PLGB 54937/0009 -0012/OD1

Hypoparathyroidism

Natpar is indicated as adjunctive treatment of adult patients with chronic hypoparathyroidism who cannot be adequately controlled with standard therapy alone.

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.

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). 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). 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 toxicity if hypercalcaemia develops. No drug-drug

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). 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.

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

Summary of the safety profile The most frequent adverse reactions among patients treated with Natpar were hypercalcaemia, hypocalcaemia, and their associated clinical manifestations including headache, diarrhoea, vomiting, paraesthesia, hypoaesthesia and hypercalciuria. In the clinical studies, these reactions were generally mild to moderate in severity and transient, and were managed with adjustments of Natpar, calcium and/or active vitamin D doses (see sections 4.4 and 5.1). Tabulated list of adverse reactions Adverse reactions for 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 disorders cough† 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-hydroxycholecalc iferol 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 7.4 years, the immunogenicity incidence rate was 16/87 (18.4%) and did not appear to increase over time. These 16 patients had low titre anti-PTH antibodies and, of these, 12 subsequently became antibody 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 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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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).

3 years. 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.

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 with 2 bromobutyl rubber stoppers and a crimp cap (aluminium) with a bromobutyl rubber seal. 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: 100 micrograms – Blue

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 Gx8 mm pen needles. After reconstitution, the liquid must be colourless and practically free of foreign particles; parathyroid hormone (rDNA) must not be used if the reconstituted solution is cloudy, coloured, or contains visible particles. DO NOT SHAKE during or after reconstitution; shaking may cause denaturation of the active substance. Read the instructions for use provided in the package leaflet before using the reusable pen. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

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