ROZLYTREK Hard capsule Ref.[10280] Active ingredients: Entrectinib

5.1 Congestive Heart Failure

Among the 355 patients who received ROZLYTREK across clinical trials, congestive heart failure (CHF) occurred in 3.4% of patients, including Grade 3 (2.3%) [see Adverse Reactions (6.1)]. In clinical trials, baseline cardiac function and routine cardiac monitoring other than electrocardiograms (ECGs) were not conducted and eligibility criteria excluded patients with symptomatic CHF, myocardial infarction, unstable angina, and coronary artery bypass graft within 3 months of study entry. Among the 12 patients with CHF, the median time to onset was 2 months (range: 11 days to 12 months). ROZLYTREK was interrupted in 6 of these patients (50%) and discontinued in 2 of these patients (17%). CHF resolved in 6 patients (50%) following interruption or discontinuation of ROZLYTREK and institution of appropriate medical management. In addition, myocarditis in the absence of CHF was documented in 0.3% of patients.

Assess left ventricular ejection fraction (LVEF) prior to initiation of ROZLYTREK in patients with symptoms or known risk factors for CHF. Monitor patients for clinical signs and symptoms of CHF, including shortness of breath and edema. For patients with myocarditis, with or without a decreased ejection fraction, MRI or cardiac biopsy may be required to make the diagnosis. For patients with new onset or worsening CHF, withhold ROZLYTREK, institute appropriate medical management, and reassess LVEF. Based on the severity of CHF or worsening LVEF, resume ROZLYTREK at a reduced dose upon recovery to baseline or permanently discontinue [see Dosage and Administration (2.4)].

5.2 Central Nervous System Effects

A broad spectrum of central nervous system (CNS) adverse reactions occurred in patients receiving ROZLYTREK, including cognitive impairment, mood disorders, dizziness, and sleep disturbances.

Among the 355 patients who received ROZLYTREK across clinical trials, 96 (27%) experienced cognitive impairment; symptoms occurred within 3 months of starting ROZLYTREK in 74 (77%). Cognitive impairment included cognitive disorders (8%), confusional state (7%), disturbance in attention (4.8%), memory impairment (3.7%), amnesia (2.5%), aphasia (2.3%), mental status changes (2%), hallucinations (1.1%), and delirium (0.8%). Grade 3 cognitive adverse reactions occurred in 4.5% of patients. Among the 96 patients with cognitive impairment, 13% required a dose reduction, 18% required dose interruption and 1% discontinued ROZLYTREK due to cognitive adverse reactions.

Among the 355 patients who received ROZLYTREK across clinical trials, 36 (10%) experienced mood disorders. The median time to onset of mood disorders was 1 month (range: 1 day to 9 months). Mood disorders occurring in ≥ 1% of patients included anxiety (4.8%), depression (2.8%) and agitation (2%). Grade 3 mood disorders occurred in 0.6% of patients. One completed suicide was reported 11 days after treatment had ended. Among the 36 patients who experienced mood disorders, 6% required a dose reduction, 6% required dose interruption and no patients discontinued ROZLYTREK due to mood disorders.

Dizziness occurred in 136 (38%) of the 355 patients. Among the 136 patients who experienced dizziness, Grade 3 dizziness occurred in 2.2% of patients. Ten percent of patients required a dose reduction, 7% required dose interruption and 0.7% discontinued ROZLYTREK due to dizziness.

Among the 355 patients who received ROZLYTREK across clinical trials, 51 (14%) experienced sleep disturbances. Sleep disturbances included insomnia (7%), somnolence (7%), hypersomnia (1.1%), and sleep disorder (0.3%). Grade 3 sleep disturbances occurred in 0.6% of patients. Among the 51 patients who experienced sleep disturbances, 6% required a dose reduction and no patients discontinued ROZLYTREK due to sleep disturbances.

The incidence of CNS adverse reactions was similar in patients with and without CNS metastases; however, the incidence of dizziness (38% vs 31%), headache (21% vs 13%), paresthesia (20% vs 6%), balance disorder (13% vs 4%), and confusional state (11% vs 2%) appeared to be increased in patients with CNS metastases who had received prior CNS irradiation (N=90) compared to those who did not (N=48).

Advise patients and caregivers of these risks with ROZLYTREK. Advise patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue ROZLYTREK based on severity [see Dosage and Administration (2.4)].

5.3 Skeletal Fractures

ROZLYTREK increases the risk of fractures. In an expanded safety population that included 338 adult patients and 30 pediatric patients who received ROZLYTREK across clinical trials, 5% of adult patients and 23% of pediatric patients experienced fractures [see Use in Specific Population (8.4)]. In adult patients, some fractures occurred in the setting of a fall or other trauma to the affected area, while in pediatric patients all fractures occurred in patients with minimal or no trauma. In general, there was inadequate assessment for tumor involvement at the site of fracture; however, radiologic abnormalities possibly indicative of tumor involvement were reported in some patients. In both adult and pediatric patients, most fractures were hip or other lower extremity fractures (e.g., femoral or tibial shaft). In a limited number of patients, bilateral femoral neck fractures occurred. The median time to fracture was 3.8 months (range 0.3 to 18.5 months) in adults and 4.0 months (range: 1.8 months to 7.4 months) in pediatric patients. ROZLYTREK was interrupted in 41% of adults and 43% of pediatric patients due to fractures. No patients discontinued ROZLYTREK due to fractures.

Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of ROZLYTREK on healing of known fractures and risk of future fractures.

5.4 Hepatotoxicity

Among the 355 patients who received ROZLYTREK, increased AST of any grade occurred in 42% of patients and increased ALT of any grade occurred in 36%. Grade 3 – 4 increased AST or ALT occurred in 2.5% and 2.8% of patients, respectively; the incidence may be underestimated as 4.5% of patients had no post-treatment liver function tests [see Adverse Reactions (6.1)]. The median time to onset of increased AST was 2 weeks (range: 1 day to 29.5 months). The median time to onset of increased ALT was 2 weeks (range: 1 day to 9.2 months). Increased AST or ALT leading to dose interruptions or reductions occurred in 0.8% and 0.8% of patients, respectively. ROZLYTREK was discontinued due to increased AST or ALT in 0.8% patients.

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue ROZLYTREK based on the severity. If withheld, resume ROZLYTREK at the same or reduced dose [see Dosage and Administration (2.4)].

5.5 Hyperuricemia

Among 355 patients who received ROZLYTREK across clinical trials, 32 patients (9%) experienced hyperuricemia reported as adverse reactions with symptoms, as well as elevated uric acid levels. Grade 4 hyperuricemia occurred in 1.7% of patients, including one patient who died due to tumor lysis syndrome. Among the 32 patients with hyperuricemic adverse reactions, 34% required urate-lowering medication to reduce uric acid levels, 6% required dose reduction and 6% required dose interruption. Hyperuricemia resolved in 73% of patients following initiation of urate-lowering medication without interruption or dose reduction of ROZLYTREK. No patients discontinued ROZLYTREK due to hyperuricemia.

Assess serum uric acid levels prior to initiating ROZLYTREK and periodically during treatment. Monitor patients for signs and symptoms of hyperuricemia. Initiate treatment with urate-lowering medications as clinically indicated and withhold ROZLYTREK for signs and symptoms of hyperuricemia. Resume ROZLYTREK at same or reduced dose upon improvement of signs or symptoms based on severity [see Dosage and Administration (2.4)].

5.6 QT Interval Prolongation

Among the 355 patients who received ROZLYTREK across the clinical trials, 3.1% of patients with at least one post-baseline ECG assessment experienced QTcF interval prolongation of >60 ms after starting ROZLYTREK and 0.6% had a QTcF interval >500 ms [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)].

Monitor patients who already have or who are at significant risk of developing QTc interval prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Assess QT interval and electrolytes at baseline and periodically during treatment, adjusting frequency based upon risk factors such as congestive heart failure, electrolyte abnormalities, or concomitant medications known to prolong the QTc interval. Based on the severity of QTc interval prolongation, withhold ROZLYTREK and then resume at same or reduced dose, or permanently discontinue [see Dosage and Administration (2.4)].

5.7 Vision Disorders

Among the 355 patients who received ROZLYTREK across clinical trials, vision changes occurred in 21% of patients, including Grade 1 (82%), Grade 2 (14%) and Grade 3 (0.8%) [see Adverse Reactions (6.1)]. Vision disorders occurring in ≥1% included blurred vision (8.7%), photophobia (5.1%), diplopia (3.1%), visual impairment (2%), photopsia (1.3%), cataract (1.1%), and vitreous floaters (1.1%).

For patients with new visual changes or changes that interfere with activities of daily living, withhold ROZLYTREK until improvement or stabilization and conduct an ophthalmological evaluation as clinically appropriate. Upon improvement or stabilization, resume ROZLYTREK at same or reduced dose [see Dosage and Administration (2.4)].

5.8 Embryo-Fetal Toxicity

Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, ROZLYTREK can cause fetal harm when administered to a pregnant woman. Administration of entrectinib to pregnant rats resulted in malformations at exposures approximately 2.7 times the human exposure at the 600 mg dose based on area under the curve (AUC).

Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 5 weeks following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 3 months after the final dose [see Use in Specific Populations (8.1, 8.3)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Congestive Heart Failure [see Warnings and Precautions (5.1)]
• Central Nervous System Effects [see Warnings and Precautions (5.2)]
• Skeletal Fractures [see Warnings and Precautions (5.3)]
• Hepatotoxicity [see Warnings and Precautions (5.4)]
• Hyperuricemia [see Warnings and Precautions (5.5)]
• QT Interval Prolongation [see Warnings and Precautions (5.6)]
• Vision Disorders [see Warnings and Precautions (5.7)]

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.

Data in WARNINGS AND PRECAUTIONS and below reflect exposure to ROZLYTREK in 355 patients, including 172 (48%) patients exposed for 6 months or longer and 84 (24%) patients exposed for 1 year or longer. ROZLYTREK was studied in one dose-finding trial in adults [ALKA (n=57)], one dose-finding and activity-estimating trial in adults [STARTRK-1 (n=76)], one dose-finding and activity-estimating trial in pediatric and adult patients [STARTRK-NG (n=16)], and one single arm, activity-estimating trial in adults [STARTRK-2 (n=206)].

The population characteristics were: median age 55 years (range: 4 to 86 years); 5% (n=17) were less than 18 years of age; 55% were female; and 66% were White, 23% were Asian, and 5% were Black; 3% were Hispanic/Latino. The most common tumors (≥5%) were lung (56%), sarcoma (8%), and colon (5%). ROS1 gene fusions were present in 42% and NTRK gene fusions were present in 20%. Most adults (75%) received ROZLYTREK 600 mg orally once daily. The doses ranged from 100 mg/m² to 1600 mg/m² once daily in adults and 250 mg/m² to 750 mg/m² once daily in pediatric patients. ROZLYTREK is not indicated for pediatric patients less than 12 years of age [see Use in Specific Populations (8.4)].

Serious adverse reactions occurred in 39% of patients. The most frequent serious adverse reactions (≥2%) were pneumonia (3.9%), dyspnea (3.7%), pleural effusion (3.4%), sepsis (2.5%), pulmonary embolism (2.3%), respiratory failure (2%), and pyrexia (2%). Grade 3 or 4 adverse reactions occurred in 60% of patients; the most common (≥2%) were lung infection (5%), increased weight (7%), dyspnea (6%), fatigue/asthenia (5%), cognitive disorders (4.5%), syncope (2.5%), pulmonary embolism (3.4%), hypoxia (3.4%), pleural effusion (3.1%), hypotension (2.8%), diarrhea (2%), and urinary tract infection (2.5%). Fatal events included dyspnea (0.6%), pneumonia (0.6%), sepsis (0.6%), completed suicide (0.3%), large intestine perforation (0.3%) and tumor lysis syndrome (0.3%). One patient developed Grade 4 myocarditis after one dose of ROZLYTREK which resolved after discontinuation of ROZLYTREK and administration of high-dose corticosteroids.

Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received ROZLYTREK. The most frequent adverse reactions (<1% each) that resulted in permanent discontinuation were pneumonia, cardio-respiratory arrest, dyspnea, and fatigue.

Dose interruptions due to adverse reactions occurred in 46% of patients. The most frequent adverse reactions (≥2%) that resulted in interruption were increased blood creatinine (4%), fatigue (3.7%), anemia (3.1%), diarrhea (2.8%), pyrexia (2.8%), dizziness (2.5%), dyspnea (2.3%), nausea (2.3%), pneumonia (2.3%), cognitive disorder (2%) and neutropenia (2%).

Dose reductions due to adverse reactions occurred in 29% of patients who received ROZLYTREK. The most frequent adverse reactions resulting in dose reductions (≥1%) were dizziness (3.9%), increased blood creatinine (3.1%), fatigue (2.3%), anemia (1.7%), and increased weight (1.4%).

The most common adverse reactions (≥20%) were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia and vision disorders.

Table 4 summarizes the adverse reactions observed in these 355 patients.

Table 4. Adverse Reactions (≥10%) in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG:

* Grades 3–5, inclusive of fatal adverse reactions, including 2 events of pneumonia and 2 events of dyspnea.
^† Includes fatigue, asthenia‡Includes face edema, fluid retention, generalized edema, localized edema, edema, edema peripheral, peripheral swelling
^§ Includes abdominal pain upper, abdominal pain, lower abdominal discomfort, abdominal tenderness
^¶ Includes dizziness, vertigo, dizziness postural
^# Includes paresthesia, hyperesthesia, hypoesthesia, dysesthesia, oral hypoesthesia, palmar-plantar erythrodysesthesia, oral paresthesia, genital hypoesthesia
^Þ Includes amnesia, aphasia, cognitive disorder, confusional state, delirium, disturbance in attention, hallucinations, visual hallucination, memory impairment, mental disorder, mental status changes
^ß Includes neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy
^à Includes ataxia, balance disorder, gait disturbances
^è Includes hypersomnia, insomnia, sleep disorder, somnolence
^ð Includes anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric mood, mood altered, mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation
^ø Includes musculoskeletal pain, musculoskeletal chest pain, myalgia, neck pain
^ý Includes blindness, cataract, cortical cataract, corneal erosion, diplopia, eye disorder, photophobia, photopsia, retinal hemorrhage, vision blurred, visual impairment, vitreous adhesions, vitreous detachment, vitreous floaters
^£ Includes lower respiratory tract infection, lung infection, pneumonia, respiratory tract infection
^¥ Includes hypotension, orthostatic hypotension
^ΠIncludes rash, rash maculopapular, rash pruritic, rash erythematous, rash papular

Clinically relevant adverse reactions occurring in ≤10% of patients include dysphagia (10%), fall (8%), pleural effusion (8%), fractures (6%), hypoxia (4.2%), pulmonary embolism (3.9%), syncope (3.9%), congestive heart failure (3.4%), and QT prolongation (3.1%).

Table 5 summarizes the laboratory abnormalities.

Table 5. Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Receiving ROZLYTREK in ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG:

AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase
* Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 111 to 34 6 patients.
^† Based on NCI CTCAE v5.0
^‡ NE = Not evaluable. Grade 1 and 2 could not be determined per NCI CTCAE v5.0, as fasting glucose values were not collected.

7.1 Effect of Other Drugs on ROZLYTREK

Moderate and Strong CYP3A Inhibitors

Adults and Pediatric Patients 12 Years and Older with BSA Greater than 1.50 m²:

Coadministration of ROZLYTREK with a strong or moderate CYP3A inhibitor increases entrectinib plasma concentrations [see Clinical Pharmacology (12.3)], which could increase the frequency or severity of adverse reactions. Avoid coadministration of strong or moderate CYP3A inhibitors with ROZLYTREK. If coadministration is unavoidable, reduce the ROZLYTREK dose [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

Pediatric Patients 12 Years and Older with BSA Less Than or Equal to 1.50 m²:

Avoid coadministration of ROZLYTREK with moderate or strong CYP3A inhibitors [see Clinical Pharmacology (12.3)].

Avoid grapefruit products during treatment with ROZLYTREK, as they contain inhibitors of CYP3A.

Moderate and Strong CYP3A Inducers

Coadministration of ROZLYTREK with a strong or moderate CYP3A inducer decreases entrectinib plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce ROZLYTREK efficacy. Avoid coadministration of strong and moderate CYP3A inducers with ROZLYTREK.

7.2 Drugs That Prolong QT Interval

QTc interval prolongation can occur with ROZLYTREK. Avoid coadministration of ROZLYTREK with other products with a known potential to prolong QT/QTc interval [see Warnings and Precautions (5.6), Clinical Pharmacology (12.2)].

Risk Summary

Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], ROZLYTREK can cause fetal harm when administered to a pregnant woman. There are no available data on ROZLYTREK use in pregnant women. Administration of entrectinib to pregnant rats during the period of organogenesis resulted in malformations at maternal exposures approximately 2.7 times the human exposure at the 600 mg dose (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.

Animal Data

Entrectinib administration to pregnant rats during the period of organogenesis at a dose of 200 mg/kg [resulting in exposures up to 2.7 times the human exposure (AUC) at the 600 mg dose] resulted in maternal toxicity and fetal malformations including body closure defects (omphalocele and gastroschisis) and malformations of the vertebrae, ribs, and limbs (micromelia and adactyly), but not embryolethality. Lower fetal weights and reduced skeletal ossification occurred at doses ≥12.5 and 50 mg/kg [approximately 0.2 and 0.9 times the human exposure (AUC) at the 600 mg dose], respectively.

Risk Summary

There are no data on the presence of entrectinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential adverse reactions in breastfed children from ROZLYTREK, advise a lactating woman to discontinue breastfeeding during treatment with ROZLYTREK and for 7 days after the final dose.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating ROZLYTREK [see Use in Specific Populations (8.1)].

Contraception

ROZLYTREK can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise female patients of reproductive potential to use effective contraception during treatment with ROZLYTREK and for at least 5 weeks following the final dose [see Use in Specific Populations (8.1)].

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ROZLYTREK and for 3 months following the final dose [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of ROZLYTREK in pediatric patients aged 12 years and older with solid tumors that have an NTRK gene fusion have been established. The effectiveness of ROZLYTREK in adolescent patients was established based on extrapolation of data from three open-label, single-arm clinical trials in adult patients with solid tumors harboring an NTRK gene fusion (ALKA, STARTRK-1, and STARTRK-2) and pharmacokinetic data in adolescents enrolled in STARTRK-NG. ROZLYTREK doses based on body surface area in pediatric patients 12 years and older resulted in similar systemic exposure compared to that in adults who received a ROZLYTREK dose of 600 mg [see Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)].

There is limited clinical experience with ROZLYTREK in pediatric patients. The safety of ROZLYTREK in pediatric patients 12 years of age and older was established based on extrapolation of data in adults and data from 30 pediatric patients enrolled in STARTRK-NG. Of these 30 patients, 7% were <2 years (n=2), 77% were 2 to <12 years (n=23), 17% were 12 to <18 years (n=5); 57% had metastatic disease (n=17) and 44% had locally advanced disease (n=13); and all patients had received prior treatment for their cancer, including surgery, radiotherapy, or systemic therapy. The most common cancers were neuroblastoma (47%), primary CNS tumors (30%), and sarcoma (10%). The median duration of exposure for all pediatric patients was 4.2 months (range: 0.2 to 22.7 months).

Due to the small number of pediatric and adult patients, the single arm design of clinical studies of ROZLYTREK, and confounding factors such as differences in susceptibility to infections between pediatric and adult patients, it is not possible to determine whether the observed differences in the incidence of adverse reactions to ROZLYTREK are related to patient age or other factors. In an expanded safety database that included 338 adult patients and 30 pediatric patients who received ROZLYTREK across clinical trials, the Grade 3 or 4 adverse reactions and laboratory abnormalities that occurred more frequently (≥5%) in pediatric patients (n=30) compared with adults (n=338) were neutropenia (27% vs 2%), bone fractures (23% vs 5%), increased weight (20% vs 7%), thrombocytopenia (10% vs 0.3%), lymphopenia (7% vs 1%), increased gamma-glutamyl transferase (7% vs 0%), and device-related infection (7% vs 0.3%). Three pediatric patients discontinued ROZLYTREK due to an adverse reaction (Grade 4 pulmonary edema, Grade 3 dyspnea, and Grade 4 pancreatitis).

The safety and effectiveness of ROZLYTREK in pediatric patients less than 12 years of age with solid tumors who have an NTRK gene fusion have not been established.

The safety and effectiveness of ROZLYTREK in pediatric patients with ROS1-positive NSCLC have not been established.

Juvenile Animal Toxicity Data

In a 13-week juvenile rat toxicology study, animals were dosed daily from post-natal day 7 to day 97 (approximately equivalent to neonate to adulthood). Entrectinib resulted in:

• decreased body weight gain and delayed sexual maturation at doses ≥4 mg/kg/day (approximately 0.06 times the human exposure (AUC) at the 600 mg dose),
• deficits in neurobehavioral assessments including functional observational battery and learning and memory (at doses ≥8 mg/kg/day, approximately 0.14 times the human exposure at the 600 mg dose), and
• decreased femur length at doses ≥16 mg/kg/day (approximately 0.18 times the human exposure at the 600 mg dose).

Of the 355 patients who received ROZLYTREK across clinical trials, 25% were 65 years or older, and 5% were 75 years of age or older. Clinical studies of ROZLYTREK did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger patients.

No dose adjustment is recommended for patients with mild or moderate renal impairment (CLcr 30 to <90 mL/min calculated by Cockcroft-Gault equation). ROZLYTREK has not been studied in patients with severe renal impairment (CLcr <30 mL/min) [see Clinical Pharmacology (12.3)].

No dose adjustment is recommended for patients with mild (total bilirubin ≤1.5 times ULN) hepatic impairment. ROZLYTREK has not been studied in patients with moderate (total bilirubin >1.5 to 3 times ULN) and severe (total bilirubin >3 times ULN) hepatic impairment [see Clinical Pharmacology (12.3)].