Vadadustat

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.

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).

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.

Vadadustat may increase the AUC of OAT3 substrates when co-administered. The AUC of furosemide (40 mg) increased 2-fold following multiple doses of vadadustat (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.

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.

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.

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.

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.

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.

Vadadustat 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, vadadustat 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.

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.

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.

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. As a precautionary measure, it is preferable to avoid the use of vadadustat during pregnancy.

It is unknown whether vadadustat is excreted in human milk. Available pharmacokinetic data in animals have shown excretion of vadadustat in milk. 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.

The potential risk for humans is unknown.

Vadadustat 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 vadadustat and 1955 treated with darbepoetin alfa, including 1514 exposed for at least 6 months and 1047 exposed for greater than one year to vadadustat.

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 the following table.

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.

Elevated liver enzymes and blood bilirubin increased

Hepatocellular injury attributed to vadadustat was uncommonly reported (in less than 0.2% of patients). The majority of events were non-serious, asymptomatic and resolved after discontinuation of vadadustat. 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 vadadustat, 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 vadadustat. This case was multifactorial and resolved after vadadustat 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.