Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Takeda Pharmaceuticals International AG Ireland Branch, Block 3 Miesian Plaza, 50 – 58 Baggot Street Lower, Dublin 2, Ireland
Natpar is contraindicated in patients:
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.
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 was reported in clinical trials with Natpar. Hypercalcaemia commonly occurred during the titration period, during which doses of oral calcium, active vitamin D, and Natpar were being adjusted. Hypercalcaemia may be minimised by following the recommended dosing, the monitoring information, and asking patients about any symptoms of hypercalcaemia. If severe hypercalcaemia (>3.0 mmol/L or above upper limit of normal with symptoms) develops, hydration and temporarily stopping Natpar, calcium and active vitamin D should be considered until serum calcium returns to the normal range. Then consider resuming Natpar, calcium and active vitamin D at lower doses (see sections 4.2 and 4.8).
Hypocalcaemia, a common clinical manifestation of hypoparathyroidism, was reported in clinical trials with Natpar. Most of the hypocalcaemic events occurring in the clinical trials were mild to moderate in severity. 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).
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).
Natpar should be used with caution in patients with severe renal or hepatic disease because they have not been evaluated in clinical trials.
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).
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.
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).
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.
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).
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.
There are no data from the use of Natpar in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
A risk to the pregnant woman or developing foetus cannot be excluded. A decision must be made whether to initiate or discontinue treatment with Natpar during pregnancy taking into account the known risks of therapy versus the benefit for the woman.
It is unknown whether Natpar is excreted in human milk.
Available pharmacology data in animals have shown excretion of Natpar in milk (see section 5.3).
A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue 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.
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.
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).
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-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. 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).
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.
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 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.
This medicinal product must not be mixed with other medicinal products.
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