YORVIPATH Solution for injection Ref.[51687] Active ingredients: Palopegteriparatide

Hypercalcaemia

Serious events of hypercalcaemia have been reported with Yorvipath (see section 4.8). The risk is highest when starting or increasing the dose. During treatment, serum calcium should be measured (see section 4.2) and patients should be monitored for signs and symptoms of hypercalcaemia. If severe hypercalcaemia occurs, treatment should be as per clinical guidelines and dose adjustment of Yorvipath should be considered (see section 4.2).

Hypocalcaemia

Serious events of hypocalcaemia have been reported with Yorvipath (see section 4.8). The risk is highest when treatment is abruptly discontinued but may occur at any time. During treatment, serum calcium should be measured and patients should be monitored for signs and symptoms of hypocalcaemia. If severe hypocalcaemia occurs, treatment should be as per clinical guidelines, dose adjustment of Yorvipath should be considered, and dose adjustment of standing or as needed doses of active vitamin D and/or calcium supplements should be considered (see section 4.2).

Concomitant use with cardiac glycosides

Hypercalcaemia of any cause may predispose to digitalis toxicity. In patients using Yorvipath concomitantly with cardiac glycosides (such as digoxin or digitoxin), serum calcium and cardiac glycoside levels should be monitored and patients should be observed for signs and symptoms of digitalis toxicity (see section 4.5).

Severe renal or hepatic disease

No studies have been performed in patients with severe renal impairment and severe hepatic impairment. Use with caution in these patient populations. Patients with eGFR of <45 mL/min may be more susceptible for hypercalcaemic reactions and transient eGFR decrease, particularly when initiating treatment. If treatment is initiated in these patients, it is recommended to closely monitor serum calcium levels.

Use in patients at increased risk of osteosarcoma

Yorvipath has not been studied in and should be used with caution in patients;

• with skeletal malignancies and bone metastases
• who are receiving or who have received radiation therapy to the skeleton
• with unexplained elevations of bone-specific alkaline phosphatase
• with metabolic bone diseases who are at increased baseline risk for osteosarcoma (e.g., Paget’s disease of the bone)

Use in patients with osteoporosis

Screening for and monitoring of osteoporosis should be consistent with local clinical practice for any patient at increased risk of fragility fractures (see section 4.8).

Sodium content

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

No interaction studies have been performed.

Cardiac glycosides (such as digoxin or digitoxin) have a narrow therapeutic index and are affected by calcium. Patients should be monitored for signs and symptoms of digitalis toxicity when taking Yorvipath and cardiac glycosides.

Other medicinal products can exert effects on serum calcium and may alter the therapeutic response to Yorvipath, including but not limited to bisphosphonates, denosumab, romosozumab, thiazide and loop diuretics, systemic corticosteroids, and lithium. Patients should be monitored for changes in serum calcium when treated concomitantly with these medicinal products.

Pregnancy

There are no or limited amount of data from the use of Yorvipath in pregnant females. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). However, a risk to the pregnant female or developing foetus cannot be excluded. A decision to initiate or discontinue treatment with Yorvipath during pregnancy should take into account the possible risks versus the benefits for the pregnant female. It is recommended to closely monitor maternal serum calcium levels in pregnant females with hypoparathyroidism, including if treated with Yorvipath.

Breast-feeding

It is unknown whether palopegteriparatide is excreted in human milk. As palopegteriparatide is not orally absorbed, it is unlikely to adversely affect the breast-fed child. A decision to discontinue breast-feeding or Yorvipath therapy should take into account the benefit of breast-feeding for the child and the benefit of therapy for the female. It is recommended to closely monitor maternal serum calcium levels if breast-feeding with hypoparathyroidism, including if treated with Yorvipath.

Fertility

No studies have been performed on the effects of palopegteriparatide on human fertility. Data from animal studies do not indicate that administration of palopegteriparatide impairs fertility (see section 5.3).

Yorvipath has no or negligible influence on the ability to drive and use machines. However, dizziness, presyncope, syncope and/or orthostatic hypotension was observed in some patients. These patients should refrain from driving or the use of machines until symptoms have subsided.

Summary of the safety profile

The most frequently reported adverse reactions in clinical trials with palopegteriparatide were injection site reactions (21.6%), headache (18.7%), and paraesthesia (13.7%). The most serious adverse reaction reported in clinical trials was hypercalcaemia (1.40%).

Tabulated list of adverse reactions

Table 2 presents the adverse reactions for palopegteriparatide-treated patients identified in all phase 2 and phase 3 placebo-controlled studies within the MedDRA system organ class. The adverse reactions listed in the table below are presented by system organ class and frequency categories, defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), and frequency not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 2. Frequency of adverse reactions of palopegteriparatide:

^a For these adverse reactions, the first occurrence was almost exclusively within the first 3 months of treatment (titration period).
^b Injection site reactions include injection site reaction, injection site erythema, injection site bruising, injection site pain, injection site haemorrhage, injection site rash, and injection site swelling.
^c Dizziness includes dizziness and dizziness postural.
^d Vasodilatory symptoms include dizziness postural, headache, palpitations, Postural orthostatic tachycardia syndrome, orthostatic hypotension, Blood pressure orthostatic decreased and syncope. Vasodilatory symptoms (as identified in clinical
trials) occurred more frequently in the first 3 months of treatment and constituted a subset of total events reported as adverse reactions. A total of 3 events (in 2 patients) considered related to palopegteriparatide occurred within the first 3 months in TCP-304: dizziness postural (n=1), and headache and palpitations (n=1).
^e These signs and symptoms are potentially associated with hypercalcaemia, as observed in clinical trials.
^f These signs and symptoms are potentially associated with hypocalcaemia, as observed in clinical trials.

Description of selected adverse reactions

Hypercalcaemia

Serious events of hypercalcaemia have been reported with Yorvipath. The incidence of hypercalcemia was greater in patients treated with Yorvipath compared to placebo. During the blinded period, symptomatic hypercalcemia was reported in 8.6% of patients treated with Yorvipath, and all occurred within the first 3 months after initiation of Yorvipath.

Immunogenicity

Patients may develop antibodies to palopegteriparatide. The proportion of patients testing positive for binding antibodies at any time during treatment was low, with 0.7% having low titre, non-neutralising antibodies towards PTH and 5% having low titre treatment-emergent antibodies against PEG. In 2.2% of the palopegteriparatide-treated patients with pre-existing PEG antibodies, a transient impact on PK (increased clearance of total PTH, mPEG and decreased PTH concentrations) with decreasing serum calcium was observed. However, therapeutic effectiveness was maintained by appropriate dose adjustment of palopegteriparatide according to the trial titration algorithm.

Injection site reactions

Injection site reactions were the most common adverse reactions reported in clinical trials (median onset was 2.5 days; incidence of 21.6%). The most common injection site reactions were localised erythema (all <5 cm with the majority 0 to <2 cm) and were mild or moderate (grade 1 or 2) in severity with median duration of 72 hours. All injection site reactions resolved without treatment; none were serious or led to discontinuation.

Vasodilatory symptoms

Vasodilatory symptoms have been reported with Yorvipath. These symptoms are usually transient and resolved without treatment; none were serious or led to discontinuation. If symptoms occur, dosing at bedtime while reclining is recommended.

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.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.