PYRUKYND Film-coated tablet Ref.[50547] Active ingredients: Mitapivat

Acute haemolysis

Acute haemolysis with subsequent anaemia has been observed following abrupt interruption or discontinuation of Pyrukynd (see section 4.8). Abrupt interruption or discontinuation of treatment with Pyrukynd should be avoided. A gradual reduction in dosing rather than abrupt cessation is recommended (see section 4.2). 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. Patients with these mutations are less likely to respond to treatment with Pyrukynd (see section 5.1). Treatment should be discontinued if clinical benefit is not observed (see section 4.2).

Drug-drug interactions

Hormonal contraceptives

Mitapivat may decrease the systemic exposure of hormonal contraceptives that are sensitive substrates of cytochrome P450 3A4 (CYP3A4) (e.g. ethinylestradiol) (see section 4.5). Women of childbearing potential should be counselled regarding the use of additional or alternative contraception methods (see section 4.6).

Co-administration of other medicinal products

Co-administration of specific medicinal products with mitapivat may result in increased risk of insomnia or changes in efficacy of mitapivat or changes in efficacy of the co-administered medicinal products (see section 4.5). 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’.

Mitapivat is primarily metabolised by CYP3A4 and is a substrate for P-glycoprotein (P-gp). Mitapivat induces CYP3A4 and may also induce CYP2B6, CYP2C8, CYP2C9, CYP2C19 and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). Mitapivat may inhibit CYP3A4. Mitapivat may induce and inhibit P-gp (see section 5.2).

Effects of other medicinal products on Pyrukynd

CYP3A4 inhibitors

The effect of itraconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of a single dose of mitapivat was evaluated in a Phase 1 study. Itraconazole increased mitapivat AUC_0-t, AUC_∞ and C_max by 4.7-fold, 4.9-fold and 1.7-fold, respectively. Increased mitapivat plasma exposures may increase the risk of insomnia. The concomitant use of CYP3A4 inhibitors with Pyrukynd should be avoided (see section 4.4). If concomitant use of a CYP3A4 inhibitor is unavoidable, patients should be monitored for increased risk of insomnia (see section 4.2).

CYP3A4 inducers

The effect of rifampicin (a strong CYP3A4 inducer) on the pharmacokinetics of a single dose of mitapivat was evaluated in a Phase 1 study. Rifampicin decreased mitapivat AUC_0-t, AUC_∞ and C_max by 91%, 91% and 77%, respectively. Decreased mitapivat plasma exposures may reduce the efficacy of Pyrukynd. The concomitant use of CYP3A4 inducers with Pyrukynd should be avoided (see section 4.4). If concomitant use of a CYP3A4 inducer is unavoidable, patients should be monitored for reduced efficacy of mitapivat.

Gastric acid-reducing agents

Mitapivat exhibits pH-dependent solubility (see section 5.2) and coadministration with gastric acid-reducing agents (e.g. famotidine) may decrease mitapivat absorption (see section 4.4). Concomitant use of Pyrukynd with medicinal products that elevate gastric pH was not evaluated in a clinical drug-drug interaction study. If concomitant use of gastric acid-reducing agents is unavoidable, patients should be monitored for reduced efficacy of mitapivat.

Effect of Pyrukynd on other medicinal products

CYP3A4 substrates

Mitapivat induces and may inhibit CYP3A4 (see section 5.2) and co-administration with sensitive CYP3A4 substrates (e.g. midazolam) may alter systemic exposure of these medicinal products. Concomitant use of Pyrukynd with substrates of this enzyme was not evaluated in a clinical drug-drug interaction study. Alternative therapies that are not sensitive substrates of CYP3A4 should be considered during treatment with Pyrukynd (see section 4.4). If co-administration of Pyrukynd with sensitive CYP3A4 substrates is unavoidable, patients should be carefully monitored especially for those substrates with a narrow therapeutic index (e.g. alfentanil, carbamazepine, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus).

Hormonal contraceptives

Mitapivat may alter the systemic exposure of hormonal contraceptives that are sensitive substrates of CYP3A4 (e.g. ethinylestradiol) (see section 4.4) and may affect their efficacy (see section 4.6).

UGT1A1, CYP2B6 and CYP2C substrates

Based on in vitro data, mitapivat may induce UGT1A1, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 (see section 5.2) and may decrease systemic exposure to substrates of these enzymes (e.g. irinotecan [UGT1A1]; bupropion [CYP2B6]; omeprazole [CYP2C19]; repaglinide [CYP2C8]; warfarin [CYP2C9]). Concomitant use of Pyrukynd with substrates of these enzymes was not evaluated in a clinical drug-drug interaction study. Alternative therapies that are not UGT1A1 substrates or sensitive substrates of CYP2B6 or CYP2C should be considered during treatment with Pyrukynd (see section 4.4). If co-administration is unavoidable, patients should be monitored for loss of therapeutic effect of substates of these enzymes, especially for those with a narrow therapeutic index (e.g. irinotecan [UGT1A1]; cyclophosphamide [CYP2B6]; valproic acid [CYP2C19]; paclitaxel [CYP2C8]; warfarin, phenytoin [CYP2C9]).

P-gp substrates

Based on in vitro data, mitapivat may induce and inhibit P-gp (see section 5.2) and may alter systemic exposure of substrates (e.g. dabigatran etexilate) of this transporter. Concomitant use of Pyrukynd with substrates of P-gp was not evaluated in a clinical drug-drug interaction study. Alternative therapies that are not P-gp substrates should be considered during treatment with Pyrukynd (see section 4.4). If co-administration of Pyrukynd with P-gp substrates is unavoidable, patients should be carefully monitored especially for those substrates with a narrow therapeutic index (e.g. colchicine, digoxin).

Women of childbearing potential / Contraception in females

Women of childbearing potential should avoid becoming pregnant while receiving Pyrukynd.

Women of childbearing potential should use contraception during treatment with Pyrukynd and for at least 1 month after the last dose. Mitapivat may decrease the systemic exposure of hormonal contraceptives that are sensitive substrates of CYP3A4 (see sections 4.4 and 4.5). Additional or alternative methods of contraception should be considered.

Pregnancy

There are no or limited amount of data from the use of mitapivat in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Pyrukynd is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether mitapivat and/or its metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to abstain from Pyrukynd therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no human data on the effect of mitapivat on fertility. Animal studies have shown reversible effects on reproductive organs of males and females (see section 5.3). While taking mitapivat, there may be an impact on the ability of a woman and a man to conceive.

Pyrukynd has a minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines in case they experience insomnia during treatment with Pyrukynd (see section 4.8).

Summary of the safety profile

The safety evaluation of Pyrukynd is based on experience from a randomised, double-blind, placebocontrolled 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).

The most common adverse reaction across both studies was insomnia (19.4%) and the most common laboratory abnormalities observed were oestrone decreased (males) (43.5%) and oestradiol decreased (males) (8.7%).

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.

Table 3. Adverse reactions:

Description of selected adverse reactions

Acute haemolysis

Abrupt interruption or discontinuation of Pyrukynd can lead to acute haemolysis (see section 4.4). For guidance on how to interrupt or discontinue treatment see section 4.2.

In a Phase 2 study, 2 of 52 patients (3.8%) 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. In ACTIVATE, 1 of 16 (6.3%) males experienced increases in testosterone to above normal levels and 2 of 16 (12.5%) and 9 of 16 (56.3%) males experienced decreases in oestradiol and oestrone below the lower limit of normal, respectively. In ACTIVATE-T, 1 of 7 males (14.3%) 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.

Insomnia

In ACTIVATE, insomnia was reported with a similar incidence between patients who received Pyrukynd and patients who received placebo and was reported in 6 of 27 (22.2%) patients in ACTIVATE-T. In a Phase 2 study, 5 of 27 (18.5%) patients treated at 50 mg twice daily and 16 of 25 (64%) patients treated at 300 mg twice daily experienced insomnia during the core period.

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.

Not applicable.