VAFSEO Film-coated tablet Ref.[50970] Active ingredients: Vadadustat

Cardiovascular and mortality risk

In controlled clinical trials patients with dialysis-dependent (DD) CKD treated with Vafseo, experienced similar risks for death, myocardial infarction and stroke compared to darbepoetin alfa (see section 5.1).

Patients with signs and symptoms of serious adverse cardiovascular reactions or stroke should be promptly evaluated and treated according to standard of care. The decision to interrupt or discontinue treatment should be based on a benefit-risk consideration for the individual patient.

Thromboembolic events

Thromboembolic events were reported as very common amongst the patients from two activecontrolled clinical trials in CKD (see section 4.8). Therefore, patients with pre-existing risk factors for thromboembolic event and prior history of thromboembolic events (e.g., deep venous thrombosis, pulmonary embolism, and cerebral vascular accident) should be monitored carefully.

Patients with signs and symptoms of thromboembolic events should be promptly evaluated and treated according to standard of care. The decision to interrupt or discontinue treatment should be based on a benefit-risk consideration for the individual patient.

Hepatic impairment

Vafseo is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C) (see sections 4.2 and 5.2).

Hepatotoxicity

An increase in ALT, AST (frequency common) and/or bilirubin (frequency uncommon) attributed to Vafseo was reported (see section 4.8). ALT, AST, and bilirubin must be evaluated prior to the initiation of Vafseo, monthly for three months after initiation and as clinically indicated thereafter (see section 4.2).

Vafseo must be discontinued if ALT or AST elevations > 3x ULN are accompanied by a bilirubin increase > 2x ULN, or if there is persistent ALT or AST > 3x ULN (see sections 4.2 and 4.8).

Worsening of hypertension

Administration of Vafseo in patients with CKD may be associated with worsening of hypertension (see section 4.8). Blood pressure should be monitored before initiation and regularly thereafter at a frequency determined by a patient’s individual situation and local clinical practice. Patients should be advised on the importance to comply with antihypertensive therapy and monitoring of blood pressure.

Convulsions

Convulsions were commonly reported in patients receiving vadadustat (see section 4.8). Vadadustat should be used with caution in patients with a history of convulsions or fits, epilepsy or medical conditions associated with a predisposition to convulsion activity such as central nervous system (CNS) infections. The decision to interrupt or discontinue treatment should be based on a benefit-risk consideration for the individual patient.

Initial decrease in Hb levels in patients converting from ESA

Hb levels may initially decrease when converting patients from an ESA to Vafseo especially in patients who were on high baseline ESA doses. Generally, the higher the baseline ESA dose, the deeper the initial decrease in Hb levels will be before levels gradually return to baseline Hb by Weeks 16 to 20 (see section 5.1 for course of Hb during treatment in individual studies). Rescue therapy such as RBC transfusion or ESA treatment may be considered during the transition phase if Hb values fall below 9.0 g/dL or if response is considered not acceptable. Patients receiving RBC transfusions are recommended to continue Vafseo treatment during the transfusion period. Vafseo should be paused temporarily during ESA rescue treatment and may be resumed when Hb levels are ≥10 g/dL (see section 4.2).

Inadequate response to therapy

Inadequate response to therapy with vadadustat should prompt a search for causative factors. A reticulocyte count should be considered as part of the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, an examination of the bone marrow should be considered. In the absence of an addressable cause for an inadequate response by 24 weeks of therapy, Vafseo should be discontinued.

Misuse

Misuse may lead to an excessive increase in red blood cell volume. This may be associated with lifethreatening complications.

Excipients

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

Vadadustat was metabolically stable in vitro and metabolism via cytochrome P450s (CYPs) was minimal. The metabolic pathways involved were oxidation and mainly glucuronidation. The major circulating metabolite vadadustat-O-glucuronide was catalyzed by multiple uridine 5'-diphosphoglucuronosyltransferases (UGTs, UGT1A1, 1A7, 1A8 and 1A9).

Vadadustat has potentially clinically relevant interactions with breast cancer resistance protein (BCRP) substrates, OAT3 substrates, OAT1/3 inhibitors and CYP2C9 substrates with a narrow therapeutic index.

Vadadustat induced CYP2B6, inhibited CYP2C8 and caused down-regulation of CYP3A4 in in vitro experiments. However, these interactions have not been examined in vivo.

Effect of other medicinal products on the pharmacokinetics of vadadustat

Iron supplements, phosphate binders, and other medicinal products whose primary component consists of multivalent cations.

Co-administration with oral iron supplements (e.g., ferric citrate, ferrous sulphate, sodium ferrous citrate), products which contain iron, iron-containing phosphate binders (e.g., ferric citrate, sucroferric oxyhydroxide) and non-iron-containing phosphate binders (calcium acetate, sevelamer carbonate) decreases the exposure (C_max and AUC) of vadadustat.

The co-administration of oral iron-based medicinal products reduced the bioavailability of vadadustat up to 90% and 92% in terms of the AUC_∞ and C_max.

The co-administration of non-iron-containing phosphate binders reduced the bioavailability of vadadustat up to 55% and 52% for AUC_∞ and C_max.

Vafseo should be administered at least 1 hour before oral iron supplements, products whose primary component consists of iron or iron-containing phosphate binders. As vadadustat may form a chelate with multivalent cations, Vafseo should be administered at least 1 hour before or 2 hours after noniron-containing phosphate binders or other medicinal products whose primary component consists of multivalent cations such as calcium, magnesium or aluminium.

Organic anion transporter (OAT) OAT1/OAT3 inhibitors

Co-administration with probenecid, an OAT1/OAT3 inhibitor, increased vadadustat AUC values almost 2-fold. If co-administration with strong or moderate OAT1 or OAT3 inhibitors (e.g. benzylpenicillin, teriflunomide or p-aminohippuric acid) occurs, patients should be managed cautiously and evaluated for excessive effects of vadadustat. For potential adverse reactions and dose adjustment in case of rapid Hb rise please refer to sections 4.8 and 4.2.

Effect of vadadustat on the pharmacokinetics of other medicinal products

BCRP substrates and some statins

Vadadustat may increase the AUC of BCRP substrates, and some statins when co-administered. Dose adjustment of co-prescribed BCRP substrates may be needed. The following have been studied (see Table 2).

Table 2. Potential clinically significant drug interactions between vadadustat and BCRP substrates, and select statins:

In addition to sulfasalazine, simvastatin, and rosuvastatin, monitor for signs of excessive effects of coadministered BCRP substrates such as fluvastatin, nelfinavir, pitavastatin, and topotecan, and for the need of their dose reduction.

OAT3 substrates

Vadadustat may increase the AUC of OAT3 substrates when co-administered. The AUC of furosemide (40 mg) increased 2-fold following multiple doses of Vafseo (600 mg once daily). Monitor for signs of excessive effects of the co-administered OAT3 substrates such as famotidine, furosemide, methotrexate, olmesartan, sitagliptin, and zidovudine.

Dose adjustment of concomitantly administered OAT3 substrate may be needed.

CYP2C9 substrates

Co-administration of vadadustat (600 mg) with celecoxib (200 mg) increased celecoxib C_max and AUC 60% and 11%, respectively. Patients receiving warfarin or other narrow therapeutic CYP2C9 substrates (e.g., phenytoin) must therefore be managed cautiously and evaluated for excessive effects when treated with vadadustat.

CYP2B6 substrates

Vadadustat is an in vitro inducer of CYP2B6. Co-administration of vadadustat with sensitive substrates of CYP2B6 (e.g. efavirenz, bupropion) may alter their pharmacokinetics, and therefore caution should be exercised when vadadustat is co-administered with CYP2B6 substrates.

CYP3A4 substrates

Based on in vitro data, vadadustat may have a potential for CYP3A4 downregulation. Coadministration of vadadustat with CYP3A4 substrates may alter their pharmacokinetics and therefore caution should be exercised when vadadustat is co-administered with CYP3A4 substrates.

CYP2C8 substrates

Based on in vitro data, vadadustat may inhibit CYP2C8 and therefore may increase exposure to CYP2C8 substrates and therefore caution should be exercised when vadadustat is co-administered with CYP2C8 substrates.

Pregnancy

There are limited data for the use of vadadustat in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of vadadustat during pregnancy.

Breast-feeding

It is unknown whether vadadustat is excreted in human milk. Available pharmacokinetic data in animals have shown excretion of vadadustat in milk (for details, see section 5.3). A risk to infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue vadadustat therapy, taking into account the benefit of breast feeding for the child and benefit of therapy for the woman.

Fertility

Studies in animals showed no effects of vadadustat on fertility (see section 5.3).

The potential risk for humans is unknown.

Vafseo has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The adverse reactions are based on pooled data from two active-controlled studies in DD-CKD of 1947 patients treated with Vafseo and 1955 treated with darbepoetin alfa, including 1514 exposed for at least 6 months and 1047 exposed for greater than one year to Vafseo.

The most frequent (>10%) adverse reactions in patients treated with vadadustat are thromboembolic events (13.7%), diarrhoea (12.7%) and hypertension (11.1%).

The most frequent (≥1%) serious adverse reactions in patients treated with vadadustat are thromboembolic events (10.0%), hypotension (1.6%) and hypertension (1.1%).

Tabulated list of adverse reactions

All adverse reactions (ADRs) are listed by system organ class (SOC) 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) and not known (cannot be estimated from the available data) and are show in Table 3.

Table 3. Adverse reactions:

^a for further details, please refer to “Thromboembolic events” and "Convulsions"below.
^b Includes preferred terms transaminases increased, ALT increased, AST increased, hepatic enzyme increased, liver function test abnormal

Description of selected adverse reactions

Thromboembolic events

Cerebrovascular accident events occurred in 0.8% vs 0.9% (0.5 vs 0.5 events/100 PY) in the vadadustat and darbepoetin alfa groups respectively.

Deep vein thrombosis (DVT) events occurred in 0.7% vs 0.5% (0.4 vs 0.3 events/100 PY) in the vadadustat and darbepoetin alfa groups respectively.

Pulmonary embolism events occurred in 0.3% vs 0.5% (0.2 vs 0.3 events/100 PY) in the vadadustat and darbepoetin alfa groups respectively.

Transient ischaemic attack events occurred in 0.8% vs 0.4% (0.5 vs 0.3 events/100 PY) in the vadadustat and darbepoetin alfa groups respectively.

Acute myocardial infarction events occurred in 4.3% vs 4.2% (3.1 vs 2.9 events/100 PY) in the vadadustat and darbepoetin alfa groups respectively.

Arteriovenous graft thrombosis events occurred in 1.1% vs 1.1% (0.9 vs 1.0 events/100 PY) in the vadadustat and darbepoetin alfa groups respectively.

Arteriovenous fistula thrombosis events occurred in 3.0% vs 2.3% (2.1 vs 1.6 events/100 PY) in the vadadustat and darbepoetin alfa groups respectively.

For information on cardiovascular and mortality risk and thromboembolism please see sections 4.4 and 5.1.

Elevated liver enzymes and blood bilirubin increased

Hepatocellular injury attributed to Vafseo was uncommonly reported (in less than 0.2% of patients). The majority of events were non-serious, asymptomatic and resolved after discontinuation of Vafseo. The time to onset was generally within the first 3 months of treatment. Abnormal liver enzymes tests: elevated serum ALT (3x ULN), AST (3x ULN), and bilirubin (2x ULN) were seen in 1.8%, 1.4% and 0.3% of patients treated with Vafseo, respectively.

There was one serious adverse event of hepatocellular injury with jaundice in an NDD-CKD clinical trial patient which occurred approximately 8 weeks after initiating Vafseo. This case was multifactorial and resolved after Vafseo and other concomitant medicinal products were discontinued.

This single case did not meet Hy’s law criteria due to a significantly elevated alkaline phosphatase (ALP), which preceded the bilirubin elevation, indicating cholestasis as a contributing factor to the elevated bilirubin.

Convulsions

In DD-CKD patients, convulsions occurred in 1.6% (1.1 patients with events per 100 patient years of exposure) in the vadadustat group, and 1.6% (1.3 patients with events per 100 patient years of exposure) in the darbepoetin alfa group (see section 4.4).

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.