Pyrukynd · 4.1 Therapeutic indications · 1

HOS-099789 · has-adverse-reaction-information · PDF-Seite 7

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 7 (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 System organ class Very common Common Psychiatric disorders Insomnia Gastrointestinal disorders Nausea General disorders and administration Hot flush site conditions Investigations Oestrone decreased Blood testosterone increased (males) (males) Oestradiol decreased (males) 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 treat

Auszug; vollständigen Abschnitt im Original lesen.

HOS-099795 · has-adverse-reaction-information · PDF-Seite 23

Summary of the safety profile The safety evaluation of Pyrukynd is based on experience from two randomised, double-blind, placebo-controlled clinical studies: one in adult patients with non-transfusion-dependent alpha- or beta-thalassaemia (ENERGIZE) and one in adult patients with transfusion-dependent alpha- or beta- thalassaemia (ENERGIZE-T). Across both studies, 301 subjects received Pyrukynd during the double- blind period and 292 subjects had > 12 months of exposure to Pyrukynd with continued exposure during the open-label extension period. The safety profile for Pyrukynd was characterized considering the data from both the double-blind and open-label extension periods. The most common adverse reactions across both studies were headache (24.9%) and insomnia (24.3%) and the most common laboratory abnormalities observed were oestrone decreased (males) (57.8%), free testosterone increased (males) (57.4%), blood testosterone increased (males) (40.2%), and oestradiol decreased (males) (15.6%). 23 Tabulated list of adverse reactions The adverse reactions associated with Pyrukynd as identified in clinical studies of patients with thalassaemia 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 1: Adverse reactions System organ class Very common Common Uncommon Psychiatric disorders Insomnia Nervous system Headache Dizziness disorders Cardiac disorders Palpitations Hepatobiliary Hypertransaminasaemia disorders Skin and subcutaneous Pruritus tissue disorders Rash Musculoskeletal and Arthralgia connective tissue Pain in extremity disorders Renal and urinary Proteinuria disorde

Auszug; vollständigen Abschnitt im Original lesen.

HOS-099791 · has-contraindication-information · PDF-Seite 20

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 20

HOS-099785 · has-contraindication-information · PDF-Seite 5

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

HOS-099790 · has-indication-information · PDF-Seite 19

Pyrukynd is indicated in adults for the treatment of anaemia associated with transfusion-dependent and non-transfusion-dependent alpha- or beta-thalassaemia (see section 5.1).

HOS-099784 · has-indication-information · PDF-Seite 3

Pyrukynd is indicated for the treatment of pyruvate kinase deficiency (PK deficiency) in adult patients (see section 4.4).

HOS-099787 · has-interaction-information · PDF-Seite 6

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 mitapivat 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 AUC0-t, AUC∞ and Cmax by 4.7-fold, 4.9-fold and 1.7-fold, respectively. Increased mitapivat plasma exposures may increase the risk of adverse reactions. The concomitant use of CYP3A4 inhibitors with mitapivat should be avoided (see section 4.4). If concomitant use of a CYP3A4 inhibitor is unavoidable, patients should be monitored for increased risk of adverse reactions (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 AUC0-t, AUC∞ and Cmax by 91%, 91% and 77%, respectively. Decreased mitapivat plasma exposures may reduce the efficacy of mitapivat. The concomitant use of CYP3A4 inducers with mitapivat 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 mitapivat 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 mitapivat on other medicinal products CYP3A4 substrates The effect of mitapivat (100 mg twice daily) on the pharmacokinetics of a single dose of midazolam (a sensitive CYP3A4 substrate) was evaluated in a Phase 1 study. Mitapivat at steady state decreased midazolam AUCs (AUC0-t, AUC∞) and Cmax by 53% and 37%, respectively. Alternative therapies that are not sensitive substrates of CYP3A4 should be considered during treatment with mitapivat (see section 4.4). If co-administration of mitapivat with sensitive CYP3A4 s

Auszug; vollständigen Abschnitt im Original lesen.

HOS-099793 · has-interaction-information · PDF-Seite 21

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 mitapivat 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 AUC0-t, AUC∞ and Cmax by 4.7-fold, 4.9-fold and 1.7-fold, respectively. Increased mitapivat plasma exposures may increase the risk of adverse reactions. The concomitant use of CYP3A4 inhibitors with mitapivat should be avoided (see section 4.4). If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of mitapivat should be 100 mg once daily and patients should be monitored for increased risk of 21 adverse reactions. When used with a moderate CYP3A inhibitor, patients should not exceed a dose of 100 mg once daily. 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 AUC0-t, AUC∞ and Cmax by 91%, 91% and 77%, respectively. Decreased mitapivat plasma exposures may reduce the efficacy of mitapivat. The concomitant use of CYP3A4 inducers with mitapivat 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. Patients should not exceed the recommended dose of 100 mg twice daily. Gastric acid-reducing agents Concomitant use of mitapivat with medicinal products that elevate gastric pH was not evaluated in a clinical drug-drug interaction study; however, there were no clinically meaningful changes in steady-state AUC and Cmax with concomitant administration of proton pump inhibitors in thalassaemia patients based on population PK analysis. Effect of mitapivat on other medicinal products CYP3A4 substrates The effect of mitapivat (100 mg twice daily) on the pharmacokinetics of a single dose of midazolam (a sensitive CYP3A4 substrate) was evaluated in a Phase 1 study. Mitapivat at steady state decreased midazolam AUCs (AUC0-t, AUC∞) and Cmax by 53% and 37%, respectively. Alternative therapies that are not sensitive

Auszug; vollständigen Abschnitt im Original lesen.

HOS-099788 · has-pregnancy-information · PDF-Seite 7

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.

HOS-099794 · has-pregnancy-information · PDF-Seite 23

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.

HOS-099792 · has-warning-information · PDF-Seite 21

Hypertransaminasaemia Liver injury has been observed in patients with thalassaemia treated with mitapivat within the first 6 months of exposure (see section 4.8). Liver tests should be obtained prior to the initiation of Pyrukynd and monthly thereafter for the first 6 months and as clinically indicated. Pyrukynd should be interrupted if clinically significant increases in liver tests are observed or alanine aminotransferase is > 5 times the ULN. Pyrukynd should be discontinued if hepatic injury due to mitapivat is suspected. 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 adverse reactions 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 This medicinal product 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’. Limitation of the Clinical Data The clinical studies did not include patients with active and/or uncontrolled cardiac or pulmonary disease.

HOS-099786 · has-warning-information · PDF-Seite 5

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 adverse reactions 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 This medicinal product 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’. 5