Vanrafia (atrasentan hydrochloride)

Dosage of atrasentan hydrochloride is expressed in terms of atrasentan.

No dosing information is available for this tab.

No dosing information is available for this tab.

Atrasentan is a cytochrome P-450 (CYP) 3A substrate. Atrasentan inhibits in vitro CYP3A, CYP2B6, CYP2C8, and CYP2C9 and induces CYP3A and CYP2B6.

Atrasentan does not inhibit CYP1A2, CYP2C19, or CYP2D6 and is not an inducer of CYP1A2.

Atrasentan is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptides (OATP) 1B1/1B3 in vitro, but not a substrate of breast cancer resistance protein (BCRP), multidrug resistance-associated proteins (MRP) 2/4, sodium/taurocholate cotransporting polypeptide (NTCP), organic cation transporter (OCT) 1, or OATP2B1.

Atrasentan inhibits P-gp, OATP1B1, and OATP1B3 and does not inhibit MRP, NTCP, OCT, OAT1, multidrug and toxin extrusion (MATE) 1, or MATE2K.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Ace Inhibitors; Arbs; Eras; Aliskiren/Sparsentan

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Sparsentan is an antagonist of the endothelin type A receptor and the angiotensin II type 1 receptor which are thought to contribute to the pathogenesis of IgA nephropathy.(1) Coadministration with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) may result in additive inhibition of angiotensin. RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.

CLINICAL EFFECTS: Concurrent use of sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) may result in hypotension, syncope, hyperkalemia, and changes in renal function (including renal failure).(1)

PREDISPOSING FACTORS: Patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion may be at risk of developing acute kidney injury on sparsentan.(1) Patients with advanced kidney disease or taking concomitant potassium-increasing drugs (e.g., potassium supplements, potassium-sparing diuretics), or using potassium-containing salt substitutes are at increased risk for developing hyperkalemia.(1)

PATIENT MANAGEMENT: Do not coadminister sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs). Prior to initiating treatment with sparsentan, discontinue use of renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs).(1) RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.

DISCUSSION: The US manufacturer of sparsentan states that concomitant use of sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) is contraindicated.(1) RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.

Atrasentan/Dual Strong 3A4 Inducers & Oatp1b1-3 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Atrasentan is a substrate of CYP3A4 and of the OATP1B1 and OATP1B3 transporters.(1) Agents that are both strong CYP3A4 inducers and OATP1B1 and OATP1B3 inhibitors such as encorafenib and rifampin may induce the metabolism and increase the absorption of atrasentan.(2,3)

CLINICAL EFFECTS: The net effect of this interaction is unknown. Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of atrasentan. Concurrent use of OATP1B1 and OATP1B3 inhibitors may result in elevated levels and toxicities of atrasentan including fluid retention or hepatotoxicity.(1)

PREDISPOSING FACTORS: CYP3A4 induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Coadministration of atrasentan with combined strong CYP3A4 inducers and OATP1B1 and OATP1B3 inhibitors should be avoided.(1)

DISCUSSION: In a study, atrasentan trough concentration (Ctrough) decreased by 90% following coadministration of a single dose of 10 mg of atrasentan with rifampin (dual strong CYP3A4 inducer and OATP1B1 and OATP1B3 inhibitor).(1) Combined strong CYP3A4 inducers and OATP1B1 and OATP1B3 inhibitors linked to this monograph include: encorafenib and rifampin.(2,3)

Atrasentan/Moderate Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of atrasentan.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of atrasentan.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of atrasentan states that concurrent use of moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: In a study, atrasentan trough concentration (Ctrough) decreased by 90% following coadministration of a single dose of 10 mg of atrasentan with rifampin (strong CYP3A4 inducer).(1) The effects of a moderate CYP3A4 inducer on atrasentan concentrations has not been studied. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Atrasentan/Oatp1b1-3 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: OATP1B1 and 1B3 inhibitors may increase the absorption and/or decrease the hepatic uptake of atrasentan.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 or 1B3 inhibitors may result in elevated levels of and side effects from atrasentan, including fluid retention and hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of atrasentan states that concurrent use of OATP1B1 or 1B3 inhibitors should be avoided.(1)

DISCUSSION: In a clinical study, atrasentan maximum concentration (Cmax) was 4.3 times higher and area-under-curve (AUC) was 3.8 times higher following coadministration of a single dose of 0.75 mg atrasentan with cyclosporine (OATP1B1 and 1B3 inhibitor) compared to atrasentan alone. OATP1B1 and OATP1B3 inhibitors include: atazanavir, belumosudil, boceprevir, clarithromycin, cobicistat, cyclosporine, eltrombopag, erythromycin, fostemsavir, gemfibrozil, glecaprevir-pibrentasvir, leflunomide, leniolisib, letermovir, lopinavir, nirmatrelvir, ombitasvir-paritaprevir, resmetirom, ritonavir, roxadustat, saquinavir, simeprevir, telaprevir, teriflunomide, tipranavir, vadadustat, velpatasvir, voclosporin, and voxilaprevir.(1,2)

Atrasentan/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of atrasentan.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may reduce the clinical effectiveness of atrasentan.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of atrasentan states that concurrent use of strong CYP3A4 inducers should be avoided.(1)

DISCUSSION: In a study, atrasentan trough concentration (Ctrough) decreased by 90% following coadministration of a single dose of 10 mg of atrasentan with rifampin (strong CYP3A4 inducer).(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifapentine, and St. John's Wort.(2,3)

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

*Pregnancy.

*History of hypersensitivity reaction to atrasentan or any component of the product.

• Pregnancy

There are no severe contraindications for this drug.

• Disease of liver

Most common adverse reactions (>=5%) reported with atrasentan in clinical studies were peripheral edema and anemia.

There are no severe adverse reactions for this drug.

More Frequent

• Anemia
• Peripheral edema

Less Frequent

• Abnormal hepatic function tests

Rare or Very Rare

• Hypotension

No enhanced messaging available.

Safety and efficacy of atrasentan have not been established in pediatric patients.

There are no adequate data regarding the use of atrasentan in pregnant women. Animal reproductive data indicate that atrasentan can cause fetal harm, including birth defects and fetal death, when administered during pregnancy.

In pregnant rats, oral administration of atrasentan throughout organogenesis at doses of 0.1, 0.3, 1, and 3 mg/kg per day resulted in developmental abnormalities primarily including the ear, lower jaw, or skull in all treated groups with detectable plasma exposures to atrasentan. In pregnant rabbits, oral administration of atrasentan throughout organogenesis at doses of 0.1, 0.3, 1, and 3 mg/kg per day resulted in visceral malformations including deformities in the cardiovascular system in all atrasentan treated groups.

Atrasentan is contraindicated for use in pregnant individuals.

It is not known whether atrasentan is distributed into human milk, or if the drug has any effects on the breastfed infant or on milk production.

Advise patients to avoid breast-feeding while receiving atrasentan due to the potential for adverse reactions (e.g., fluid retention) in the breast-fed infant.

No specific dosage adjustments are provided for geriatric patients.

In the ALIGN study, 7% of patients receiving atrasentan were >=65 years of age. No overall difference in safety or effectiveness of atrasentan were observed between geriatric patients and younger adults.