the parathyroid hormone produced by the body 
 
Warnings and precautions 
 
Talk to your doctor, pharmacist or nurse before using Natpar. 
 
If you are treated with Natpar, you may have side effects related to low or high levels of calcium in 
your blood (see section 4 for these side effects). 
 
These effects are more likely to occur: 
- when first starting Natpar, 
- if you change your Natpar dose, 
- if you miss one of your daily injections, 
- if you stop taking Natpar for a short time or altogether. 
 
You may be given medicines to treat or help prevent these side effects, or you may be asked to stop 
some of the medicines you are taking. These medicines include calcium or vitamin D. 
 
If your symptoms are severe, your doctor may give you additional medical treatment. 
 
Your doctor will check your calcium levels. You may need to change your Natpar dose or stop the 
injections for a short time. 
 
Tests and checks 
Your doctor will check how you respond to the treatment: 
- during the first 7 days of starting treatment and 
- if your dose is changed. 
 
This will be done using tests to measure the level of calcium in your blood or urine. Your doctor may 
tell you to change the amount of calcium or vitamin D you take (in any form, including foods rich in 
calcium). 
 
Talk to your doctor or pharmacist before using Natpar if you suffer from kidney stones. 
 
Children and adolescents 
 
Natpar should not be used in children or adolescents under 18 years old. 
 
Other medicines and Natpar 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including: 
- digoxin, also known as digitalis, a heart medicine 
- medicines used to treat osteoporosis, called bisphosphonates, such as alendronic acid 
- medicines that can affect calcium levels in your blood such as lithium or some medicines used 

to increase the amount of urine (diuretics). 
 
Pregnancy, breast-feeding and fertility 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. There is limited information on the 



28 

safety of Natpar in pregnant women. Natpar has been shown to pass into breast milk in rats, but it is 
not known if Natpar would pass into breast milk in humans. 
 
Your doctor will decide whether to start treatment with Natpar. Your doctor will also decide if you 
should keep taking this medicine if you become pregnant or start breast-feeding while taking it. 
 
It is not known if Natpar has any effects on fertility. 
 
Driving and using machines 
 
Natpar has no effect on your being able to drive or use machines. However, hypoparathyroidism itself 
may affect your ability to concentrate. If your ability to concentrate is impaired, you should not drive 
or use machines until your ability to concentrate is improved. 
 
Natpar contains sodium 
 
This medicinal product contains less than 1 mmol (23 mg) sodium per dose. This means that it is 
essentially “sodium-free”. 
 
 
3. How to use Natpar 
 
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. Your doctor or nurse will train you on how to use the Natpar pen. 
 
Natpar is given as a subcutaneous (under the skin) injection every day, using a pen to help you inject 
your medicine. 
 
The ‘Natpar reusable pen’ is called ‘Natpar pen’ or ‘pen’ in this leaflet. 
 
Dose 
 
The recommended starting dose of Natpar is 50 micrograms per day. 
- However, your doctor may start you on 25 micrograms per day based on a blood test result. 
- After 2 to 4 weeks, your doctor may adjust the dose. 
 
The dose of Natpar varies from person to person. People may need between 25 and100 micrograms of 
Natpar per day. 
 
Your doctor may tell you to take other medicines such as calcium supplements or vitamin D while you 
are taking Natpar. Your doctor will tell you how much you should take each day. 
 
How to use the pen 
 
Read “Section 7. Instructions for use” in this leaflet before you use the pen. 
 
Do not use the pen if the solution is cloudy or coloured or if it contains visible particles. 
 
Before the pen is used for the first time, the medicine has to be mixed. 
 
After you have mixed the medicine, the Natpar pen is ready for use and the medicine can be injected 
under the skin of your thigh. Inject in the other thigh the following day and continue to alternate 
between the two. 
 
It is strongly recommended that every time you receive a dose of Natpar, the name and batch number 
of the product are recorded in order to maintain a record of the batches used. 
 



29 

How long to use 
 
Keep using Natpar for as long as your doctor prescribes it for you. 
 
If you use more Natpar than you should 
 
If, by mistake, you inject more than one dose of Natpar in a day, contact your doctor or pharmacist 
immediately. 
 
If you forget to use Natpar 
 
If you forget to use Natpar (or cannot inject it at your usual time), use your injection as soon as you 
can but do not inject more than one dose in the same day. 
 
Take your next dose of Natpar at the usual time the next day. You may need to take more calcium 
supplements if you have signs of low blood calcium; see section 4 for symptoms. 
 
Do not inject a double dose to make up for a forgotten dose. 
 
If you stop using Natpar 
 
Discuss with your doctor if you want to stop treatment with Natpar. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects 
 
The following potentially serious side effects can occur when using Natpar: 
• Very common: high levels of calcium in your blood, which can occur more often when you start 

treatment with Natpar. 
• Very common: low levels of calcium in your blood; this can occur more often if you suddenly 

stop taking Natpar. 
 
Symptoms related to high or low calcium levels are included in the list below. If you experience any 
of these side effects, contact your doctor right away. 
 
Other side effects include: 
 
Very common (may affect more than 1 in 10 people): 
• headaches*,† 
• tingling and numbness of the skin† 
• diarrhoea*,† 
• nausea and vomiting* 
• joint pain* 
• muscle spasms† 
 
Common (may affect up to 1 in 10 people): 
• feeling nervous or anxious† 
• sleep problems (feeling sleepy during the day or having trouble sleeping at night)* 
• fast or uneven heart beat*,† 
• high blood pressure* 



30 

• cough† 
• stomach pain* 
• muscle twitching or cramping† 
• pain in your muscles† 
• neck pain† 
• pain in your arms and legs 
• increased level of calcium in your urine* 
• need to pass urine often† 
• fatigue and lack of energy* 
• chest pain 
• redness and pain at injection site 
• thirst* 
• antibodies (produced by your immune system) to Natpar 
• in blood tests, your doctor may see decreased levels of vitamin D and magnesium† 
 
Not known (frequency cannot be estimated from the available data): 
• allergic reactions (hypersensitivity), such as: swelling of the face, lips, mouth, or tongue; 

shortness of breath; itching; rash; hives 
• seizures (fits) due to low levels of calcium in your blood† 
 
*These side effects may be related to high level of calcium in your blood. 
†These side effects may be related to low level of calcium in your blood. 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Natpar 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the cartridge and carton after EXP. 
The expiry date refers to the last day of that month. 
 
Before mixing 
 
• Store in a refrigerator (2°C to 8°C). 
• Do not freeze. 
• Keep the cartridge within its cartridge holder in the outer carton in order to protect from light. 
 
After mixing 
 
• Store in a refrigerator (2°C to 8°C). 
• Do not freeze. 
• Keep the pen containing a mixed cartridge tightly closed in order to protect from light.  
• Do not use this medicine for more than 14 days after it has been mixed. 
• Do not use this medicine if it has not been stored correctly. 
• Before attaching a new needle to your Natpar pen, check that the solution is clear and colourless. 

It is common to see small bubbles. Do not use this medicine if it has become cloudy, coloured, 
or contains visible particles. 

 



31 

Do not throw away any medicines via household waste. Ask your pharmacist how to throw away 
medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Natpar contains 
 
The active substance is parathyroid hormone (rDNA). 
It is available in 4 different strengths of cartridge (each cartridge contains 14 doses): 
 
Natpar 25 micrograms 
Each dose contains 25 micrograms parathyroid hormone in 71.4 microlitre solution following 
reconstitution. 
 
Natpar 50 micrograms 
Each dose contains 50 micrograms parathyroid hormone in 71.4 microlitre solution following 
reconstitution. 
 
Natpar 75 micrograms 
Each dose contains 75 micrograms parathyroid hormone in 71.4 microlitre solution following 
reconstitution. 
 
Natpar 100 micrograms 
Each dose contains 100 micrograms parathyroid hormone in 71.4 microlitre solution following 
reconstitution. 
 
The other ingredients in the cartridge (for all strengths) are: 
 
In the powder: 
• sodium chloride 
• mannitol 
• citric acid monohydrate 
• sodium hydroxide (for pH adjustment) 
 
In the solvent: 
• metacresol 
• water for injections 
 
What Natpar looks like and contents of the pack 
 
Each cartridge of Natpar contains medicine as a powder together with a solvent to make a solution for 
injection. The cartridge is made of glass, with a rubber seal on top. The cartridge is contained in a 
plastic cartridge holder. 
 
Natpar is available in a pack with 2 cartridges inside their cartridge holders. 
 
The carton/cartridge colour shows the strength of your Natpar medicine: 
 
Natpar 25 micrograms/dose 
Purple cartridge. 
 
Natpar 50 micrograms/dose 
Red cartridge. 
 
Natpar 75 micrograms/dose 
Grey cartridge. 
 



32 

Natpar 100 micrograms/dose 
Blue cartridge. 
 
Marketing Authorisation Holder and Manufacturer 
 
Shire Pharmaceuticals Ireland Limited 
Block 2 & 3 Miesian Plaza 
50 – 58 Baggot Street Lower 
Dublin 2 
Ireland 
Tel: +44(0)1256 894 959 
E-mail: medinfoEMEA@shire.com 
 
This leaflet was last revised in . 
 
This medicine has been given ‘conditional approval’. This means that there is more evidence to come 
about this medicine. 
 
The European Medicines Agency will review new information on this medicine at least every year and 
this leaflet will be updated as necessary. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 



33 

7. Instructions for use 
 

This guide is designed to help you prepare, inject, and store your Natpar pen. 
 

These instructions are divided into 5 stages 
 

Getting to know the parts of your Natpar pen and your Natpar medicine 
 
Preparing and mixing your Natpar 
 
Preparing your Natpar pen 
 
Giving your daily dose 
 
How to store your medicine 
 

 
If you require assistance at any time, contact your doctor, pharmacist or nurse. 

You may also contact Shire at +44(0)1256 894 959 or email at medinfoEMEA@shire.com. 
 

What you need to know before getting started 
• Do NOT use your Natpar pen until your doctor or nurse has shown you how to use it. 
• Use these instructions for use every time you mix your medicine, prepare your pen, or give an 

injection so you do not forget to do a step. 
• A new needle must be attached to the pen every day. 
• A new cartridge should be prepared once every 14 days. 
• Do NOT use this medicine if you notice that it has become cloudy, coloured, or contain visible 

particles. 
• Always store the cartridge in the refrigerator (at 2°C – 8°C). 
• Do NOT freeze your cartridge. 
• Do NOT use a cartridge that has been frozen. 
• Discard all mixed cartridges older than 14 days. 
• Only take your dose once per day. 
• To clean your Natpar pen, wipe the outside of the pen with a damp cloth. DO NOT place the 

pen in water or wash or clean it with any liquid. 
• Throw away the used Natpar cartridge and used needles as instructed by your doctor, 

pharmacist or nurse. 
• Your Natpar pen can be re-used for up to 2 years 
 



34 

Getting to know the parts of your Natpar pen and your Natpar medicine 
 
Get to know the Natpar pen components 
Parts of your Natpar pen 
 
Note: The rod protector (dummy cartridge) protects the rod during shipment from the factory. Throw 
away the rod protector when you are ready to use your pen. 

 
 

Your Natpar cartridge 
 
Your Natpar cartridge contains medicine powder and solvent to mix the powder with. You must mix the 
powder and the solvent in the cartridge before using your Natpar pen. 
• Each cartridge contains 14 doses. 
• The dose indicator shows you the number of doses left in the cartridge. 
 

 
 



35 

Other supplies that are needed: 
 
Note: The alcohol swabs, injection needles and the puncture resistant container are not included in the 
pack. 
The Medicine Cartridge Tracker is located within this instructions for use. 

 

 
 



36 

 
Preparing and mixing your Natpar 
 
 You need to mix Natpar before you can use it. Once the medicine is mixed, it can be used for up to 

14 injections (14 doses). 
If this is your first time using Natpar by yourself, your doctor or nurse will guide you through how 
to mix your Natpar cartridge. 
 

1. When preparing to inject a dose, be sure to remove your Natpar 
cartridge from the refrigerator. 
 
Note: You should store your cartridge in the refrigerator at all 
times, except when preparing and injecting your medicine. 
 

 
 
 
 
 

 

 • Wash and dry your hands. 
• Gather your supplies, including: 

o Your mixing device 
o New Natpar cartridge from the refrigerator 
o New disposable pen needle 
o Puncture resistant sharps container 
o A pencil or pen to write the dates you mix your 

cartridge 
o Your medicine cartridge tracker (located within this 

instructions for use) 
o Your Natpar pen to inject your medicine 
o This instructions for use 

 
2. Fill in the dates in your medicine cartridge tracker. 

 
 Medicine cartridge tracker 

Instructions: 
• Enter today’s date in the space next to “Date mixed.” 
• Enter the date 14 days from today in the space next to “Discard on” (Same day of the week, 

2 weeks later). 
• Dispose of your cartridge on the “Discard on” date even if you have medicine left in your 

cartridge. Do not use your cartridge on the “Discard on” date. 
• A pen needle must be attached to mix a new cartridge. 

 

 
 
3. Remove the paper tab from the needle cap. 

 



37 

4. Screw the Pen Needle onto the cartridge in 
a clockwise direction. 
 
• Ensure the Pen Needle is straight and 

tight on the cartridge (the wider edge of 
the needle cap must touch the ‘shoulder’ 
of the cartridge) 

• Do not remove the needle cap or guard 
until you are ready to give your 
medicine. 
 

 

5. Turn the wheel of the mixing device in a 
counterclockwise direction to lower the rod if 
it is not already lowered. 

 
 • Make sure the rod in the mixing device 

looks like this (completely retracted). 

 
6. Screw the Natpar cartridge onto your mixing 

device in a clockwise direction. 
 
• The pen needle must be firmly attached. 

 
7. With the needle cap pointing up, turn the 

wheel slowly in a clockwise direction until 
the stoppers within the cartridge no longer 
move and until the wheel turns freely. 
 
• Keep the needle pointing up. 
• Do NOT hold the mixing device at an 

angle. 

 
8. Make sure the stoppers look like this and stay 

together. 
 

 



38 

9. Hold the mixing device with the attached 
cartridge, with the needle pointed up, and 
gently move the cartridge from side to side 
(from 9 o’clock to 3 o’clock) about 10 times 
to dissolve the powder that is in the 
cartridge. 
 
• Do NOT shake the cartridge. 
• Ensure the needle is pointing up. 
• Put the mixing device down with the 

cartridge attached and wait for 5 minutes 
to allow complete dissolution of the 
powder. 

 
Check the solution before giving every daily 
dose. If the solution is cloudy, contains 
visible particles, or is not colourless after 
5 minutes, do not use this medicine. 
Contact your doctor, pharmacist or nurse. 
It is normal to see small bubbles. 
 

 

Preparing your Natpar pen 
 

 You will prepare your Natpar pen once every 
14 days. 
 

 

1. Pick up your pen and remove the cap. Save 
the cap for later use. 

 
2. Unscrew the rod protector (dummy 

cartridge) or the empty medicine cartridge 
in a counterclockwise direction and throw it 
in a puncture resistant sharps container. 

 
3. Press the injection button. You should see 

“0” line up with the notch in the dose 
window. If you do not see “0” line up, press 
the injection button until it is lined up. 

 



39 

4. Lower the rod. If the rod is extended, turn 
the dark red ring counterclockwise to lower 
it. Do not tighten the ring too much. 

 
5. Check the rod. It will have a small gap when 

done the right way. 

 
6. Unscrew the cartridge from the mixing 

device in a counterclockwise direction and 
put the mixing device down. 

 
7. Attach the cartridge to the pen. Pick up the 

pen base and hold it with the rod pointed 
upright. 

 



40 

8. With the needle cap pointing up, screw the 
cartridge onto the pen in a clockwise 
direction until there is no space between the 
cartridge and the pen. 

 
9. Priming your Natpar pen. 

 
Turn the dosage knob in a clockwise 
direction until “GO” lines up with the notch 
in the dose window. 

 
10. Hold the pen with the needle cap pointing 

up. 

 
11. Press the injection button on a flat surface, 

such as a table top, until the “0” lines up with 
the notch in the dose window. 
 
• It is normal for 1 or 2 drops of liquid to 

appear on the needle during this step. 
• Do not remove the medicine cartridge 

from the pen until the “Discard on” date 
or the cartridge is empty. 

• Prime your pen only 1 time for each new 
cartridge. 

 

 

 
 



41 

Giving your daily dose 
 
 NOTE: If you have just finished mixing your medicine and preparing your pen and the 

pen needle is on, go straight to “Before injecting your daily dose” (step 6 in this section) 
for instructions on how to inject using your Natpar pen. 
If you need help at any time, ask your doctor or nurse. 
 

1. Wash and dry your hands. 
 

 

2. Gather your supplies, including: 
 
• Your Natpar pen from the refrigerator 
• New disposable pen needle 
• Puncture resistant sharps container 
• Alcohol swab 
 
Note: You should store your mixed cartridge within the pen 
in the refrigerator at all times, except when preparing and 
injecting your medicine. 
 

 

3. Check the cartridge. 
 
Remove the pen cap from your Natpar pen. The mixed 
cartridge should be inside. 

 
4. Before attaching a new needle to your pen, check: 

 
• If the solution is clear, colourless and free from visible particles. It is 

normal to see small bubbles. 
If the liquid is not clear, colourless or free from visible particles, do not 
use this medicine. Contact your doctor, pharmacist or nurse. 

 
You will have to prepare a new Natpar cartridge if: 
 
• There are no remaining doses in the pen (dose counter at “0”) 

or 
• The “Discard on” date has been reached (see medicine tracker). 

 
5. Attaching a new needle. 

 
• Remove the paper tab from the needle cap. 
• Firmly hold the Natpar pen upright. 
• While keeping the needle cap straight, screw it firmly 

onto the cartridge in a clockwise direction (the wider 
edge of the needle cap must touch the ‘shoulder’ of the 

 



42 

cartridge). 
• Leave the needle cap on. 
 

 
6. Before injecting your daily dose. 

 
• Do NOT use a cartridge that has been frozen. 
• Discard all mixed cartridges if the “Discard on” date has been reached (see medicine 

tracker). 
 

7. Wipe the injection area of your thigh with an alcohol swab. 
Inject into an alternate thigh each day. 

 
 Make sure the needle cap is pointing downward at all times 

during step 8 to step 17. 
 

8. Hold the Natpar pen with the needle pointing straight down. 
 
• Keep the needle pointing down until the injection is 

complete. 
 

 
9. Hold the pen so you can see the dose window. 

 



43 

10. Turn the dosage knob until “GO” lines up with the notch in 
the window. Do not turn the dosage knob past “GO.” 
 
• If the dosage knob is hard to turn, you may not have 

enough liquid left. 
Check the dose indicator on the cartridge to see if there 
are any doses left or check the “Discard on” date on the 
medicine cartridge tracker to see if it has been more 
than 14 days. 
 

 

11. Gently tap the cartridge 3 to 5 times. This moves any air 
bubbles away from the needle. 

 
12. Prepare the pen needle for giving the injection. 

 
Without unscrewing, 
 
• Pull the needle cap straight off and set it aside. 
• Then pull off the needle guard and discard it. 
 

 
13. Hold the pen so you can see “GO” in the dose window with 

the pen needle pointing down. 

 
14. Read steps 15, 16, and 17 carefully before you inject the medicine. 

 
15. Insert the needle fully into your thigh (you can pinch a fold of 

the skin if told by your doctor or nurse). Make sure you can 
see “GO” in the window. 
 

 



44 

16. Press the injection button until the “0” lines up with the notch 
in the dose window. You should see and feel the dosage knob 
turn back to “0.” Slowly count to 10. 
 

 
 

 Important note about injecting: 
 
To avoid under-dosing, you will need to keep the needle in the 
skin for 10 seconds AFTER pressing the injection button. 
 

 
 

  
17. Pull the needle straight out of your thigh. 

 
• It is normal to see 1 or 2 drops of liquid appear on the needle during this step. 
• If you do not think you received your full dose, do not take another dose. Call your doctor. 

You may need to take calcium and vitamin D. 
 

18. Carefully recap the exposed needle with the large needle cap 
by using a scooping technique. 
 
• Make sure that the needle is pressed all the way into the 

cap. 
 

 
19. Unscrew the needle cap (with the pen needle inside) in a 

counterclockwise direction while holding the cartridge. 
 
• Do not share your pen or pen needles with anyone else. 

You may give an infection to them or get an infection 
from them. 

 

 



45 

20. Discard the used needle into a puncture resistant container. 
 
Ask your doctor, pharmacist or nurse how to properly 
dispose of a full puncture resistant container. 
 
 

 
21. Put the cap back on your pen. 

 
• A cartridge must be attached to the pen before you can put 

the pen cap on. 
• Line up the pocket clip of the tab on the pen. 
• Press the cap and pen together until you hear it click. 
 

 
22. Place the Natpar pen in the refrigerator. 

 
 

 
 
How to store your medicine 
 

 
The Natpar cartridges and any pen that contains a mixed cartridge should always be stored in 
the refrigerator (2°C – 8°C). 
 
• Do NOT freeze your 

cartridge. 
 

• Do NOT use a cartridge 
that has been frozen. 

• Discard all mixed 
cartridges older than 
14 days. 

 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET