On November 27, 2018 Takeda Pharmaceutical Company Limited (TSE: 4502) reported that the European Commission (EC) granted marketing authorization for ALUNBRIG (brigatinib) as a monotherapy for the treatment of adult patients with anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib (Press release, Takeda, NOV 27, 2018, View Source [SID1234531645]). The decision follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) on September 20, 2018.
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"The introduction of targeted therapies has greatly improved the treatment of ALK+ NSCLC, yet for the approximately 70 percent of patients who progress on crizotinib with brain metastases, additional therapeutic options are needed," said Enriqueta Felip, M.D., PhD., Head of the Thoracic Oncology Unit, Oncology Department at Vall d’Hebron University Hospital in Barcelona. "Data from the ALTA trial investigating ALUNBRIG showed sustained systemic and intracranial efficacy results and a manageable safety profile, leading to the longest progression-free survival and overall survival reported in this setting. This approval gives physicians in the European Union another choice in addressing ALK+ NSCLC patients previously treated with crizotinib."
"The European Commission’s decision to approve ALUNBRIG for patients with ALK+ NSCLC is a significant advancement for European patients impacted by this life-threatening disease," said Jesús Gómez-Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. "This is the first time a median progression-free survival of over 16 months as assessed by an independent review committee and median overall survival of 34 months have been reported in the post-crizotinib setting, which highlights the strength of the ALTA trial data. The authorization of ALUNBRIG in the EU speaks to our ongoing commitment to developing innovative solutions to improve the lives of the approximately 40,000 patients diagnosed with this disease worldwide each year."
"Many people are unaware of ALK+ NSCLC and its nuances, including the fact this type of lung cancer tends to affect people at a younger age, and it is not associated with smoking," said Stefania Vallone, President, Lung Cancer Europe. "These younger patients are often in the prime of their lives and in the middle of raising their families, focusing on their careers, and contributing to their community. The availability of new treatments to potentially extend time without disease progression is very important and cannot be underestimated."
The European Commission’s approval is based on data from the global Phase 2 ALTA trial, in which patients were randomized to receive one of two dosing regimens of ALUNBRIG: 90 mg once daily (n=112) or the recommended dosing regimen of 180 mg once daily with seven-day lead-in at 90 mg once daily (n=110). Results showed that of the patients who received the recommended dosing regimen, 56 percent achieved an objective response rate (ORR), and the median duration of response (DOR) was 15.7 months as assessed by independent review committee (IRC). ALUNBRIG demonstrated a median progression-free survival (PFS) of 16.7 months by IRC assessment and overall survival of 34.1 months for patients with locally advanced or metastatic ALK+ NSCLC who had progressed on crizotinib.
The most common adverse reactions (≥25%) reported in patients treated with ALUNBRIG at the recommended 180 mg dosing regimen were increased aspartate aminotransferase (AST), hyperglycemia, hyperinsulinemia, anemia, increased creatine phosphokinase (CPK), nausea, increased lipase, decreased lymphocyte count, increased alanine aminotransferase (ALT), diarrhea, increased amylase, fatigue, cough, headache, increased alkaline phosphatase, hypophosphatemia, increased abnormal activated partial thromboplastin time (APTT), rash, vomiting, dyspnea, hypertension, decreased blood cell count, myalgia, and peripheral neuropathy. The most common serious adverse reactions (≥ 2 percent) reported in patients treated with ALUNBRIG at the recommended dosing regimen other than events related to neoplasm progression were pneumonitis, pneumonia, and dyspnea.
This decision by the European Commission means that ALUNBRIG is now approved for marketing of this indication in the 28 member states of the European Union, and applicable in Norway, Liechtenstein and Iceland. For further details about the European Commission decision, please visit the European Medicines Agency website: www.ema.europe.eu/ema.
About the ALTA Trial
The Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial of ALUNBRIG in adults is a global, ongoing, two-arm, open-label, multicenter trial, which enrolled 222 patients with locally advanced or metastatic ALK+ NSCLC who had progressed on crizotinib. Patients received either 90 mg of ALUNBRIG once daily (n=112) or 180 mg once daily with seven-day lead-in at 90 mg once daily regimen (n=110). Investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1 was the primary endpoint. Key additional endpoints included Independent Review Committee (IRC)-assessed ORR, duration of response (DOR), progression-free survival (PFS), intracranial ORR, intracranial DOR, safety and tolerability.
Results of the ALTA trial demonstrated that of the patients who received the 180 mg dosing regimen, 56 percent achieved an ORR as assessed by investigator and 56 percent as assessed by IRC. The median DOR was 13.8 months as assessed by investigator and 15.7 months by IRC assessment. Median PFS was 15.6 months as assessed by investigator and 16.7 months by IRC assessment. Additionally, of the patients with measurable brain metastases at baseline (n=18), 67 percent achieved an intracranial ORR by IRC assessment; median duration of intracranial response was 16.6 months by IRC assessment. Median overall survival was 34.1 months.
Among patients who received the 90 mg dosing regimen, 46 percent achieved an ORR as assessed by investigator and 51 percent as assessed by IRC. The median DOR was 12.0 months as assessed by investigator and 16.4 months by IRC assessment. Median PFS was 9.2 months as assessed by both investigator and IRC assessment. Additionally, of the patients with measurable brain metastases at baseline (n=26), 50 percent achieved an intracranial ORR by IRC assessment; median duration of intracranial response was 9.4 months by IRC assessment. Median overall survival was 29.5 months.
About ALK+ NSCLC
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 1.8 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization. Genetic studies indicate that chromosomal rearrangements in anaplastic lymphoma kinase (ALK) are key drivers in a subset of NSCLC patients. Approximately three to five percent of patients with metastatic NSCLC have a rearrangement in the ALK gene.
Takeda is committed to continuing research and development in NSCLC to improve the lives of the approximately 40,000 patients diagnosed with this serious and rare form of lung cancer worldwide each year.
About ALUNBRIG (brigatinib)
ALUNBRIG is a targeted cancer medicine discovered by ARIAD Pharmaceuticals, Inc., which was acquired by Takeda in February 2017. In April 2017, ALUNBRIG received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for ALK+ metastatic NSCLC patients who have progressed on or are intolerant to crizotinib. This indication is approved under Accelerated Approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. In July 2018, Health Canada approved ALUNBRIG for the treatment of adult patients with ALK+ metastatic NSCLC who have progressed on or who were intolerant to an ALK inhibitor (crizotinib). The FDA and Health Canada approvals of ALUNBRIG were primarily based on results from the pivotal Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial.
ALUNBRIG received Breakthrough Therapy Designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib and was granted Orphan Drug Designation by the FDA for the treatment of ALK+ NSCLC, ROS1+ and EGFR+ NSCLC.
The brigatinib clinical development program further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with ALK+ NSCLC worldwide and the healthcare professionals who treat them. The comprehensive program includes the following clinical trials:
Phase 1/2 trial, which was designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of ALUNBRIG
Pivotal Phase 2 ALTA trial investigating the efficacy and safety of ALUNBRIG at two dosing regimens in patients with ALK+ locally advanced or metastatic NSCLC who had progressed on crizotinib
Phase 3 ALTA-1L, a global randomized trial assessing the efficacy and safety of ALUNBRIG in comparison to crizotinib in patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor
Phase 2 single-arm, multicenter trial in Japanese patients with ALK+ NSCLC, focusing on patients who have progressed on alectinib
Phase 2 global, single arm trial evaluating ALUNBRIG in patients with advanced ALK+ NSCLC who have progressed on alectinib or ceritinib
Phase 3 global randomized trial comparing the efficacy and safety of ALUNBRIG versus alectinib in participants with ALK+ NSCLC who have progressed on crizotinib
For additional information on the brigatinib clinical trials, please visit www.clinicaltrials.gov.
ALUNBRIG (brigatinib): EUROPEAN IMPORTANT SAFETY INFORMATION
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Pulmonary Adverse Reactions: Severe, life-threatening, and fatal pulmonary adverse reactions, including those with features consistent with ILD/pneumonitis, can occur. Most pulmonary adverse reactions were observed within the first 7 days of treatment. Grade 1-2 pulmonary adverse reactions resolved with interruption of treatment or dose modification. Increased age and shorter interval (less than 7 days) between the last dose of crizotinib and the first dose of ALUNBRIG were independently associated with an increased rate of these pulmonary adverse reactions. Consider these factors when initiating treatment with ALUNBRIG. Some patients experienced pneumonitis later in treatment with ALUNBRIG. Patients should be monitored for new or worsening respiratory symptoms (e.g., dyspnoea, cough, etc.), particularly in the first week of treatment. Evidence of pneumonitis in any patient with worsening respiratory symptoms should be promptly investigated. If pneumonitis is suspected, the dose of ALUNBRIG should be withheld, and the patient evaluated for other causes of symptoms (e.g., pulmonary embolism, tumour progression, and infectious pneumonia). The dose should be modified accordingly.
Hypertension has occurred. Blood pressure should be monitored regularly during treatment with ALUNBRIG. Hypertension should be treated according to standard guidelines to control blood pressure. Heart rate should be monitored more frequently in patients if concomitant use of a medication known to cause bradycardia cannot be avoided. For severe hypertension (≥ Grade 3), ALUNBRIG should be withheld until hypertension has recovered to Grade 1 or to baseline. The dose should be modified accordingly.
Bradycardia has occurred. Caution should be exercised when administering ALUNBRIG in combination with other agents known to cause bradycardia. Heart rate and blood pressure should be monitored regularly. Treatment with ALUNBRIG should be withheld if symptomatic bradycardia occurs. Concomitant medications known to cause bradycardia should be evaluated. Upon recovery, dose should be modified accordingly. In case of life-threatening bradycardia, permanently discontinue ALUNBRIG if no contributing concomitant medication is identified or in the case of recurrence. If contributing concomitant medication is identified, modify dose accordingly.
Visual Disturbance has occurred with ALUNBRIG. Patients should be advised to report any visual symptoms. For new or worsening severe visual symptoms, an ophthalmologic evaluation and dose reduction should be considered.
Creatine Phosphokinase (CPK) Elevation has been reported. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels regularly during treatment. Based on the severity of the CPK elevation, withhold treatment with ALUNBRIG and modify dose accordingly.
Pancreatic Enzyme Elevation: Elevations of amylase and lipase have occurred. Lipase and amylase should be monitored regularly during treatment with ALUNBRIG. Based on the severity of the laboratory abnormalities, withhold ALUNBRIG and modify dose accordingly.
Hepatotoxicity: Elevations of hepatic enzymes (aspartate aminotransferase, alanine aminotransferase) and bilirubin have occurred. Liver function, including AST, ALT and total bilirubin should be assessed prior to the initiation of ALUNBRIG and then every 2 weeks during the first 3 months of treatment. Thereafter, monitoring should be performed periodically. Based on the severity of the laboratory abnormalities, withhold ALUNBRIG and modify dose accordingly.
Hyperglycemia: Elevations of serum glucose have occurred. Fasting serum glucose should be assessed prior to initiation of ALUNBRIG and monitored periodically thereafter. Antihyperglycaemic treatment should be initiated or optimised as needed. If adequate hyperglycaemic control cannot be achieved with optimal medical management, ALUNBRIG should be withheld until adequate hyperglycaemic control is achieved; upon recovery reducing the dose may be considered or ALUNBRIG may be permanently discontinued.
Drug drug interactions: Concomitant use of ALUNBRIG with strong CYP3A inhibitors should be avoided. If concomitant use of strong CYP3A inhibitors cannot be avoided, reduce dose of ALUNBRIG from 180 mg to 90 mg, or from 90 mg to 60 mg. After discontinuation of a strong CYP3A inhibitor, ALUNBRIG should be resumed at the dose that was tolerated prior to the initiation of the strong CYP3A inhibitor. The concomitant use of ALUNBRIG with strong and moderate CYP3A inducers should be avoided.
Fertility: Women of childbearing potential should be advised to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Men with female partners of childbearing potential should be advised to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG
Lactose: ALUNBRIG contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medication.
UNDESIRABLE EFFECTS
The most common adverse reactions (≥ 25%) reported in patients treated with ALUNBRIG at the recommended dosing regimen were increased AST, hyperglycaemia, hyperinsulinaemia, anaemia, increased CPK, nausea, increased lipase, decreased lymphocyte count, increased ALT, diarrhoea, increased amylase, fatigue, cough, headache, increased alkaline phosphatase, hypophosphataemia, increased APTT, rash, vomiting, dyspnoea, hypertension, decreased white blood cell count, myalgia, and peripheral neuropathy.
The most common serious adverse reactions (≥ 2%) reported in patients treated with ALUNBRIG at the recommended dosing regimen other than events related to neoplasm progression were pneumonitis, pneumonia, and dyspnoea.
SPECIAL POPULATIONS
Elderly patients: The limited data on the safety and efficacy of ALUNBRIG in patients aged 65 years and older suggest that a dose adjustment is not required in elderly patients. There are no available data on patients over 85 years of age.
Hepatic impairment: No dose adjustment of ALUNBRIG is required for patients with mild hepatic impairment (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B). A reduced starting dose of 60 mg once daily for the first 7 days, then 120 mg once daily is recommended for patients with severe hepatic impairment (Child-Pugh class C).
Renal impairment: No dose adjustment of ALUNBRIG is required for patients with mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) ≥ 30 mL/min). A reduced starting dose of 60 mg once daily for the first 7 days, then 90 mg once daily is recommended for patients with severe renal impairment (eGFR < 30 mL/min). Patients with severe renal impairment should be closely monitored for new or worsening respiratory symptoms that may indicate ILD/pneumonitis (e.g., dyspnoea, cough, etc.) particularly in the first week.
Paediatric population: The safety and efficacy of ALUNBRIG in patients less than 18 years of age have not been established. No data are available.
IMPORTANT SAFETY INFORMATION (U.S.)
WARNINGS AND PRECAUTIONS
Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG. In Trial ALTA (ALTA), ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily). Adverse reactions consistent with possible ILD/pneumonitis occurred early (within 9 days of initiation of ALUNBRIG; median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%. Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume ALUNBRIG with dose reduction after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.
Hypertension: In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall. Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume ALUNBRIG at a reduced dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension. Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia.
Bradycardia: Bradycardia can occur with ALUNBRIG. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. Monitor heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided. For symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue ALUNBRIG for life-threatening bradycardia if no contributing concomitant medication is identified.
Visual Disturbance: In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4 visual disturbances.
Creatine Phosphokinase (CPK) Elevation: In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3-4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group. Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.
Pancreatic Enzyme Elevation: In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.
Hyperglycemia: In ALTA, 43% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reducing the dose of ALUNBRIG or permanently discontinuing ALUNBRIG.
Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.
ADVERSE REACTIONS
Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).
The most common adverse reactions (≥25%) in the 90 mg group were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%) and in the 90→180 mg group were nausea (40%), diarrhea (38%), fatigue (36%), cough (34%), and headache (27%).
DRUG INTERACTIONS
CYP3A Inhibitors: Avoid concomitant use of ALUNBRIG with strong CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG.
CYP3A Inducers: Avoid concomitant use of ALUNBRIG with strong CYP3A inducers.
CYP3A Substrates: Coadministration of ALUNBRIG with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of CYP3A substrates.
USE IN SPECIFIC POPULATIONS
Pregnancy: ALUNBRIG can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.
Lactation: There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with ALUNBRIG.
Females and Males of Reproductive Potential:
Contraception: Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 3 months after the final dose.
Infertility: ALUNBRIG may cause reduced fertility in males.
Pediatric Use: The safety and efficacy of ALUNBRIG in pediatric patients have not been established.
Geriatric Use: Clinical studies of ALUNBRIG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were 75 years or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 and younger patients.
Hepatic or Renal Impairment: No dose adjustment is recommended for patients with mild hepatic impairment or mild or moderate renal impairment. The safety of ALUNBRIG in patients with moderate or severe hepatic impairment or severe renal impairment has not been studied.