Vadadustat

Vafseo

150MG, 300MG, 450MG tabletÉtats-UnisCommercialiséAutorisé le 27 mars 2024

Contenu en anglais

Indications

VAFSEO is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months. Limitations of Use VAFSEO has not been shown to improve quality of life, fatigue, or patient well-being. VAFSEO is not indicated for use: As a substitute for red blood cell transfusions in patients who require immediate correction of anemia In patients with anemia due to CKD not on dialysis [see Warnings and Precautions ( 5.6 )] .

VAFSEO is a hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months. ( 1 ) Limitations of Use Not been shown to improve quality of life, fatigue, or patient well-being. Not indicated for use: As a substitute for transfusion in patients requiring immediate correction of anemia.

( 1 ) In patients with anemia due to CKD not on dialysis. ( 1 , 5.6 )

Contre-indications

VAFSEO is contraindicated in patients: with a known hypersensitivity to VAFSEO or any of its components [see Description ( 11 )] . with uncontrolled hypertension [see Warnings and Precautions ( 5.3 )] . Known hypersensitivity to VAFSEO or any of its components ( 4 ) Uncontrolled hypertension ( 4 )

Mises en garde et précautions d’emploi

Hepatotoxicity: Has been reported in patients taking VAFSEO. Measure ALT, AST and bilirubin prior to the initiation of VAFSEO, monthly after initiation for the first 6 months, then as clinically indicated. Discontinue VAFSEO if ALT or AST is persistently elevated or accompanied by elevated bilirubin. ( 5.2 ) Hypertension: Worsening hypertension, including hypertensive crisis may occur. Monitor blood pressure. Adjust anti-hypertensive therapy as needed.

( 5.3 ) Seizures: Seizures have occurred in patients with CKD taking VAFSEO. Monitor for new-onset seizures, premonitory symptoms, or change in seizure frequency. ( 5.4 ) Gastrointestinal Erosion: Gastric or esophageal erosions and gastrointestinal bleeding have been reported. ( 5.5 ) Malignancy: May have unfavorable effects on cancer growth. Not recommended if active malignancy. ( 5.7 )

Indications

( 1 ) In patients with anemia due to CKD not on dialysis. ( 1 , 5.6 )

Mises en garde et précautions d’emploi

Interactions

Iron supplements and iron-containing phosphate binders: Administer VAFSEO at least 1 hour before products containing iron. ( 7.1 ) Non-iron-containing phosphate binders: Administer VAFSEO at least 1 hour before or 2 hours after non-iron-containing phosphate binders. ( 7.1 ) BCRP substrates: Monitor for signs of substrate adverse reactions and consider substrate dose reduction. ( 7.2 ) Statins: Monitor for statin-related adverse reactions ( 7.2 ).

7.1Effect of Other Drugs on

VAFSEO Table 3 describes clinically significant drug interactions where concomitant use of another drug affects VAFSEO. Table 3 Drug Interactions with VAFSEO that Affect Vadadustat Exposure Iron supplements and phosphate binders Clinical Effect Co-administration with oral iron supplements, products containing iron, or phosphate binders decreases the exposure of vadadustat [ see Clinical Pharmacology ( 12.3 )] , which may reduce the effectiveness of VAFSEO.

Prevention or Management Stagger administration when VAFSEO is used with oral iron supplements, products containing iron, iron-containing phosphate binders, or non-iron-containing phosphate binders [see Dosage and Administration ( 2.5 )] . Examples * Iron supplements : ferric citrate, ferrous sulfate, sodium ferrous citrate Iron-containing phosphate binders : ferric citrate, sucroferric oxyhydroxide Non-iron-containing phosphate binders : calcium acetate, sevelamer carbonate Organic anion transporter (OAT) OAT1/OAT3 inhibitors Clinical Effect Co-administration with OAT1/OAT3 (Organic Anion Transporter) inhibitors may increase the area under the concentration curve (AUC) of vadadustat [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of VAFSEO adverse reactions.

Prevention or Management Closely monitor for too large or too rapid an increase in Hb response and for adverse reactions. Examples * OAT1 inhibitors: probenecid, rifampicin OAT3 inhibitors: gemfibrozil, probenecid, teriflunomide * These examples are not a comprehensive list of all possible drugs that may fit this category.

7.2Effect of

VAFSEO on Other Drugs Table 4 describes clinically significant drug interactions where VAFSEO affects the co-administered drug. Table 4 Drug Interactions with VAFSEO that affect co-administered drugs BCRP substrates Clinical Effect Vadadustat may increase the exposure of BCRP substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to the BCRP substrate. Prevention or Management Monitor for signs of adverse effects of the co-administered BCRP substrate and reduce substrates’ dosage in accordance with their approved product labeling, if needed.

Example * sulfasalazine Statins Clinical Effect Vadadustat increases the maximal concentration (C max ) and AUC of some statins when co-administered [see Clinical Pharmacology ( 12.3 )] . Prevention or Management Monitor for possible statin-related adverse reactions. Concomitant Drug Name Recommendation Simvastatin Starting dose of simvastatin should be 5 mg/day. Maximum daily dose of simvastatin not to exceed 20 mg.

Rosuvastatin Maximum daily dose of rosuvastatin not to exceed 5 mg. OAT3 substrates Clinical Effect Vadadustat may increase the exposure of co-administered OAT3 substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates. Prevention or Management Monitor for signs of adverse reactions of the co-administered OAT3 substrates and adjust substrates’ dosage in accordance with their approved product labeling, if needed.

Examples * cefaclor, ceftizoxime, famotidine, furosemide, oseltamivir carboxylate, penicillin G, sitagliptin * These examples are not a comprehensive list of all possible drugs that may fit this category.

Grossesse et allaitement

8.1Pregnancy Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VAFSEO during pregnancy. Health care providers and patients are encouraged to report pregnancies by calling 1-844-445-3799. Risk Summary Available data with VAFSEO use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with CKD (see Clinical Considerations) .

Vadadustat administration orally to pregnant rats and rabbits during the period of organogenesis was associated with reduced fetal weight at doses that caused maternal toxicity. In rat and rabbit studies, vadadustat was not teratogenic (see Data) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. VAFSEO should only be used during pregnancy if the benefit justifies the potential risk to the fetus. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: CKD in pregnancy increases the risk for maternal hypertension, preeclampsia, miscarriage, stillbirth, preterm delivery, low birth weight infants, and polyhydramnios.

Data Animal Data Vadadustat decreased fetal weight and reduced fetal skeletal ossification in rats at a dose of 160 mg/kg/day (1.7 times the maximum recommended human dose [MRHD] based on AUC), which was associated with maternal toxicity defined by reduced body weight gain and food consumption. Vadadustat was orally administered to pregnant rabbits at doses of 10, 25, or 50 mg/kg/day from gestation day 6 until gestation day 18 during the period of organogenesis.

Vadadustat administration at 50 mg/kg/day resulted in maternal toxicity of reduced body weight gain, but no adverse effects on embryofetal development were observed at doses less than or equal to 50 mg/kg/day (1.5 times the MRHD based on AUC). In a pre- and postnatal development study, pregnant rats were dosed orally with vadadustat 20, 40, or 80 mg/kg/day from implantation until weaning (gestation day 6 to lactation day 20) at 20, 40, or 80 mg/kg/day.

There were decreased body weights of offspring at the dose of 80 mg/kg/day but no adverse effects were observed at doses less than or equal to 80 mg/kg/day (0.3 times the MRHD based on AUC) in dams.

Effets indésirables

The following clinically significant adverse reactions are discussed elsewhere in the labeling: Increased risk of death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access [see Boxed Warning and Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions ( 5.2 )] Hypertension [see Warnings and Precautions ( 5.3 )] Seizures [see Warnings and Precautions ( 5.4 )] Gastrointestinal erosion [see Warnings and Precautions ( 5.5 )] Serious adverse reactions in patients with anemia due to chronic kidney disease and not on dialysis [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (occurring at ≥ 10%) were hypertension and diarrhea.

( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Akebia Therapeutics, Inc. at 1-844-445-3799 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of VAFSEO was evaluated in adults with dialysis-dependent chronic kidney disease (DD-CKD) with anemia in the INNO 2 VATE-1 and INNO 2 VATE-2 trials [see Clinical Studies ( 14.1 )] .

Both trials randomized patients to VAFSEO or darbepoetin alfa. Results in this section are based on the pooled VAFSEO treatment arms and pooled darbepoetin alfa arms from these trials. There were 1947 patients treated with VAFSEO and 1955 patients treated with darbepoetin alfa. In the pooled VAFSEO treatment arm, 71% of the participants were treated continuously for at least 6 months of VAFSEO and 44% of participants received VAFSEO for at least 1 year.

VAFSEO was non-inferior to darbepoetin alfa on the time to first occurrence of major adverse cardiovascular events (MACE) in adults with anemia due to CKD who were on dialysis [see Clinical Studies ( 14.1 )] . Permanent treatment discontinuation due to an adverse reaction was reported in 4.9% of patients treated with VAFSEO and 1.1% of patients treated with darbepoetin alfa. Gastrointestinal symptoms (nausea, vomiting and diarrhea) resulted in permanent treatment discontinuation in 1.8% of patients treated with VAFSEO.

The most common adverse reactions (>10% of VAFSEO-treated patients) were hypertension and diarrhea. Table 1 lists the adverse reactions that occurred in at least 5% or greater of patients with DD-CKD treated with VAFSEO. Table 1 Adverse Reactions (≥5%) in Patients with DD-CKD During INNO 2 VATE-1 and INNO 2 VATE-2 * Grouped Terms Hypertension includes hypertensive crisis, pre-eclampsia and hypertensive encephalopathy.

Headache includes occipital neuralgia. Fatigue includes asthenia, lethargy and malaise. Vomiting includes hematemesis. Gastrointestinal erosion includes duodenal ulcers and perforation, gastrointestinal ulcers and perforation, esophageal ulcers and perforation, and unspecified site or hematemesis, gastrointestinal hemorrhage, helicobacter duodenitis and gastritis, melaena, and gastric hemorrhage. Dizziness includes labyrinthitis, vertigo, vestibular neuronitis and presyncope.

Dyspnea includes orthopnea and respiratory distress. Adverse Reactions VAFSEO N=1947 (%) Darbepoetin Alfa N=1955 (%) Hypertension * 14 17 Diarrhea 13 10 Headache * 9 8 Nausea 8 8 Fatigue * 8 5 Abdominal pain 7 7 Vomiting * 7 7 Gastrointestinal erosion * 6 5 Dizziness * 6 5 Dyspnea * 6 7 Arteriovenous fistula thrombosis 6 5 Dialysis related complication 5 7 Adjudicated fatal and non-fatal thrombotic vascular events were observed in 9.0 per 100 PY of patients in the pooled VAFSEO arm and in 8.7 per 100 PY of patients in the pooled darbepoetin alfa (see Table 2) .

Table 2 Adjudicated Thrombotic Vascular Events in Patients with DD-CKD (Fatal and Non-fatal Events) * PY = Person Years * These data are not an adequate basis for comparison of rates between the study drug and active control. ** Based on time to first event analysis. Event VAFSEO (N = 1947) Darbepoetin Alfa (N = 1955) Rate per 100 PY ** Rate per 100 PY ** Vascular access thrombosis 4.8

3.9 Myocardial infarction 2.9

2.8 Stroke 1.1

1.4 Deep vein thrombosis 0.5

0.6 Pulmonary embolism 0.2

0.3 Arterial thrombosis 0.2 0.1

Conditionnement	Code	Statut
VADADUSTAT 300MG	NDA215192-002	Prescription
VADADUSTAT 450MG	NDA215192-003	Prescription
VADADUSTAT 150MG	NDA215192-001	Prescription

Vafseo

Indications

Contre-indications

Mises en garde et précautions d’emploi

Deux médicaments dans une même question ?

Vafseo

Indications

Contre-indications

Mises en garde et précautions d’emploi

Deux médicaments dans une même question ?

5.2Hepatotoxicity

5.3Hypertension

5.4Seizures

5.5Gastrointestinal Erosion In the INNO 2 VATE-1 and INNO 2

5.7Malignancy

Interactions

7.1Effect of Other Drugs on

7.2Effect of

Grossesse et allaitement

8.1Pregnancy Pregnancy Exposure Registry

Effets indésirables

6.1Clinical Trials Experience

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