4.1. Therapeutic indications

Yorvipath is a parathyroid hormone (PTH) replacement therapy indicated for the treatment of adults with chronic hypoparathyroidism.

4.2. Posology and method of administration

Treatment should be initiated and monitored by physicians or qualified healthcare professionals experienced in the diagnosis and management of patients with hypoparathyroidism.

Posology

Dose recommendations of Yorvipath refer to micrograms of PTH(1-34). The dose should be individualised based on serum calcium. The optimal dose after titration is the minimum dose required to prevent hypocalcaemia. This is the dose that maintains serum calcium within the normal range without the need for active forms of vitamin D or calcium supplementation beyond recommended nutritional supplementation for the general population (generally less than 600 mg per day). Doses of active forms of vitamin D and calcium supplements will need to be adjusted prior to initiating and during treatment with Yorvipath based on serum calcium value (see section 4.4).

Patients receiving the maximum Yorvipath dose of 60 mcg per day who experience ongoing hypocalcaemia may require co-administration of therapeutic calcium and/or active forms of vitamin D.

Before initiation of Yorvipath

Serum 25(OH) vitamin D should be within the normal range and serum calcium should be stable within or slightly below the normal range (1.95 - 2.64 mmol/L [7.8 - 10.6 mg/dL]) on at least 1 laboratory value within two weeks prior to first dose of treatment.

Initiation of Yorvipath

The recommended starting dose is 18 mcg once daily with dose adjustments in 3 mcg increments thereafter every 7 days (see figure 1). The dose range is 6 to 60 mcg per day.

When initiating treatment with Yorvipath, the dose of active vitamin D or calcium supplements should be adjusted:

• If taking active vitamin D:

o If serum calcium is ≥ 2.07 mmol/L [≥ 8.3 mg/dL], active vitamin D (calcitriol or alfacalcidol) should be discontinued on the same day as the first dose of Yorvipath. Doses of calcium supplements should be maintained.

o If serum calcium is < 2.07 mmol/L [< 8.3 mg/dL], active vitamin D should be reduced by ≥ 50% on the same day as the first dose of Yorvipath. Doses of calcium supplements should be maintained.

• If not taking active vitamin D:

o Calcium supplements should be decreased by at least 1 500 mg on the same day as the first dose of Yorvipath. If taking elemental calcium doses ≤ 1 500 mg per day, calcium supplements should be discontinued entirely.

• If calcium supplements are indicated to meet dietary requirements, continuing dietary calcium supplements at doses ≤ 600 mg per day may be considered instead of discontinuing entirely.

Dose adjustment and maintenance of Yorvipath

Serum calcium concentration must be monitored during titration (see section 4.4). Yorvipath dose may be increased in increments of 3 mcg if at least 7 days have elapsed since a prior dose change (see figure 1). The dose must not be increased more often than every 7 days. Yorvipath may be reduced in increments of 3 mcg no more often than every 3 days in response to hypercalcaemia (see figure 1).

Serum calcium should be measured 7 days after the first dose and figure 1 should be followed for appropriate Yorvipath, active vitamin D, and calcium supplement dosing. After any subsequent dose change in Yorvipath, active vitamin D, or calcium supplements, serum calcium should be measured within 7 to 14 days and patients should be monitored for clinical symptoms of hypocalcaemia or hypercalcaemia. Yorvipath, active vitamin D, and/or calcium supplements should be adjusted as per figure 1. Dose adjustments of Yorvipath, active vitamin D, and calcium supplements should be made on the same day.

The maintenance dose should be the dose that achieves serum calcium within the normal range, without the need for active vitamin D or therapeutic doses of calcium. Optionally, calcium supplementation sufficient to meet dietary requirements (≤ 600 mg per day) may be continued. Serum calcium and 25(OH) vitamin D should be measured as per standard of care when a maintenance dose is achieved. 25(OH) vitamin D (non-active vitamin D) supplementation may be needed to reach normal serum levels.

Figure 1: Titration of Yorvipath, active vitamin D, and calcium supplements

Serum calcium low (< 2.07 mmol/L [< 8.3 mg/dL]):

Serum calcium normal (≥ 2.07 to ≤ 2.64 mmol/L [≥ 8.3 to ≤ 10.6 mg/dL]):

Serum calcium high (≥ 2.65 to < 3.00 mmol/L [≥ 10.7 to < 12.0 mg/dL]):

Serum calcium very high (≥ 3.00 mmol/L [≥ 12 mg/dL]):

Treatment should be withheld for 2 to 3 days and then serum calcium should be rechecked. If subsequent serum calcium is < 3.00 mmol/L [< 12 mg/dL], titration of Yorvipath, active vitamin D, and calcium supplements should be resumed as per the applicable section of figure 1 using the most recent serum calcium value obtained. If serum calcium remains ≥ 3.00 mmol/L [≥ 12 mg/dL], Yorvipath should be withheld for an additional 2 to 3 days and then serum calcium should be rechecked. See section 4.4 for more information on hypercalcaemia.

Missed dose

If a dose is missed by less than 12 hours, it should be administered as soon as possible. If a dose is missed by more than 12 hours, it should be skipped and the next dose should be administered as scheduled.

Interruption or discontinuation of Yorvipath

Interruption of daily administration should be avoided to minimise serum PTH fluctuations. Interruption or discontinuation of treatment can result in hypocalcaemia. When interrupting or discontinuing treatment for 3 or more consecutive doses, patients should be monitored for signs and symptoms of hypocalcaemia and consider to measure serum calcium. If indicated, treatment with calcium supplements and active vitamin D should be resumed. Treatment at the prescribed dose should be resumed as soon as possible after an interruption. When resuming treatment after an interruption, serum calcium should be measured and doses of Yorvipath, active vitamin D, and calcium supplements should be adjusted as per figure 1.

Special populations

Elderly

Dose adjustment is not required based on age (see section 5.2).

Hepatic impairment

Yorvipath has not been studied in patients with severe hepatic impairment and should be used with caution in these patients (see section 4.4).

Renal impairment

Dose adjustment is not required in patients with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min. Serum calcium levels should be measured more frequently when used in patients with eGFR < 45 mL/min (see section 4.4). Yorvipath has not been studied in patients with hypoparathyroidism and severe renal impairment (eGFR < 30 mL/min) (see section 5.2).

Paediatric population

The safety and efficacy of Yorvipath in children less than 18 years of age have not yet been established. No data are available.

Method of administration

Yorvipath must be administered as a subcutaneous injection to the abdomen or front of the thigh. The injection site should be rotated daily between four possible sites; abdomen (left or right) and front of the thigh (left or right).

Doses > 30 mcg per day (sequential injections)

All doses > 30 mcg per day should be administered as two single doses injected sequentially at different injection sites (table 1). It is recommended to use a different Yorvipath pen for the second daily injection, even if the two pens have the same-coloured push button (same strength).

Table 1: Recommended scheme for Yorvipath dosing > 30 mcg/day

Dose

Dosing scheme

Pen combination

33 mcg/day

15 mcg/day + 18 mcg/day

Two pre-filled pens of Yorvipath 294 mcg/0.98 mL (orange push button)*

36 mcg/day

18 mcg/day + 18 mcg/day

39 mcg/day

18 mcg/day + 21 mcg/day

42 mcg/day

21 mcg/day + 21 mcg/day

45 mcg/day

21 mcg/day + 24 mcg/day

One pre-filled pen of Yorvipath 294 mcg/0.98 mL (orange push button)

+

One pre-filled pen of Yorvipath 420 mcg/1.4 mL (burgundy push button)**

48 mcg/day

24 mcg/day + 24 mcg/day

Two pre-filled pens of Yorvipath 420 mcg/1.4 mL (burgundy push button)

51 mcg/day

24 mcg/day + 27 mcg/day

54 mcg/day

27 mcg/day + 27 mcg/day

57 mcg/day

27 mcg/day + 30 mcg/day

60 mcg/day

30 mcg/day + 30 mcg/day

*Yorvipath 294 micrograms/0.98 mL delivers doses of 15, 18, or 21 mcg of PTH(1-34) (with orange push button)

**Yorvipath 420 micrograms/1.4 mL delivers doses of 24, 27, or 30 mcg of PTH(1-34) (with burgundy push button)

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Patients with pseudohypoparathyroidism

4.4. Special warnings and precautions for use

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'.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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

MedDRA system organ class

Frequency

Adverse reaction

Metabolism and nutrition disorders

Common

Hypercalcaemiaa, Hypocalcaemia

Nervous system disorders

Very common

Headached, Paraesthesiaa

Common

Dizzinessa, c, d, Syncoped, Presyncoped

Cardiac disorders

Common

Palpitationsd, Postural orthostatic tachycardia syndromed

Vascular disorders

Common

Orthostatic hypotensiond

Uncommon

Hypertensione

Respiratory, thoracic and mediastinal disorders

Common

Oropharyngeal pain

Gastrointestinal disorders

Very common

Nauseaa

Common

Diarrhoeaa, Constipation, Vomiting, Abdominal discomfort, Abdominal pain

Musculoskeletal and connective tissue disorders

Common

Arthralgia, Myalgia, Muscle twitchingf, Musculoskeletal painf

General disorders and administration site conditions

Very common

Injection site reactionsa, b, Fatigue

Common

Asthenia, Thirst

Uncommon

Chest discomfortf, Chest painf

Skin and subcutaneous tissue disorders

Common

Rash, Photosensitivity reaction

Renal and urinary disorders

Uncommon

Nocturiae

Frequency not known

Polyuriae

Investigations

Frequency not known

Bone density decreased

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 Yellow Card Scheme at:

www.mhra.org.uk/yellowcard or search MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In the event of overdose, the patient should be carefully monitored by a medical professional.

Overdose can cause hypercalcaemia, the manifestations of which may include dehydration, heart palpitations, ECG changes, hypotension, nausea, vomiting, dizziness, muscle weakness, and confusion. Severe hypercalcaemia may require medical care and careful monitoring (see section 4.4).

One instance of accidental overdose of approximately 3-fold the prescribed dose lasting more than 7 consecutive days resulted in serum calcium as high as 16.1 mg/dL, the patient was symptomatic and required medical intervention. After withholding palopegteriparatide, calcium, and active vitamin D, the patient recovered and restarted on the correct dose.