Pyrukynd

Posology The recommended starting dose is 5 mg taken orally twice daily. To gradually increase haemoglobin (Hb) levels and maximise the effect, Pyrukynd should be titrated through sequential doses of 5 mg twice daily, 20 mg twice daily and 50 mg twice daily, with sequential dose increases occurring every 4 weeks (see Table 1).

Hb level and transfusion requirement should be assessed before increasing to the next dose level as some patients may reach and maintain normal Hb levels at 5 mg twice daily or 20 mg twice daily. The maximum recommended dose is 50 mg twice daily.

Treatment with Pyrukynd is intended to be long-term. g. bleeding, surgery, other concomitant illnesses).

Table 1:

Dose titration and maintenance schedule Duration Dose titration and maintenance Day 1 to Week 4 All patients: • 5 mg twice daily Week 5 to Week 8 If Hb level is below normal range or patient has required a transfusion within the last 8 weeks: • Increase to 20 mg twice daily and maintain for 4 weeks.

If Hb level is within normal range and patient has not required a transfusion within the last 8 weeks: • Maintain 5 mg twice daily. Week 9 to Week 12 If Hb level is below normal range or patient has required a transfusion within the last 8 weeks: • Increase to 50 mg dose twice daily and maintain thereafter.

If Hb level is within normal range and patient has not required a transfusion within the last 8 weeks: • Maintain current dose (5 mg twice daily or 20 mg twice daily). Maintenance If Hb level decreases, consider up-titration to the maximum of 50 mg twice daily as per the above schedule.

Interruption or discontinuation To minimise the risk of acute haemolysis, abrupt interruption or discontinuation of Pyrukynd should be avoided. The dose should be tapered to gradually discontinue the medicinal product over a 1-2 week period (see Table 2).

8). 4 Table 2: Dose taper schedule Current dose Dose taper schedule Day 1-7 Day 8-14 Day 15 5 mg twice daily 5 mg once daily Discontinue N/A 20 mg twice daily 20 mg once daily 5 mg once daily Discontinue 50 mg twice daily 50 mg once daily 20 mg once daily Discontinue N/A: not applicable.

Missed dose If a dose of Pyrukynd is missed by 4 hours or less, the dose should be administered as soon as possible. If a dose is missed by more than 4 hours, a replacement dose should not be administered, and the patient should wait until the next scheduled dose.

Summary of the safety profile The safety evaluation of Pyrukynd is based on experience from a randomised, double-blind, placebo- controlled clinical study of adult patients with PK deficiency who were not regularly transfused (ACTIVATE) and a single-arm clinical study of adult patients with PK deficiency who were regularly transfused (ACTIVATE-T).

7%). Tabulated list of adverse reactions The adverse reactions associated with Pyrukynd as identified in clinical studies of patients with PK deficiency are tabulated below. Adverse reactions are listed by MedDRA system organ class and frequency: 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); not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. 4). 2. 8%) experienced haemolysis upon sudden withdrawal of Pyrukynd, including 1 serious adverse event of acute haemolysis. In both patients who received an initial Pyrukynd dose of 300 mg twice daily, a rapid and large Hb increase was observed during the first 3 weeks of treatment.

This was followed by a sudden discontinuation of Pyrukynd without taper, which resulted in acute haemolysis with anaemia. Patients who missed a few doses of Pyrukynd later in their treatment course, or for whom the dose was tapered, did not experience events of acute haemolysis.

Changes in sex hormone levels Mitapivat is a weak aromatase inhibitor in vitro. 3%) males experienced decreases in oestradiol and oestrone below the lower limit of normal, respectively. 3%) experienced oestrone decrease below the lower limit of normal.

These changes in hormone levels were maintained throughout the study period. In patients who discontinued Pyrukynd at the end of the core period, the hormone changes were reversible. Sex hormone analysis in female patients was limited due to physiological variations in hormone levels expected throughout the normal menstrual cycle and the various types of hormonal contraceptives used by patients.

8). Abrupt interruption or discontinuation of treatment with Pyrukynd should be avoided. 2). If discontinuing treatment abruptly, patients should be monitored for signs of acute haemolysis and anaemia which may include among other symptoms and signs: jaundice, scleral icterus and dark urine.

Efficacy across mutation types The 2 Phase 3 clinical studies ACTIVATE and ACTIVATE-T excluded patients who were homozygous for the R479H mutation or who had 2 non-missense mutations (without the presence of another missense mutation) in the PKLR gene.

In the Phase 2 clinical study, there were 10 subjects with 2 non-missense mutations (without the presence of another missense mutation) in the PKLR gene, and 5 subjects homozygous for the R479H mutation. 1). 2). g. 5). 6). 5). Potential drug-drug interactions should be considered whenever beginning or discontinuing treatment with mitapivat or other medicinal products concomitantly administered with mitapivat.

Lactose Pyrukynd contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

1.