Alunbrig

Brigatinib.

Each tablet contains 30 mg, 90 mg, 180 mg of brigatinib.
Brigatinib is a kinase inhibitor. The chemical name for brigatinib is 5-chloro-N⁴-[2-(dimethylphosphoryl)phenyl]-N²-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine. The molecular formula is C₂₉H₃₉ClN₇O₂P which corresponds to a formula weight of 584.10 g/mol. Brigatinib has no chiral centers.
Brigatinib is an off-white to beige/tan solid. The pK_as were determined to be: 1.73 ± 0.02 (base), 3.65 ± 0.01 (base), 4.72 ± 0.01 (base), and 8.04 ± 0.01 (base).
Excipients/Inactive Ingredients: Lactose monohydrate, Microcrystalline cellulose, Sodium starch glycolate (type A), Silica colloidal hydrophobic, Magnesium stearate.
Tablet coating: Talc, Macrogol, Polyvinyl alcohol, Titanium dioxide.

Pharmacology: Pharmacodynamics: Cardiac Electrophysiology: The QT interval prolongation potential of brigatinib was assessed in 123 patients following once daily ALUNBRIG doses of 30 mg to 240 mg. Brigatinib did not prolong the QT interval to a clinically relevant extent.
Mechanism of Action: Brigatinib is a tyrosine kinase inhibitor that targets ALK, ROS1, and insulin-like growth factor 1 receptor (IGF-1R). Among these, brigatinib is most active against ALK. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signalling protein STAT3 in in vitro and in vivo assays.
Brigatinib inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice.
At concentrations (≤ 500 nM) that are achieved clinically, brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib. No ALK mutations associated with resistance to brigatinib were observed. Brigatinib demonstrated in vivo and clinical activity against multiple mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumours in patients who have progressed on crizotinib.
Administration of brigatinib resulted in antitumor activity and prolonged survival in mice with an ALK-driven tumour cell line implanted intracranially.
Clinical Studies: The safety and efficacy of ALUNBRIG was evaluated in a randomised (1:1), open-label, multicenter trial (ALTA) in 222 adult patients with locally advanced or metastatic ALK-positive NSCLC who had progressed on crizotinib. Eligibility criteria permitted enrollment of patients with a documented ALK rearrangement based on a validated ALK test, ECOG Performance Status of 0-2, prior chemotherapy, and central nervous system (CNS) metastases provided they were neurologically stable and did not require an increasing dose of corticosteroids. Patients with a history of pulmonary interstitial disease or drug-related pneumonitis were excluded.
Patients were randomised in a 1:1 ratio to receive brigatinib either 90 mg once daily (90 mg regimen, n=112) or 180 mg once daily with 7-day lead-in at 90 mg once daily (180 mg regimen, n=110). The median duration of follow-up was 17.9 months. Randomisation was stratified by brain metastases (present, absent) and best prior response to crizotinib therapy (complete or partial response, any other response/unknown).
The major outcome measure was confirmed objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by investigator. Additional outcome measures included confirmed ORR as evaluated by an Independent Review Committee (IRC); time to response; progression free survival (PFS); duration of response (DOR); overall survival; quality of life; and intracranial ORR, intracranial DOR and intracranial PFS as evaluated by an IRC. The analysis of study measured outcomes across both arms informed the recommended dose.
Baseline demographics and disease characteristics in ALTA (Table 1) were median age 54 years old (range 18 to 82; 23% 65 and over), 67% White and 31% Asian, 57% female, 36% ECOG PS 0 and 57% ECOG PS 1, 95% never or former smokers, 98% Stage IV, 97% adenocarcinoma, and 74% prior chemotherapy. The most common sites of extra-thoracic metastasis included 69% brain (of whom 62% had received prior radiation to the brain), 40% bone, and 26% liver.
Efficacy results from ALTA analysis are summarised in Table 1 and the Kaplan-Meier (KM) curves for investigator-assessed and IRC-assessed systemic PFS are shown in Figure 1 and Figure 2, respectively. (See Tables 1 and 2, Figures 1 and 2.)

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In ALTA, 201 patients had at least 1 evaluable post-baseline assessment out of the 222 patients. Waterfall plots displaying the maximum decrease from baseline in the sum of the longest tumor diameters shows that the majority of patients treated with ALUNBRIG had a reduction in tumor burden in both the 90 mg and 180 mg regimens in ALTA (see Figures 3 and 4).

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Of the 222 enrolled patients, baseline tumour tissue samples were evaluable in 17 patients. Responses were seen in patients with and without secondary ALK kinase domain mutations, including one patient with a secondary ALK kinase domain mutation of G1202R.
In Study 101, 25 patients with ALK-positive NSCLC that progressed on crizotinib were administered brigatinib at 180 mg once daily with 7-day lead-in at 90 mg once daily regimen. Of these, 19 patients had an investigator-assessed confirmed objective response (76%; 95% CI: 55, 91) and the KM median PFS was 16.3 months (95% CI: 9.2, NE) and the 12-month probability of overall survival was 84.0% (95% CI: 62.8, 93.7).
IRC assessments of intracranial ORR and duration of intracranial response in patients from ALTA with measurable brain metastases (≥10 mm in longest diameter) at baseline are summarized in Table 3. (See Table 3.)

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In ALTA, patients overall experienced positive changes relative to baseline in quality-of-life (QOL) during treatment with brigatinib. The mean QOL, measured by the summary Global Health Status /QOL score of the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ)-C30, was maintained above baseline mean values throughout follow-up (median: 17.9 months) across both dose groups.
Pharmacokinetics: Absorption: Following administration of single oral doses of brigatinib of 30 to 240 mg, the median time to peak concentration (T_max) ranged from 1 to 4 hours postdose. The geometric mean (CV%) steady-state C_max of brigatinib at doses of 90 mg and 180 mg once daily was 552 (65%) and 1452 (60%) ng/mL, respectively, and the corresponding AUC_0-tau was 8165 (57%) and 20276 (56%) h·ng/mL, respectively. After a single dose and repeat dosing of brigatinib, systemic exposure was dose proportional over the dose range of 60 mg to 240 mg once daily. The mean accumulation ratio after repeat dosing was 1.9 to 2.4.
Brigatinib C_max was reduced by 13% with no effect on AUC in healthy subjects administered ALUNBRIG after a high-fat meal compared to the C_max and AUC after overnight fasting.
Distribution: Brigatinib is 66% bound to human plasma proteins and the binding is not concentration-dependent in vitro. The blood-to-plasma concentration ratio is 0.69. Following oral administration of brigatinib 180 mg once daily, the geometric mean apparent volume of distribution (V_z/F) at steady-state was 153 L.
Metabolism: In vitro studies demonstrated that brigatinib is primarily metabolized by CYP2C8 and CYP3A4. Following oral administration of a single 180 mg dose of [¹⁴C]-brigatinib to healthy subjects, N-demethylation and cysteine conjugation were the two major metabolic clearance pathways. Unchanged brigatinib (92%) and its primary metabolite, AP26123 (3.5%), were the major circulating radioactive components. In patients, the steady-state AUC of AP26123 was less than 10% of brigatinib exposure. The metabolite, AP26123, inhibited ALK with approximately 3-fold lower potency than brigatinib in vitro.
Excretion and Elimination: Following oral administration of brigatinib 180 mg once daily, the geometric mean apparent oral clearance (CL/F) of brigatinib at steady-state was 13 L/h and the mean plasma elimination half-life was 25 h.
Following administration of a single 180 mg oral dose of [¹⁴C]-brigatinib to 6 healthy male subjects, 65% of the administered dose was recovered in feces and 25% of the administered dose was recovered in urine. Unchanged brigatinib represented 41% and 86% of the total radioactivity in feces and urine, respectively.
Special Populations: Impaired Renal Function: The pharmacokinetics of brigatinib is similar in patients with normal renal function and in patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min) based on the results of population pharmacokinetic analyses. In a pharmacokinetic study, unbound AUC_0-INF was 94% higher in patients with severe renal impairment (eGFR < 30 mL/min, N = 6) as compared to patients with normal renal function (eGFR ≥ 90 mL/min, N = 8) (see Dosage & Administration).
Impaired Hepatic Function: The pharmacokinetics of brigatinib was characterised in healthy subjects with normal hepatic function (N = 9), and patients with mild hepatic impairment (Child-Pugh class A, N = 6), moderate hepatic impairment (Child-Pugh class B, N = 6), or severe hepatic impairment (Child-Pugh class C, N = 6). The pharmacokinetics of brigatinib was similar between healthy subjects with normal hepatic function and patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Unbound AUC_0-INF was 37% higher in patients with severe hepatic impairment (Child-Pugh class C) as compared to healthy subjects with normal hepatic function (see Dosage & Administration).
Age, Gender, Race: Population pharmacokinetic analyses showed that age, gender or race had no clinically meaningful effect on the pharmacokinetics of brigatinib.
Drug Interactions: Agents that may increase brigatinib plasma concentrations: CYP3A Inhibitors: In vitro studies demonstrated that brigatinib is a substrate of CYP3A4/5. Coadministration of multiple 200 mg twice daily doses of itraconazole, a strong CYP3A inhibitor, with a single 90 mg brigatinib dose increased brigatinib C_max by 21%, AUC_0-INF by 101% (2-fold), and AUC_0-120 by 82% (<2-fold), relative to a 90 mg brigatinib dose administered alone. The concomitant use of strong CYP3A inhibitors with ALUNBRIG, including but not limited to certain antivirals (e.g., indinavir, nelfinavir, ritonavir, saquinavir), macrolide antibiotics (e.g., clarithromycin, telithromycin, troleandomycin), antifungals (e.g., ketoconazole, voriconazole), mibefradil, and nefazodone should be avoided. If concomitant use of strong CYP3A inhibitors cannot be avoided, the dose of ALUNBRIG should be reduced by approximately 50% (i.e., 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.
Moderate CYP3A inhibitors (e.g., diltiazem and verapamil) may increase the AUC of brigatinib by 30 to 40% based on simulations from a physiologically-based pharmacokinetic model. No dose adjustment is required for ALUNBRIG in combination with moderate CYP3A inhibitors. Patients should be closely monitored when ALUNBRIG is coadministered with moderate CYP3A inhibitors.
Grapefruit or grapefruit juice may also increase plasma concentrations of brigatinib and should be avoided.
CYP2C8 Inhibitors: In vitro studies demonstrated that brigatinib is a substrate of CYP2C8. Coadministration of multiple 600 mg twice daily doses of gemfibrozil, a strong CYP2C8 inhibitor, with a single 90 mg brigatinib dose decreased brigatinib C_max by 41%, AUC_0-INF by 12%, and AUC_0-120 by 15%, relative to a 90 mg brigatinib dose administered alone. No dose adjustment is required for ALUNBRIG during coadministration with strong CYP2C8 inhibitors.
P-gp and BCRP Inhibitors: Brigatinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro. Brigatinib exhibits high solubility and high permeability. Additionally, simulations from a physiologically-based pharmacokinetic model suggested that inhibition of P-gp and BCRP is not expected to result in a clinically meaningful change in the systemic exposure of brigatinib. No dose adjustment is required for ALUNBRIG during coadministration with P-gp and BCRP inhibitors.
Agents that may decrease brigatinib plasma concentrations: CYP3A Inducers: Coadministration of multiple 600 mg daily doses of rifampin, a strong CYP3A inducer, with a single 180 mg brigatinib dose decreased brigatinib C_max by 60%, AUC_0-INF by 80% (5-fold), and AUC_0-120 by 80% (5-fold), relative to a 180 mg brigatinib dose administered alone. The concomitant use of strong CYP3A inducers with ALUNBRIG, including but not limited to rifampin, carbamazepine, phenytoin, rifabutin, phenobarbital, and St. John's Wort should be avoided.
Moderate CYP3A inducers may decrease the AUC of brigatinib by approximately 50% based on simulations from a physiologically-based pharmacokinetic model. The concomitant use of moderate CYP3A inducers with ALUNBRIG, including but not limited to efavirenz, modafinil, bosentan, etravirine, and nafcillin should be avoided.
Agents that may have their plasma concentrations altered by brigatinib: CYP3A Substrates: In vitro studies in hepatocytes have shown that brigatinib is an inducer of CYP3A. Clinical drug-drug interaction studies with sensitive CYP3A substrates have not been conducted. Brigatinib may reduce plasma concentrations of coadministered medications that are predominantly metabolized by CYP3A.
Brigatinib may also induce other enzymes and transporters (e.g., CYP2C, P-gp) via the same mechanisms responsible for induction of CYP3A (e.g., pregnane X receptor activation).
Transporter Substrates: Brigatinib is an inhibitor of P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro. Coadministration of brigatinib with substrates of P-gp, (e.g. digoxin, dabigatran, colchicine, pravastatin), BCRP (e.g., methotrexate, rosuvastatin, sulfasalazine), OCT1, MATE1, and MATE2K may increase their plasma concentrations.
Toxicology: Nonclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity: Carcinogenicity studies have not been performed with brigatinib.
Mutagenicity: Brigatinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) or the mammalian cell chromosomal aberration assays, but slightly increased the number of micronuclei in a rat bone marrow micronucleus test. The mechanism of micronucleus induction was abnormal chromosome segregation (aneugenicity) and not a clastogenic effect on chromosomes. This effect was observed at approximately five fold the human exposure at the 180 mg once daily dose.
Impairment of Fertility: Brigatinib may impair male fertility. Testicular toxicity was observed in repeat-dose animal studies. In rats, findings included lower weight of testes, seminal vesicles and prostate gland, and testicular tubular degeneration; these effects were not reversible during the recovery period. In monkeys, findings included reduced size of testes along with microscopic evidence of hypospermatogenesis; these effects were reversible during the recovery period. Overall, these effects on the male reproductive organs in rats and monkeys occurred at exposures as low as 0.2-times the AUC in patients at the 180 mg once daily dose. No apparent adverse effects on female reproductive organs were observed in general toxicology studies in rats and monkeys.
Animal Toxicology and/or Pharmacology: Nonclinical safety assessment in rats and monkeys identified potential risk for toxicity in multiple organs such as gastrointestinal system, bone marrow, eyes, testes, liver, kidney, bone, and heart. These effects were generally reversible during the non-dosing recovery period; however, effects in the eyes and testes were notable exceptions due to lack of recovery.

ALUNBRIG is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib.

Dosage: The recommended starting dose of ALUNBRIG is 90 mg once daily for the first 7 days, then 180 mg once daily.
Treatment should continue as long as clinical benefit is observed.
If a dose of ALUNBRIG is missed or vomiting occurs after taking a dose, an additional dose should not be administered and the next dose of ALUNBRIG should be taken at the scheduled time.
Dose Adjustments: Dosing interruption and/or dose reduction may be required based on individual safety and tolerability.
ALUNBRIG dose modification levels are summarised in Table 4. (See Table 4.)

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Permanently discontinue ALUNBRIG if patient is unable to tolerate the 60 mg once daily dose.
If ALUNBRIG is interrupted for 14 days or longer for reasons other than adverse reactions, treatment should be resumed at 90 mg once daily for 7 days before increasing to the previously tolerated dose.
Recommendations for dose modifications of ALUNBRIG for the management of adverse reactions are summarized in Table 5. (See Table 5.)

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Special Patient 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 (see Pharmacology under Actions). There are no available data on patients over 85 years of age.
Pediatric Patients: The safety and efficacy of ALUNBRIG in patients less than 18 years of age have not been established. No data are available.
Impaired Renal Function: No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance ≥ 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) (see Pharmacology: Pharmacokinetics under Actions). 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. (See Pharmacology under Actions.)
Impaired Hepatic Function: 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 (see Pharmacology under Actions).
Method of Administration: ALUNBRIG is for oral use. The tablets should be swallowed whole and with water. Do not crush or chew tablets.
ALUNBRIG may be taken with or without food.

There is no specific antidote for overdose with ALUNBRIG. In the event of an overdose, monitor the patient for adverse reactions (see Adverse Reactions) and provide appropriate supportive care.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

Pulmonary adverse reactions: Severe, life-threatening, and fatal pulmonary adverse reactions, including those with features consistent with ILD/pneumonitis, can occur in patients treated with ALUNBRIG (see Adverse Reactions).
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. These factors should be considered 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, ALUNBRIG should be withheld, and the patient evaluated for other causes of symptoms (e.g., pulmonary embolism, tumour progression, and infectious pneumonia) and dosing modified accordingly (see Dosage & Administration).
Hypertension: Hypertension has occurred in patients treated with ALUNBRIG (see Adverse Reactions).
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 medicinal product 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 (see Dosage & Administration).
Bradycardia: Bradycardia has occurred in patients treated with ALUNBRIG (see Adverse Reactions). 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.
If symptomatic bradycardia occurs, treatment with ALUNBRIG should be withheld and concomitant medications known to cause bradycardia should be evaluated. Upon recovery, the dose should be modified accordingly (see Dosage & Administration). In case of life-threatening bradycardia, if no contributing concomitant medication is identified or in case of recurrence, treatment with ALUNBRIG should be discontinued (see Dosage & Administration).
Visual Disturbance: Visual disturbances have occurred in patients treated with ALUNBRIG (see Adverse Reactions). 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 (see Dosage & Administration).
Creatine Phosphokinase (CPK) Elevation: Elevations of CPK have occurred in patients treated with ALUNBRIG (see Adverse Reactions). Patients should be advised to report any unexplained muscle pain, tenderness, or weakness. CPK levels should be monitored regularly during ALUNBRIG treatment. Based on the severity of the CPK elevation, treatment with ALUNBRIG should be withheld, and the dose modified accordingly (see Dosage & Administration).
Pancreatic Enzyme Elevation: Elevations of amylase and lipase have occurred in patients treated with ALUNBRIG (see Adverse Reactions). Lipase and amylase should be monitored regularly during treatment with ALUNBRIG. Based on the severity of the laboratory abnormalities, treatment with ALUNBRIG should be withheld, and the dose modified accordingly (see Dosage & Administration).
Hyperglycemia: Elevations of serum glucose have occurred in patients treated with ALUNBRIG. Fasting serum glucose should be assessed prior to initiation of ALUNBRIG and monitored periodically thereafter. Antihyperglycemic medications should be initiated or optimized as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, ALUNBRIG should be withheld until adequate hyperglycemic control is achieved; upon recovery reducing the dose of ALUNBRIG as described in Dosage & Administration may be considered or ALUNBRIG may be permanently discontinued.
Hepatotoxicity: Elevations of hepatic enzymes (aspartate aminotransferase, alanine aminotransferase) and bilirubin have occurred in patients treated with ALUNBRIG (see Adverse Reactions). 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, treatment should be withheld, and the dose modified accordingly (see Dosage & Administration).
Drug-drug interactions: The concomitant use of Alunbrig with strong CYP3A inhibitors should be avoided. If concomitant use of strong CYP3A inhibitors cannot be avoided, the dose of Alunbrig should be reduced 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 (see Interactions).
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. 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 (see Use in Pregnancy & Lactation).
Drug Abuse and Dependence: ALUNBRIG has no known potential for abuse or dependence.
Effects on Ability to Drive and Use Machines: There are no data on the effect of ALUNBRIG on the ability to drive and use machines. Visual disturbance, dizziness, and fatigue have been observed in clinical trials. Patients should be advised not to drive or operate machines if they experience any of these symptoms while taking ALUNBRIG.

Pregnancy: ALUNBRIG may cause fetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Nonclinical Safety Data under Actions). There are no clinical data on the use of ALUNBRIG in pregnant women. ALUNBRIG should not be used during pregnancy unless the clinical condition of the mother requires treatment. If ALUNBRIG is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Women of childbearing age being treated with ALUNBRIG should be advised not to become pregnant and men being treated with ALUNBRIG should be advised not to father a child during treatment. Women of reproductive potential should be advised to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Male patient with female partners of reproductive potential should be advised to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.
In an embryo-fetal development study in which pregnant rats were administered daily doses of brigatinib during organogenesis, dose-related skeletal (incomplete ossification, small incisors) and visceral anomalies were observed at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily). Malformations observed at 25 mg/kg/day (approximately 1.26 times the human AUC at 180 mg once daily) included anasarca (generalized subcutaneous edema), anophthalmia (absent eyes), forelimb hyperflexion, small, short and/or bent limbs, multiple fused ribs, bent scapulae, omphalocele (intestine protruding into umbilicus), and gastroschisis (intestines protruding through a defect in the abdominal wall) along with visceral findings of moderate bilateral dilatation of the lateral ventricles.
Lactation: It is unknown whether ALUNBRIG is excreted in human milk. Available data cannot exclude potential excretion in human milk. Breast-feeding should be stopped during treatment with ALUNBRIG.
Fertility: No human data on the effect of ALUNBRIG on fertility are available. Based on reproductive studies in male animals, ALUNBRIG may cause reduced fertility in males (see Pharmacology: Toxicology: Nonclinical Safety Data under Actions). The clinical relevance of these findings to human fertility is unknown.

Clinical Trials: The adverse reactions described in this section were identified in a randomised, open-label, multicentre trial in patients treated with ALUNBRIG (N = 219) with ALK+ NSCLC who previously progressed on crizotinib (Study 201). Patients were randomised in a 1:1 ratio to receive ALUNBRIG either 90 mg once daily continuously (90 mg regimen) or 180 mg once daily with 7-day lead-in at 90 mg once daily (180 mg regimen).
The median duration of treatment with ALUNBRIG was 15.4 months in all treated patients (13.2 months and 17.1 months in 90 mg regimen and 180 mg regimen, respectively).
The most common adverse reactions excluding laboratory abnormalities (see Table 6) reported in patients (≥20%) treated with ALUNBRIG at the 180 mg regimen were nausea (47%), diarrhea (44%), fatigue (42%), cough (40%), headache (35%), rash (32%), vomiting (30%), hypertension (27%), dyspnea (26%), myalgia (25%), decreased appetite (24%), muscle spasms (22%), and constipation (20%).
The most common serious adverse reactions reported in 2% or more of patients in the 180 mg regimen other than neoplasm progression included pneumonia (8.2%) and pneumonitis (8.2%). Treatment-emergent adverse events that led to discontinuation of brigatinib occurred in 10.9% (12/110) of patients receiving the 180 mg regimen. The most common TEAEs (occurring in ≥2 patients receiving the 180 mg regimen) that led to brigatinib discontinuation were pneumonitis, neoplasm progression, and pneumonia (2.7% [3/110], 1.8% [2/110], and 1.8% [2/110], respectively).
Treatment-emergent adverse events that led to dose reduction occurred in 30% (33/110) of patients receiving the 180 mg regimen. The TEAE leading to dose reduction that occurred in ≥2% of patients receiving the 180 mg regimen were blood CPK increased (6.4% (7/110), pneumonitis (2.7% [3/110]) and rash (2.7%[3/110]).
The following convention is used for the classification of the frequency of an adverse drug reaction (ADR) and is based on the Council for International Organizations of Medical Sciences (CIOMS) guidelines: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to< 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). (See Table 6.)

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Pulmonary Adverse Reactions: Pulmonary adverse reactions of any grade, including ILD/pneumonitis, pneumonia and dyspnea, early in treatment (within 9 days, median onset: 2 days) were experienced in 6.4% of patients; 2.7% of patients had Grade 3-4 pulmonary adverse reactions and 1 patient (0.5%) had fatal pneumonia. Following Grade 1-2 pulmonary adverse reactions, treatment with brigatinib was either interrupted and then restarted or the dose was reduced. Additionally, 2.3% of patients experienced pneumonitis later in treatment, with 2 patients having Grade 3 pneumonitis (see Dosage & Administration and Precautions).
Hypertension: Hypertension was reported in 27% of patients treated with brigatinib at the 180 mg regimen with 8.2% having Grade 3 hypertension. Dose reduction for hypertension occurred in 0.9% of patients at the 180 mg regimen. Systolic and diastolic blood pressure increased over time (see Dosage & Administration and Precautions).
Bradycardia: Bradycardia was reported in 4.5% of patients treated with brigatinib at the 180 mg regimen.
Heart rates of less than 50 beats per minute (bpm) were reported in 8.2% of patients at the 180 mg regimen. In a separate dose finding study (Study 101), a decrease in heart rate was associated with increased brigatinib plasma concentrations (Cmax) (see Dosage & Administration and Precautions).
Visual Disturbance: Visual disturbances were reported in 16% of patients treated with brigatinib at the 180 mg regimen. Of these, two grade 3 adverse reactions (1.8%) including macular oedema and cataract were reported.
Dose reduction for visual disturbance occurred in two patients (1.8%) at the 180 mg regimen (see Dosage & Administration and Precautions).
Creatine Phosphokinase (CPK) Elevation: Elevations of creatine phosphokinase (CPK) were reported in 50% of patients treated with brigatinib at the 180 mg regimen. The incidence of Grade 3-4 elevations of CPK was 14%. The median time to onset for CPK elevations was 27 days.
Dose reduction for CPK elevation occurred in 6.4% patients at the 180 mg regimen (see Dosage & Administration and Precautions).
Elevations of Pancreatic Enzymes: Elevations of amylase and lipase were reported in 41% and 46% of patients treated with brigatinib, respectively at the 180 mg regimen. For elevations to Grades 3 - 4, the incidences for amylase and lipase were 7.3% and 10%, respectively. The median time to onset for amylase elevations and lipase elevations was 16 days and 29 days, respectively.
The elevations of amylase and lipase were not associated with clinical pancreatitis in Study 201.
Dose reduction for elevation of lipase and amylase occurred in 1.8% and 0.9% of patients, respectively at the 180 mg regimen (see Dosage & Administration and Precautions).
Hyperglycemia: In Study 201, 67% of patients experienced hyperglycemia. Grade 3 hyperglycemia occurred in 5.5% of patients (see Dosage & Administration and Precautions).
No patients had dose reductions due to hyperglycaemia.

Agents that may increase brigatinib plasma concentrations: CYP3A Inhibitors: The concomitant use of strong CYP3A inhibitors with ALUNBRIG, including but not limited to certain antivirals (e.g., indinavir, nelfinavir, ritonavir, saquinavir), macrolide antibiotics (e.g., clarithromycin, telithromycin, troleandomycin), antifungals (e.g., itraconazole, ketoconazole, posaconazole, voriconazole), mibefradil, and nefazodone should be avoided. If concomitant use of strong CYP3A inhibitors cannot be avoided, the dose of ALUNBRIG should be reduced by approximately 50% (i.e., 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.
No dose adjustment is required for ALUNBRIG in combination with moderate CYP3A inhibitors (e.g., diltiazem and verapamil). Patients should be closely monitored when ALUNBRIG is coadministered with moderate CYP3A inhibitors.
Grapefruit or grapefruit juice may also increase plasma concentrations of brigatinib and should be avoided.
CYP2C8 Inhibitors: No dose adjustment is required for ALUNBRIG during coadministration with strong CYP2C8 inhibitors.
P-gp and BCRP Inhibitors: No dose adjustment is required for ALUNBRIG during coadministration with P-gp and BCRP inhibitors.
Agents that may decrease brigatinib plasma concentrations: CYP3A Inducers: The concomitant use of strong CYP3A inducers with ALUNBRIG, including but not limited to rifampin, carbamazepine, phenytoin, rifabutin, phenobarbital, and St. John's Wort should be avoided.
The concomitant use of moderate CYP3A inducers with ALUNBRIG, including but not limited to efavirenz, modafinil, bosentan, etravirine, and nafcillin should be avoided.
Agents that may have their plasma concentrations altered by brigatinib: CYP3A Substrates: Brigatinib induces CYP3A in vitro and may reduce plasma concentrations of coadministered medications that are predominantly metabolized by CYP3A. Coadministration of ALUNBRIG with CYP3A substrates with a narrow therapeutic index (e.g. alfentanil, fentanyl, quinidine, cyclosporine, sirolimus, tacrolimus) should be avoided as their effectiveness may be reduced.
Brigatinib may also induce other enzymes and transporters (e.g., CYP2C, P-gp) via the same mechanisms responsible for induction of CYP3A (e.g., pregnane X receptor activation).
Transporter Substrates: Brigatinib is an inhibitor of P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro. Coadministration of brigatinib with substrates of P-gp, (e.g. digoxin, dabigatran, colchicine, pravastatin), BCRP (e.g., methotrexate, rosuvastatin, sulfasalazine), OCT1, MATE1, and MATE2K may increase their plasma concentrations. Patients should be closely monitored when ALUNBRIG is coadministered with substrates of these transporters with a narrow therapeutic index (e.g., digoxin, dabigatran, methotrexate).

Instructions for Use/Handling: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.

Store below 30°C.

Targeted Cancer Therapy

L01XE43 - brigatinib ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer.

POM

FC tab 30 mg (white to off-white, round, debossed "U3" on one side and plain on the other side) x 28's. 90 mg (white to off-white, oval, debossed "U7" on one side and plain on the other side) x 7's, 28's. 180 mg (white to off-white, oval, debossed "U13" on one side and plain on the other side) x 28's.