ALUNBRIG Film-coated tablet Ref.[10636] Active ingredients: Brigatinib

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 section 4.8).

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. Patients with a history of ILD or drug-induced pneumonitis were excluded from the pivotal trials.

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 (see section 4.2).

Hypertension

Hypertension has occurred in patients treated with Alunbrig (see section 4.8).

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 section 4.2).

Bradycardia

Bradycardia has occurred in patients treated with Alunbrig (see section 4.8). 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 medicinal products known to cause bradycardia should be evaluated. Upon recovery, the dose should be modified accordingly (see section 4.2). 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 section 4.2).

Visual disturbance

Visual disturbance adverse reactions have occurred in patients treated with Alunbrig (see section 4.8). 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 section 4.2).

Creatine phosphokinase (CPK) elevation

Elevations of CPK have occurred in patients treated with Alunbrig (see section 4.8). 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, and if associated with muscle pain or weakness, treatment with Alunbrig should be withheld, and the dose modified accordingly (see section 4.2).

Elevations of pancreatic enzymes

Elevations of amylase and lipase have occurred in patients treated with Alunbrig (see section 4.8). 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 section 4.2).

Hepatotoxicity

Elevations of hepatic enzymes (aspartate aminotransferase, alanine aminotransferase) and bilirubin have occurred in patients treated with Alunbrig (see section 4.8). 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 section 4.2).

Hyperglycaemia

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. 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 as described in Table 1 may be considered or Alunbrig may be permanently discontinued.

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 section 4.5).

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 (see section 4.6).

Lactose

Alunbrig contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Agents that may increase brigatinib plasma concentrations

CYP3A inhibitors

In vitro studies demonstrated that brigatinib is a substrate of CYP3A4/5. In healthy subjects, 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), 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 approximately 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 (see section 4.2).

CYP2C8 inhibitors

In vitro studies demonstrated that brigatinib is a substrate of CYP2C8. In healthy subjects, coadministration of multiple 600 mg twice daily doses of gemfibrozil, a strong CYP2C8 inhibitor, with a single 90 mg brigatinib dose reduced 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. The effect of gemfibrozil on the pharmacokinetics of brigatinib is not clinically meaningful and the underlying mechanism for the decreased exposure of brigatinib is unknown. No dose adjustment is required 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. Given that brigatinib exhibits high solubility and high permeability, 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

In healthy subjects, coadministration of multiple 600 mg daily doses of rifampicin, 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 rifampicin, 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 CYP3A4. Clinical drug-drug interaction studies with sensitive CYP3A substrates have not been conducted. Brigatinib may reduce plasma levels of coadministered medicinal products that are predominantly metabolised by CYP3A. Therefore, 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.

Alunbrig 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

Coadministration of brigatinib with substrates of P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin), BCRP (e.g., methotrexate, rosuvastatin, sulfasalazine), organic cation transporter 1 (OCT1), multidrug and toxin extrusion protein 1 (MATE1), and 2K (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).

Women of childbearing potential / Contraception in males and females

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. Men 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.

Pregnancy

Alunbrig may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity (see section 5.3). 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 medicinal product, the patient should be apprised of the potential hazard to a foetus.

Breast-feeding

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 repeat-dose toxicity studies in male animals, Alunbrig may cause reduced fertility in males (see section 5.3). The clinical relevance of these findings to human fertility is unknown.

Alunbrig has minor influence on the ability to drive and use machines. However, caution should be exercised when driving or operating machines as patients may experience visual disturbance, dizziness, or fatigue while taking Alunbrig.

Summary of the safety profile

The most common adverse reactions (≥25%) reported in patients treated with Alunbrig at the recommended dosing regimen were increased AST, increased CPK, hyperglycaemia, increased lipase, hyperinsulinaemia, diarrhoea, increased ALT, increased amylase, anaemia, nausea, fatigue, hypophosphataemia, decreased lymphocyte count, cough, increased alkaline phosphatase, rash, increased APTT, myalgia, headache, hypertension, decreased white blood cell count, dyspnoea, and vomiting.

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 pneumonia, pneumonitis, dyspnoea and pyrexia.

Tabulated list of adverse reactions

The data described below reflect exposure to Alunbrig at the recommended dosing regimen in three clinical trials: a Phase 3 trial (ALTA 1L) in patients with advanced ALK-positive NSCLC previously not treated with an ALK-inhibitor (N=136), a Phase 2 trial (ALTA) in patients treated with Alunbrig with ALK-positive NSCLC who previously progressed on crizotinib (N=110), and a phase ½ dose escalation/expansion trial in patients with advanced malignancies (N=28). Across these studies, the median duration of exposure in patients receiving Alunbrig at the recommended dosing regimen was 21.8 months.

Adverse reactions reported are presented in Table 3 and are listed by system organ class, preferred term and frequency. Frequency categories are very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of frequency.

Table 3. Adverse reactions reported in patients treated with Alunbrig (per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03) at the 180 mg regimen (N=274):

^† The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline.
^a Includes atypical pneumonia, pneumonia, pneumonia aspiration, pneumonia cryptococcal, lower respiratory tract infection, lower respiratory tract infection viral, lung infection
^b Includes Grade 5 events
^c Grade not applicable
^d Includes headache, sinus headache, head discomfort, migraine, tension headache
^e Includes paraesthesia, peripheral sensory neuropathy, dysaesthesia, hyperaesthesia, hypoaesthesia, neuralgia, neuropathy peripheral, neurotoxicity, peripheral motor neuropathy, polyneuropathy, burning sensation, post herpetic neuralgia
^f Includes altered visual depth perception, cataract, colour blindness acquired, diplopia, glaucoma, intraocular pressure increased, macular oedema, photophobia, photopsia, retinal oedema, vision blurred, visual acuity reduced, visual field defect, visual impairment, vitreous detachment, vitreous floaters, amaurosis fugax
^g Includes bradycardia, sinus bradycardia
^h Includes sinus tachycardia, tachycardia, atrial tachycardia, heart rate increased
ⁱ Includes blood pressure increased, diastolic hypertension, hypertension, systolic hypertension
^j Includes dyspnoea, dyspnoea exertional
^k Includes interstitial lung disease, pneumonitis
^l Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, epigastric discomfort
^m Includes aphthous stomatitis, stomatitis, aphthous ulcer, mouth ulceration, oral mucosal blistering
ⁿ Includes dermatitis acneiform, erythema, exfoliative rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, dermatitis, dermatitis allergic, dermatitis contact, generalised erythema, rash follicular, urticaria, drug eruption, toxic skin eruption
° Includes pruritus, pruritus allergic, pruritus generalised, pruritus genital, vulvovaginal pruritus
^p Includes musculoskeletal pain, myalgia, muscle spasms, muscle tightness, muscle twitching, musculoskeletal discomfort
^q Includes asthenia, fatigue
^r Includes eyelid oedema, face oedema, oedema peripheral, periorbital oedema, swelling face, generalised oedema, peripheral swelling, angioedema, lip swelling, periorbital swelling, skin swelling, swelling of eyelid
^s Includes blood cholesterol increased, hypercholesterolemia

Description of selected adverse reactions

Pulmonary adverse reactions

In ALTA 1L, 2.9% of patients experienced any Grade ILD/pneumonitis early in treatment (within 8 days), with Grade 3-4 ILD/pneumonitis in 2.2% of patients. There were no fatal ILD/pneumonitis. Additionally, 3.7% of patients experienced pneumonitis later in treatment.

In ALTA, 6.4% of patients experienced pulmonary adverse reactions of any grade, including ILD/pneumonitis, pneumonia and dyspnoea, early in treatment (within 9 days, median onset: 2 days); 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 Alunbrig was either interrupted and then restarted or the dose was reduced. Early pulmonary adverse reactions also occurred in a dose escalation study in patients (N=137) (Study 101) including three fatal cases (hypoxia, acute respiratory distress syndrome and pneumonia). Additionally, 2.3% of patients in ALTA experienced pneumonitis later in treatment, with 2 patients having Grade 3 pneumonitis (see sections 4.2 and 4.4).

Elderly

Early pulmonary adverse reaction was reported in 10.1% of patients ≥65 years of age compared with 3.1% of patients <65 years of age.

Hypertension

Hypertension was reported in 30% of patients treated with Alunbrig at the 180 mg regimen with 11% having Grade 3 hypertension. Dose reduction for hypertension occurred in 1.5% at the 180 mg regimen. Mean systolic and diastolic blood pressure, in all patients, increased over time (see sections 4.2 and 4.4).

Bradycardia

Bradycardia was reported in 8.4% of patients treated with Alunbrig at the 180 mg regimen.

Heart rates of less than 50 beats per minute (bpm) were reported in 8.4% of patients at the 180 mg regimen (see sections 4.2 and 4.4).

Visual disturbance

Visual disturbance adverse reactions were reported in 14% of patients treated with Alunbrig at the 180 mg regimen. Of these, three Grade 3 adverse reactions (1.1%) including macular oedema and cataract were reported.

Dose reduction for visual disturbance occurred in two patients (0.7%) at the 180 mg regimen (see sections 4.2 and 4.4).

Peripheral neuropathy

Peripheral neuropathy adverse reactions were reported in 20% of patients treated at the 180 mg regimen. Thirty-three percent of patients had resolution of all peripheral neuropathy adverse reactions. The median duration of peripheral neuropathy adverse reactions was 6.6 months, with a maximum duration of 28.9 months.

Creatine phosphokinase (CPK) elevation

In ALTA 1L and ALTA, elevations of CPK were reported in 64% of patients treated with Alunbrig at the 180 mg regimen. The incidence of Grade 3-4 elevations of CPK was 18%. The median time to onset for CPK elevations was 28 days.

Dose reduction for CPK elevation occurred in 10% of patients at the 180 mg regimen (see sections 4.2 and 4.4).

Elevations of pancreatic enzymes

Elevations of amylase and lipase were reported in 47% and 54% of patients treated with Alunbrig, respectively at the 180 mg regimen. For elevations to Grade 3 and 4, the incidences for amylase and lipase were 7.7% and 15%, respectively. The median time to onset for amylase elevations and lipase elevations was 17 days and 29 days, respectively.

Dose reduction for elevation of lipase and amylase occurred in 4.7% and 2.9% of patients, respectively at the 180 mg regimen (see sections 4.2 and 4.4).

Elevation of hepatic enzymes

Elevations of ALT and AST were reported in 49% and 68% of patients treated with Alunbrig, respectively at the 180 mg regimen. For elevations to Grade 3 and 4, the incidences for ALT and AST were 4.7% and 3.6%, respectively.

Dose reduction for elevation of ALT and AST occurred in 0.7% and 1.1% of patients, respectively at the 180 mg regimen (see sections 4.2 and 4.4).

Hyperglycaemia

Sixty one percent of patients experienced hyperglycaemia. Grade 3 hyperglycemia occurred in 6.6% of patients.

No patients had dose reductions due to hyperglycaemia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.