NATPAR 50mcg / dose powder + solvent for injection medication leaflet

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

Natpar 25 micrograms

Each dose contains 25 micrograms parathyroid hormone (rDNA)* in 71.4 microlitre solutionfollowing 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 followingreconstitution.

Each cartridge contains 700 micrograms parathyroid hormone (rDNA).

Natpar 75 micrograms

Each dose contains 75 micrograms parathyroid hormone (rDNA) in 71.4 microlitre solution followingreconstitution.

Each cartridge contains 1050 micrograms parathyroid hormone (rDNA).

Natpar 100 micrograms

Each dose contains 100 micrograms parathyroid hormone (rDNA) in 71.4 microlitre solutionfollowing reconstitution.

Each cartridge contains 1400 micrograms parathyroid hormone (rDNA).

*Parathyroid hormone (rDNA), produced in E. coli using recombinant DNA technology, is identical tothe 84 amino acid sequence of endogenous human parathyroid hormone.

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 whocannot be adequately controlled with standard therapy alone.

Treatment should be supervised by a physician or other qualified healthcare professional experiencedin the management of patients with hypoparathyroidism.

The goal of treatment with Natpar is to achieve calcaemic control and to reduce symptoms (see alsosection 4.4). The optimisation of parameters of calcium-phosphate metabolism should be in line withcurrent 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.

Initiating Natpar1. 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 of25 micrograms can be considered.

2. In patients using active vitamin D, decrease the dose of active vitamin D by 50%, if pre-doseserum 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 isbelow 1.87 mmol/L or above 2.55 mmol/L, this measurement should be repeated the followingday.

5. Adjust dose of active vitamin D or calcium supplement or both based on serum calcium valueand clinical assessment (i.e., signs and symptoms of hypocalcaemia or hypercalcaemia).

Suggested adjustments to Natpar, active vitamin D and calcium supplements based on serumcalcium levels are provided below:

Adjust first Adjust second Adjust third

Pre-dose serum Natpar Active vitamin D

Calcium supplementcalcium forms

Consider reducing or

Above the upper limit stopping Natpar and

Decrease orof normal (ULN) re-assess by means of Decreasediscontinue**(2.55 mmol/L)* serum calciummeasurement

Greater than Consider reduction No change, or decrease2.25 mmol/L and Decrease or if active vitamin D wasbelow the upper limit of discontinue** already discontinuednormal (2.55 mmol/L)* before this titration step

Less than or equal to No change2.25 mmol/L and No change No changeabove 2 mmol/L

Consider increase after

Lower than 2 mmol/L at least 2-4 weeks at a Increase Increasestable dose

*The value of ULN may vary by laboratory

**Discontinue in patients receiving the lowest available dose6. Repeat steps 4 and 5 until target pre-dose serum calcium concentration is within the range of2.0-2.25 mmol/L, active vitamin D has been discontinued and calcium supplementation issufficient to meet daily requirements.

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 microgramscan occur at any time.

It is recommended to measure the albumin-corrected serum calcium 8-12 hours after dosing Natpar. Ifpost-dose serum calcium is >ULN, then first reduce active vitamin D and calcium supplements andmonitor progress. Measurements of pre- and post-dose serum calcium should be repeated andconfirmed to be within an acceptable range before titration to a higher dose of Natpar is considered. Ifpost-dose serum calcium remains >ULN, oral calcium supplementation should be further reduced ordiscontinued (see also adjustment table under Initiating Natpar).

At any dose level of Natpar, if post-dose albumin-corrected serum calcium exceeds the ULN and allactive vitamin D and oral calcium have been withheld, or symptoms suggesting hypercalcaemia arepresent, the dose of Natpar should be reduced (see section 4.4).

In the case of a missed dose, Natpar must be administered as soon as reasonably feasible andadditional exogenous sources of calcium and/or active vitamin D must be taken based on symptoms ofhypocalcaemia.

Interruption or discontinuation of treatment

Abrupt interruption or discontinuation of Natpar can result in severe hypocalcaemia. Temporary orpermanent discontinuation of Natpar treatment must be accompanied by monitoring of serum calciumlevels 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 (creatinineclearance 30 to 80 mL/min). There are no data available in patients with severe renal impairment (seesection 4.4).

No dose adjustment is necessary for patients with mild or moderate hepatic impairment (total scoreof 7 to 9 on the Child-Pugh scale). There are no data available in patients with severe hepaticimpairment (see section 4.4).

The safety and efficacy of Natpar in children less than 18 years of age have not yet been established.

No data are available.

Natpar is suitable for patient self-administration. Patients must be trained on the proper injectiontechniques 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 peninjector, 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 boneor hereditary disorders

- with unexplained elevations of bone-specific alkaline phosphatase

- with pseudohypoparathyroidism.

In order to improve the traceability of biological medicinal products, the name and batch number ofthe administered product should be clearly recorded.

The aim of treatment with Natpar is to achieve a pre-dose serum calcium concentration of2.0-2.25 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 amaximum increase observed of 0.7 mmol/L. Calcium, vitamin D, or Natpar doses may need to bereduced if post-dose hypercalcaemia is observed, even if pre-dose calcium concentrations areacceptable (see section 4.2).

Hypercalcaemia

Hypercalcaemia was reported in clinical trials with Natpar. Hypercalcaemia commonly occurredduring the titration period, during which doses of oral calcium, active vitamin D, and Natpar werebeing adjusted. Hypercalcaemia may be minimised by following the recommended dosing, themonitoring information, and asking patients about any symptoms of hypercalcaemia. If severehypercalcaemia (>3.0 mmol/L or above upper limit of normal with symptoms) develops, hydrationand temporarily stopping Natpar, calcium and active vitamin D should be considered until serumcalcium returns to the normal range. Then consider resuming Natpar, calcium and active vitamin D atlower doses (see sections 4.2 and 4.8).

Hypocalcaemia, a common clinical manifestation of hypoparathyroidism, was reported in clinicaltrials with Natpar. Most of the hypocalcaemic events occurring in the clinical trials were mild tomoderate in severity. In the post-marketing setting, cases of symptomatic hypocalcaemia, includingcases that resulted in seizures, have been reported in patients being treated with Natpar. The risk forserious hypocalcaemia is highest after Natpar is withheld, missed or abruptly discontinued, but canoccur at any time. Temporary or permanent discontinuation of Natpar must be accompanied bymonitoring of serum calcium levels and increase of exogenous calcium and/or active vitamin Dsources as necessary. Hypocalcaemia may be minimised by following the recommended dosing, themonitoring information, and asking patients about any symptoms of hypocalcaemia (see sections 4.2and 4.8).

Concomitant use with cardiac glycosides

Hypercalcaemia of any cause may predispose to digitalis toxicity. In patients using Natparconcomitantly with cardiac glycosides (such as digoxin or digitoxin), monitor serum calcium andcardiac 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 havenot 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 maybe 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 determinewhether 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 serumcalcium concentration to administration of Natpar should be monitored at intervals to detect this andthe diagnosis of tachyphylaxis considered.

If serum concentration of 25-OH vitamin D is low then appropriate supplementation may restoreserum calcium response to Natpar (see section 4.2).

Urolithiasis

Natpar has not been studied in patients with urolithiasis. Natpar should be used with caution inpatients with active or recent urolithiasis because of the potential to exacerbate this condition.

There have been post-marketing reports of hypersensitivity reactions in patients taking Natpar.

Hypersensitivity reactions can include anaphylaxis, dyspnoea, angioedema, urticaria, rash, etc. If signsor symptoms of a serious hypersensitivity reaction occur, treatment with Natpar should bediscontinued and hypersensitivity reaction should be treated according to the standard of care. Patientsshould be monitored until signs and symptoms resolve (see sections 4.3 and 4.8). If Natpar is to bediscontinued, monitoring for hypocalcaemia is necessary (see section 4.2).

Sodium Content

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

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 toxicityif hypercalcaemia develops. No drug-drug interaction study has been conducted with cardiacglycosides and Natpar (see section 4.4).

For any drug that affects serum calcium levels (e.g., lithium, thiazides), patients’ serum calcium levelsshould 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 withbisphosphonates is not recommended.

Natpar is a protein that is not metabolised by and does not inhibit hepatic microsomaldrug-metabolising enzymes (e.g., cytochrome P450 isoenzymes). Natpar is not protein bound and hasa low volume of distribution.

There are no data from the use of Natpar in pregnant women. Animal studies do not indicate direct orindirect 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 madewhether to initiate or discontinue treatment with Natpar during pregnancy taking into account theknown 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 discontinuebreast-feeding or to discontinue therapy with Natpar, taking into account the benefit of breast-feedingfor the child and the benefit of therapy for the woman.

There are no data on the effects of Natpar on human fertility. Animal data do not indicate anyimpairment of fertility.

Natpar has no or negligible influence on the ability to drive and use machines. Since neurologicsymptoms may be a sign of uncontrolled hypoparathyroidism, patients with disturbances in cognitionor attention should be advised to refrain from driving or using machines until symptoms havesubsided.

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 generallymild to moderate in severity and transient, and were managed with adjustments of Natpar, calciumand/or active vitamin D doses (see sections 4.4 and 5.1).

Adverse reactions for Natpar-treated patients in the placebo-controlled study and in post-marketingexperience are listed below by MedDRA system organ class and frequency. Frequencies are defined asvery common (≥1/10), common (≥1/100 to <1/10), and not known (cannot be estimated from theavailable data). All adverse reactions identified in post-marketing experience are italicised.

System organ class Very common (1/10) Common (1/100 to Not known (cannot be<1/10) estimated from theavailable data)

Immune system Hypersensitivitydysorders reactions, (dyspnoea,angioedema, urticaria,rash)

Metabolism and hypercalcaemia, hypomagnesaemia†,nutrition disorders hypocalcaemia tetany†

Psychiatric disorders anxiety†, insomnia*

Nervous system headache*,†, somnolence*disorders hypoaesthesia†,paraesthesia†

Cardiac disorders palpitations*,†

Vascular disorders hypertension*

Respiratory, thoracic cough†and mediastinaldisorders

Gastrointestinal diarrhoea*,†, nausea*, abdominal pain upper*disorders vomiting*

Musculoskeletal and arthralgia*, muscle muscle twitching†,connective tissue spasms† musculoskeletal pain†,disorders myalgia†, neck pain†,pain in extremity

Renal and urinary hypercalciuria*,disorders pollakiuria†

General disorders and asthenia*, chest pain†,administration site fatigue, injection siteconditions reactions, thirst*

Investigations anti-PTH antibodypositive, blood25-hydroxycholecalciferol 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.

Hypercalcaemia and hypocalcaemia were commonly encountered during the dose titration period. Therisk for serious hypocalcaemia was greatest after the withdrawal of Natpar. Cases of hypocalcaemiaresulting in seizures have been reported post-marketing (see section 4.4).

In the placebo-controlled study, 9.5% (8/84) Natpar-treated patients and 15% (6/40) placebo-treatedpatients experienced an injection site reaction, all of which were mild or moderate in severity.

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 inadults with hypoparathyroidism, the incidence of anti-parathyroid hormone (PTH) antibodies was8.8% (3/34) and 5.9% (1/17) in patients who received subcutaneous administration of 50 to100 micrograms Natpar or placebo once daily for 24 weeks, respectively.

Across all clinical studies in patients with hypoparathyroidism following treatment with Natpar forup to 7.4 years, the immunogenicity incidence rate was 16/87 (18.4%) and did not appear to increaseover time. These 16 patients had low titre anti-PTH antibodies and, of these, 12 subsequently becameantibody negative. The apparent transient nature of antibodies to PTH is likely due to the low titre.

Two of these patients had antibodies with neutralising activity; these patients maintained a clinicalresponse with no evidence of immune-related adverse reactions.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked 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, ECGchanges, hypotension, nausea, vomiting, dizziness and headache. Severe hypercalcaemia may be alife-threatening condition requiring urgent medical care and careful monitoring (see section 4.4).

Pharmacotherapeutic group: Calcium homeostasis, parathyroid hormones and analogues, ATC code:

H05AA03

Endogenous parathyroid hormone (PTH) is secreted by the parathyroid glands as a polypeptide of84 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 proteinreceptors.

PTH has a variety of critical physiological functions that include its central role in modulating serumcalcium and phosphate levels within tightly regulated levels, regulating renal calcium and phosphateexcretion, activating vitamin D, and maintaining normal bone turnover.

Natpar is produced in E. coli using recombinant DNA technology, and is identical to the 84 aminoacid sequence of endogenous human parathyroid hormone.

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 ofcalcium and to lower serum phosphate concentration.

Natpar has the same primary amino acid sequence as endogenous parathyroid hormone and may beanticipated to have the same physiological actions.

The safety and clinical efficacy of Natpar in adults with hypoparathyroidism is derived from1 randomised, placebo-controlled study and an open-label extension study. In these studies, Natparwas self-administered, with daily doses ranging from 25 to 100 micrograms per subcutaneousinjection.

Study 1 - REPLACE

The objective of this trial was to maintain serum calcium with Natpar while reducing or replacing oralcalcium and active vitamin D. The study was a 24-week, randomised, double-blind,placebo-controlled, multicentre trial. In this trial, patients with chronic hypoparathyroidism receivingcalcium 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% werefemales. 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 titrationphase 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 criterionwere considered responders. A responder was defined using a composite primary efficacy endpoint ofat least a 50% reduction from the baseline active vitamin D dose AND at least a 50% reduction fromthe baseline oral calcium AND an albumin-corrected total serum calcium concentration maintained ornormalised compared with the baseline value (≥1.875 mmol/L) and did not exceed the upper limit ofthe laboratory normal range.

At the end of treatment, 46/84 (54.8%) patients treated with Natpar achieved the primary endpointversus 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 ofactive vitamin D treatment and were receiving no more than 500 mg of calcium citrate, compared with2/33 (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 frombaseline in oral calcium was -51.8% (SD 44.6) in subjects receiving Natpar compared to6.5% (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 six year long-term, open-label extension study of daily subcutaneous dosing of Natpar inhypoparathyroidism subjects who completed prior studies with Natpar.

A total of 49 subjects were enrolled in the study. Subjects received doses of 25 micrograms, 50micrograms, 75 micrograms or 100 micrograms/day for up to approximately 72 months (mean 2038days (~5.6 years). The minimum time of exposure to Natpar was 41 days, and the maximum was 2497days (~6.8 years).

61.2% (30/49) of subjects met the primary efficacy endpoint at end of treatment, defined as albumin-corrected total serum calcium concentration that was normalized or maintained compared to thebaseline value and not exceeding the upper limit of normal values; ≥50% reduction from baseline or≤500 mg of daily calcium supplementation; and ≥50% reduction from baseline or ≤0.25 μg of dailycalcitriol supplementation.

The results demonstrate durability of the physiological effects of Natpar over 72 months includingmaintenance of mean albumin-corrected serum calcium levels (n=49, 2.09 (SD 0.174) mmol/L atbaseline; n=38, 2.08 (SD 0.167) mmol/L at 72 months), a decrease in serum phosphate (n=49, 1.56(SD 0.188) mmol/L at baseline; n=36, 1.26 (SD 0.198) mmol/L at 72 months) and the maintenance ofnormal calcium phosphate product (<4.4mmol2/L2) for all subjects (n=49 at baseline, n=36 at 72months).

The long-term effects included a decrease in mean urinary calcium excretion to the normal range(n=48, 8.92 (SD 5.009) mmol/day at baseline; n=32, 5.63 (SD 3.207) mmol/day at 72 months), andstabilization of normal mean serum creatinine levels (n=49, 84.7 (SD 18.16) µmol/L at baseline; n=38,78.2 (SD 18.52) µmol/L at 72 months). In addition, there was maintenance of normal bone mineraldensity.

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 forinformation on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least everyyear and this SmPC will be updated as necessary.

The pharmacokinetics of Natpar following subcutaneous administration in the thigh ofhypoparathyroidism subjects was consistent with that observed in healthy post-menopausal womenwho received parathyroid hormone in the thigh and abdomen.

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 processwith a lesser role played by the kidneys.

In the liver, parathyroid hormone is cleaved by cathepsins. In the kidney, parathyroid hormone and

C-terminal fragments are cleared by glomerular filtration.

Parathyroid hormone (rDNA) was evaluated in an open-label PK/PD study in which 7 patients withhypoparathyroidism received single subcutaneous doses of 50 and 100 micrograms with a 7-daywashout interval between doses.

Peak plasma concentrations (mean Tmax) of Natpar occur within 5 to 30 minutes and a second usuallysmaller peak at 1 to 2 hours. The apparent terminal half-life (t1/2) was 3.02 and 2.83 hours for the50 and 100 micrograms dose, respectively. The maximum mean increases of serum calcium, whichoccurred at 12 hours, were approximately 0.125 mmol/L and 0.175 mmol/L with the 50 microgramsand 100 micrograms dose, respectively.

Effect on mineral metabolism

Treatment with Natpar increases serum calcium concentration in hypoparathyroidism patients, and thisincrease occurs in a dose-related manner. After a single injection of parathyroid hormone (rDNA), themean serum total calcium reached its peak level between 10 and 12 hours. The calcaemic response issustained 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 and100 microgram dose, respectively) to a nadir in the 3 to 6 hour time point, which returns to pre-dosinglevels by 16 to 24 hours.

Phosphate

Following injection with Natpar, serum phosphate levels decrease proportionally to PTH(1-84) levelsover 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 hourswith a return to near baseline levels by 24 hours. A greater increase in the levels of 1,25-(OH)2D inserum were observed with the 50 micrograms dose than with the 100 micrograms dose, likely due todirect inhibition of the renal 25-hydroxyvitamin D-1-hydroxylase enzyme by serum calcium.

A pharmacokinetic study in non-hypoparathyroidism subjects was conducted in 6 men and 6 womenwith moderate hepatic impairment (Child-Pugh Classification of 7-9 [Grade B]) as compared with amatched group of 12 subjects with normal hepatic function. Following a single 100 microgramssubcutaneous dose, the mean Cmax and baseline-corrected Cmax values were 18% to 20% greater in themoderately impaired subjects than in those with normal function. There were no apparent differencesin the serum total calcium concentration-time profiles between the 2 hepatic function groups. No doseadjustment for Natpar is recommended in patients with mild to moderate hepatic impairment. Thereare no data in patients with severe hepatic impairment.

Pharmacokinetics following a single 100 micrograms subcutaneous dose of Natpar was evaluatedin 16 non-impaired subjects (creatinine clearance (CLcr) >80 mL/min) and 16 subjects with renalimpairment. The mean maximum concentration (Cmax) of PTH following 100 micrograms parathyroidhormone (rDNA) in subjects with mild-to-moderate renal impairment (CLcr 30 to 80 mL/min) wasapproximately 23% higher than that observed in subjects with normal renal function. Exposure to PTHas 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 renalimpairment (CLcr 30 to 80 mL/min). No studies were conducted in patients on renal dialysis. There areno data in patients with severe renal impairment.

Pharmacokinetic data in paediatric patients are not available.

Clinical studies with Natpar did not include sufficient numbers of subjects aged 65 and over todetermine whether response in these subjects is different from younger subjects.

No clinically relevant gender differences were observed in the REPLACE study.

Weight

No dose adjustment is necessary based on weight.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, mutagenicity, toxicity to fertility and general reproduction, and local tolerance.

Rats treated with daily injections of Natpar for 2 years had dose-dependent exaggerated boneformation and an increased incidence of bone tumours, including osteosarcoma, most probably due toa non-genotoxic mechanism. Due to the differences in bone physiology in rats and humans, theclinical relevance of these findings is unknown. No osteosarcomas have been observed in clinicaltrials.

Natpar did not adversely affect fertility or early embryonic development in rats, embryo-foetaldevelopment in rats and rabbits, or pre/post-natal development in rats. A minimal amount of Natpar isexcreted in the milk of lactating rats.

In monkeys receiving daily subcutaneous doses for 6 months, there was an increased occurrence ofrenal tubular mineralisation at exposure levels 2.7 times the clinical exposure levels at the highestdose.

Sodium chloride

Mannitol

Citric acid monohydrate

Sodium hydroxide (for pH adjustment)

Metacresol

Water for injections

This medicinal product must not be mixed with other medicinal products.

3 years.

After reconstitution, chemical and physical in-use stability of the solution has been demonstrated forup to 14 days when stored in a refrigerator (2°C - 8°C) and for up to 3 days when stored outside therefrigerator 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.

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.

The glass dual-chamber cartridge inside the cartridge holder is made from type I glass with2 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 parathyroidhormone (rDNA) as powder in the first chamber and 1000 microlitres of solvent in thesecond chamber (corresponding to 14 doses).

Natpar 50 micrograms

Each cartridge in the red cartridge holder contains 700 micrograms of parathyroid hormone (rDNA) aspowder in the first chamber and 1000 microlitres of solvent in the second chamber (corresponding to14 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 (correspondingto 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 (correspondingto 14 doses).

Pack size: Carton containing 2 cartridges.

Carton/cartridge colours are used to indicate the different strengths:

25 micrograms - Purple50 micrograms - Red75 micrograms - Grey100 micrograms - Blue

Parathyroid hormone (rDNA) is injected using the cartridge with a reusable pen. Each pen must beused by only one patient. A new sterile needle must be used for every injection. Use 31 G x 8 mm penneedles. 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, orcontains visible particles.

DO NOT SHAKE during or after reconstitution; shaking may cause denaturation of the activesubstance.

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 localrequirements.

Takeda Pharmaceuticals International AG Ireland Branch

Block 2 Miesian Plaza50-58 Baggot Street Lower

Dublin 2

D02 HW68

IrelandmedinfoEMEA@takeda.com

EU/1/15/1078/001

EU/1/15/1078/002

EU/1/15/1078/003

EU/1/15/1078/004

Date of first authorisation: 24 April 2017

Date of latest renewal: 22 March 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.