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Warnings & Precautions

Diarrhea

HYRNUO can cause severe diarrhea that can lead to dehydration and electrolyte imbalances.

In the pooled safety population, diarrhea was reported in 86% of patients who received HYRNUO including Grade 3 in 15%. The median time to first onset of any grade diarrhea was four days. Dosage interruptions occurred in 15% of patients, and dose reductions occurred in 12% of patients.

At the first sign of diarrhea or increased bowel movement frequency, instruct patients to start an antidiarrheal treatment (e.g., loperamide), and to increase their fluid and electrolyte intake. Interrupt, reduce the dose or permanently discontinue HYRNUO based on severity.

Hepatotoxicity

HYRNUO can cause severe hepatotoxicity characterized by elevations of liver function tests.

In the pooled safety population, based on adverse reaction data, hepatotoxicity occurred in 24% of patients treated with HYRNUO including 3% Grade 3.

Based on laboratory data, 35% of patients treated with HYRNUO experienced increased alanine aminotransferase (ALT), including 2.3% Grade 3. Increased aspartate aminotransferase (AST) occurred in 35% of patients treated with HYRNUO, including 2.3% Grade 3. Increased bilirubin occurred in 12% of patients treated with HYRNUO. The median time to first onset of AST or ALT elevation was 1.4 (range 0.2 to 14.5) months.

HYRNUO was interrupted for an adverse reaction of hepatotoxicity in 4.1% of patients, the dose was reduced in 4.1% and permanently discontinued in 0.4%.

Monitor liver function tests including ALT, AST, and total bilirubin at baseline prior to the first administration of HYRNUO, every 2 weeks for the first month and then monthly thereafter as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on the severity of the adverse reaction.

Interstitial Lung Disease/Pneumonitis

HYRNUO can cause severe interstitial lung disease (ILD)/pneumonitis.

In the pooled safety population, ILD/pneumonitis occurred in two patients (0.7%) treated with HYRNUO, including 0.4% Grade 3. One patient required interruption of HYRNUO.

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Discontinue HYRNUO upon confirmation of ILD/pneumonitis.

Ocular Toxicity

HYRNUO can cause ocular toxicity.

In the pooled safety population, ocular toxicity occurred in 14% of patients treated with HYRNUO, including 11% Grade 1, 2.6% Grade 2 and 0.4% Grade 3. (one case of corneal epithelial microcysts with temporary unilateral blindness).

Promptly refer patients presenting with new or worsening eye symptoms to an ophthalmologist. Interrupt, reduce the dose or permanently discontinue HYRNUO based on severity.

Pancreatic Enzyme Elevation

HYRNUO can cause elevations of amylase and lipase levels.

In the pooled safety population, based on laboratory data, increased amylase occurred in 32% of patients treated with HYRNUO, including 3.2% Grade 3 or 4. Increased lipase elevation occurred in 40% of patients treated with HYRNUO, including 10% Grade 3 or 4. Two patients (0.7%) required interruption of HYRNUO due to increased lipase and three (1.1%) required interruption of HYRNUO due to increased amylase. The median time to onset of increased amylase/lipase was 1.4 months (range: 0.2 to 17 months).

Monitor amylase and lipase regularly during treatment with HYRNUO. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity.

Embryo-fetal toxicity

Based on findings from animal studies and its mechanism of action, HYRNUO can cause fetal harm when administered to a pregnant woman. In embryo-fetal development studies, oral administration of sevabertinib to pregnant rats during the period of organogenesis resulted in alterations to growth at maternal exposures ≥0.18 times the human exposure based on area under the curve (AUC) at the clinical dose of 20 mg twice daily. Animal studies with disrupted or depleted HER2/EGFR and in vitro assays have demonstrated that inhibition of HER2 and/or EGFR results in structural abnormalities, alteration to growth, and embryo-fetal and infant mortality.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with HYRNUO and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with HYRNUO and for 1 week after the last dose.

Adverse Reactions

In SOHO-01 (Groups D and E), Serious adverse reactions occurred in 31% of patients who received HYRNUO. Serious adverse reactions in ≥ 2% of patients were diarrhea (6%), pneumonia (3.7%), dyspnea (2.2%), and pleural effusion (2.2%). The most common adverse reactions (>20%) in patients who received HYRNUO were diarrhea (87%), rash (66%), paronychia (33%), stomatitis (29%), and nausea (21%). The most common Grade 3 and 4 laboratory abnormalities 
(≥ 2%) were potassium decreased (13%), lipase increased (12%), lymphocyte count decreased (6%), sodium decreased (4.4%), amylase increased (3.8%), aspartate aminotransferase (AST) increased (3%), and alanine aminotransferase (ALT) increased (3%). Laboratory abnormalities in < 20% of patients who received HYRNUO include blood bilirubin increased (14%; all were Grades 1 or 2). Clinically relevant adverse reactions in < 10% of patients who received HYRNUO included edema (8%), cardiac arrhythmia (6%; includes arrhythmia, atrioventricular block complete, electrocardiogram QT prolonged, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia) and alopecia (3.7%).

Drug Interactions

Effects of Other Drugs on HYRNUO - Sevabertinib is a CYP3 substrate. Concomitant use with a strong or moderate CYP3 inhibitor may increase sevabertinib plasma concentrations, which may increase the risk of HYRNUO adverse reactions. Monitor patients for increased HYRNUO-associated adverse reactions with moderate CYP3 inhibitors. Avoid concomitant use of HYRNUO with strong CYP3 inhibitors. If concomitant use cannot be avoided, reduce HYRNUO dose.

Concomitant use with a strong or moderate CYP3 inducer may decrease sevabertinib plasma concentrations, which may decrease the effectiveness of HYRNUO. Avoid concomitant use of HYRNUO with strong or moderate CYP3 inducers.

Effects of HYRNUO on Other Drugs – Sevabertinib is a weak to moderate CYP3 inhibitor. Sevabertinib increases exposure of CYP3 substrates, which may increase the risk of adverse reactions related to these substrates. Avoid concomitant use of HYRNUO with CYP3 substrates where minimal increases in the concentration may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information of the CYP3 substrate.

Sevabertinib is a P-gp inhibitor. Sevabertinib increases exposure of P-gp substrates, which may increase the risk of adverse reactions related to these substrates. Refer to the Prescribing Information for P-gp substrates where minimal increases in the concentration may lead to serious adverse reactions.

Sevabertinib is an inhibitor of CYP11 in vitro. Sevabertinib may increase exposure of CYP11 substrates, which may increase the risk of adverse reactions related to these substrates. Refer to the Prescribing Information of CYP11 substrates.

Please see full Prescribing Information.