4.1. Therapeutic indications

Alunbrig is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously not treated with an ALK inhibitor.

Alunbrig is indicated as monotherapy for the treatment of adult patients with ALK-positive advanced NSCLC previously treated with crizotinib.

4.2. Posology and method of administration

Treatment with Alunbrig should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

ALK-positive NSCLC status should be known prior to initiation of Alunbrig therapy. A validated ALK assay is necessary for the selection of ALK-positive NSCLC patients (see section 5.1). Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilised.

Posology

The recommended starting dose of Alunbrig is 90 mg once daily for the first 7 days, then 180 mg once daily.

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.

If a dose is missed or vomiting occurs after taking a dose, an additional dose should not be administered and the next dose should be taken at the scheduled time.

Treatment should continue as long as clinical benefit is observed.

Dose adjustments

Dosing interruption and/or dose reduction may be required based on individual safety and tolerability.

Alunbrig dose reduction levels are summarised in Table 1.

Table 1: Recommended Alunbrig dose reduction levels

Dose

Dose reduction levels

First

Second

Third

90 mg once daily

(first 7 days)

reduce to 60 mg once daily

permanently discontinue

not applicable

180 mg once daily

reduce to 120 mg once daily

reduce to 90 mg once daily

reduce to 60 mg once daily

Alunbrig should be permanently discontinued if patient is unable to tolerate the 60 mg once daily dose.

Recommendations for dose modifications of Alunbrig for the management of adverse reactions are summarised in Table 2.

Table 2: Recommended Alunbrig dose modifications for adverse reactions

Adverse reaction

Severity*

Dose modification

Interstitial lung disease (ILD)/pneumonitis

Grade 1

• If event occurs during the first 7 days of treatment, Alunbrig should be withheld until recovery to baseline, then resumed at same dose level and not escalated to 180 mg once daily.

• If ILD/pneumonitis occurs after the first 7 days of treatment, Alunbrig should be withheld until recovery to baseline, then resumed at same dose level.

• If ILD/pneumonitis recurs, Alunbrig should be permanently discontinued.

Grade 2

• If ILD/pneumonitis occurs during the first 7 days of treatment, Alunbrig should be withheld until recovery to baseline, then resumed at next lower dose level as described in Table 1 and not escalated to 180 mg once daily.

• If ILD/pneumonitis occurs after the first 7 days of treatment, Alunbrig should be withheld until recovery to baseline. Alunbrig should be resumed at next lower dose level as described in Table 1.

• If ILD/pneumonitis recurs, Alunbrig should be permanently discontinued.

Grade 3 or 4

• Alunbrig should be permanently discontinued.

Hypertension

Grade 3 hypertension (SBP ≥ 160 mmHg or DBP ≥ 100 mmHg, medical intervention indicated, more than one anti-hypertensive medicinal product, or more intensive therapy than previously used indicated)

• Alunbrig should be withheld until hypertension has recovered to Grade ≤ 1 (SBP < 140 mmHg and DBP < 90 mmHg), then resumed at same dose.

• If Grade 3 hypertension recurs, Alunbrig should be withheld until hypertension has recovered to Grade ≤ 1 then resumed at the next lower dose level per Table 1 or permanently discontinued.

Grade 4 hypertension (life threatening consequences, urgent intervention indicated)

• Alunbrig should be withheld until hypertension has recovered to Grade ≤ 1 (SBP < 140 mmHg and DBP < 90 mmHg), then resumed at the next lower dose level per Table 1 or permanently discontinued.

• If Grade 4 hypertension recurs, Alunbrig should be permanently discontinued.

Bradycardia (heart rate less than 60 bpm)

Symptomatic bradycardia

• Alunbrig should be withheld until recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above.

• If a concomitant medicinal product known to cause bradycardia is identified and discontinued, or its dose is adjusted, Alunbrig should be resumed at same dose upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above.

• If no concomitant medicinal product known to cause bradycardia is identified, or if contributing concomitant medicinal products are not discontinued or dose modified, Alunbrig should be resumed at the next lower dose level per Table 1 upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above.

Bradycardia with life-threatening consequences, urgent intervention indicated

• If contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, Alunbrig should be resumed at the next lower dose level per Table 1 upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above, with frequent monitoring as clinically indicated.

• Alunbrig should be permanently discontinued if no contributing concomitant medicinal product is identified.

• Alunbrig should be permanently discontinued in case of recurrence.

Elevation of CPK

Grade 3 or 4 elevation of CPK (> 5.0 × ULN) with Grade ≥ 2 muscle pain or weakness

• Alunbrig should be withheld until recovery to Grade ≤ 1 (≤ 2.5 × ULN) elevation of CPK or to baseline, then resumed at the same dose.

• If Grade 3 or 4 elevation of CPK recurs with Grade ≥ 2 muscle pain or weakness, Alunbrig should be withheld until recovery to Grade ≤ 1 (≤ 2.5 × ULN) elevation of CPK or to baseline, then resumed at the next lower dose level per Table 1.

Elevation of lipase or amylase

Grade 3 elevation of lipase or amylase (> 2.0 × ULN)

• Alunbrig should be withheld until recovery to Grade ≤ 1 (≤ 1.5 × ULN) or to baseline, then resumed at same dose.

• If Grade 3 elevation of lipase or amylase recurs, Alunbrig should be withheld until recovery to Grade ≤ 1 (≤ 1.5 × ULN) or to baseline, then resumed at the next lower dose level per Table 1.

Grade 4 elevation of lipase or amylase (> 5.0 x ULN)

• Alunbrig should be withheld until recovery to Grade ≤ 1 (≤ 1.5 × ULN), then resumed at the next lower dose level per Table 1.

Hepatotoxicity

Grade ≥ 3 elevation (> 5.0 × ULN) of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) with bilirubin ≤ 2 × ULN

• Alunbrig should be withheld until recovery to baseline or less than or equal to 3 × ULN, then resumed at next lower dose per Table 1.

Grade ≥ 2 elevation (> 3 × ULN) of ALT or AST with concurrent total bilirubin elevation > 2 × ULN in the absence of cholestasis or haemolysis

• Alunbrig should be permanently discontinued.

Hyperglycaemia

For Grade 3 (greater than 250 mg/dL or 13.9 mmol/L) or greater

• If adequate hyperglycaemic control cannot be achieved with optimal medical management, Alunbrig should be withheld until adequate hyperglycaemic control is achieved. Upon recovery, Alunbrig may either be resumed at the next lower dose per Table 1 or permanently discontinued.

Visual disturbance

Grade 2 or 3

• Alunbrig should be withheld until recovery to Grade 1 or baseline, then resumed at the next lower dose level per Table 1.

Grade 4

• Alunbrig should be permanently discontinued.

Other adverse reactions

Grade 3

• Alunbrig should be withheld until recovery to baseline, then resumed at the same dose level.

• If the Grade 3 event recurs, Alunbrig should be withheld until recovery to baseline, then resumed at the next lower dose level as per Table 1 or permanently discontinued.

Grade 4

• Alunbrig should be withheld until recovery to baseline, then resumed at the next lower dose level as per Table 1.

• If the Grade 4 event recurs, Alunbrig should be withheld until recovery to baseline, then resumed at the next lower dose level as per Table 1 or permanently discontinued.

bpm = beats per minute; CPK = Creatine Phosphokinase; DBP = diastolic blood pressure; SBP = systolic blood pressure; ULN = upper limit of normal

*Graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4).

Special populations

Elderly

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 section 4.8). 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) (see section 5.2).

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) (see section 5.2). 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 section 4.4).

Paediatric population

The safety and efficacy of Alunbrig in patients less than 18 years of age have not been established. No data are available.

Method of administration

Alunbrig is for oral use. The tablets should be swallowed whole and with water. Alunbrig may be taken with or without food.

Grapefruit or grapefruit juice may increase plasma concentrations of brigatinib and should be avoided (see section 4.5).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. 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 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). ). If concomitant use of moderate CYP3A inducers cannot be avoided, the dose of Alunbrig may be increased in 30 mg increments after 7 days of treatment with the current Alunbrig dose as tolerated, up to a maximum of twice the Alunbrig dose that was tolerated prior to the initiation of the moderate CYP3A inducer. After discontinuation of a moderate CYP3A inducer, Alunbrig should be resumed at the dose that was tolerated prior to the initiation of the moderate CYP3A inducer.

Photosensitivity and photodermatosis

Photosensitivity to sunlight has occurred in patients treated with Alunbrig (see section 4.8). Patients should be advised to avoid prolonged sun exposure while taking Alunbrig, and for at least 5 days after discontinuation of treatment. When outdoors, patients should be advised to wear a hat and protective clothing, and to use a broad-spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sunscreen and lip balm (SPF ≥ 30) to help protect against potential sunburn. For severe photosensitivity reactions (≥ Grade 3), Alunbrig should be withheld until recovery to baseline. The dose should be modified accordingly (see section 4.2).

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.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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 Cmax by 21%, AUC0-INF by 101% (2-fold), and AUC0-120 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 Cmax by 41%, AUC0-INF by 12%, and AUC0-120 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 Cmax by 60%, AUC0-INF by 80% (5-fold), and AUC0-120 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. If concomitant use of moderate CYP3A inducers cannot be avoided, the dose of Alunbrig may be increased in 30 mg increments after 7 days of treatment with the current Alunbrig dose as tolerated, up to a maximum of twice the Alunbrig dose that was tolerated prior to the initiation of the moderate CYP3A inducer. After discontinuation of a moderate CYP3A inducer, Alunbrig should be resumed at the dose that was tolerated prior to the initiation of the moderate CYP3A inducer.

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. In patients with cancer, coadministration of multiple 180 mg daily doses of Alunbrig with a single 3 mg oral dose of midazolam, a sensitive CYP3A substrate, decreased midazolam Cmax by 16%, AUC0-INF by 26%, and AUC0-last by 30%, relative to a 3 mg oral dose of midazolam administered alone. Brigatinib reduces plasma concentrations 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).

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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 1/2 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)

System organ class

Frequency category

Adverse reactions†

all grades

Adverse reactions

Grade 3-4

Infections and infestations

Very common

Pneumoniaa,b

Upper respiratory tract infection

Common

Pneumoniaa

Blood and lymphatic system disorders

Very common

Anaemia

Lymphocyte count decreased

APTT increased

White blood cell count decreased

Neutrophil count decreased

Lymphocyte count decreased

Common

Decreased platelet count

APTT increased

Anaemia

Uncommon

Neutrophil count decreased

Metabolism and nutrition disorders

Very common

Hyperglycaemia

Hyperinsulinaemiac

Hypophosphataemia

Hypomagnesaemia

Hypercalcaemia

Hyponatraemia

Hypokalaemia

Decreased appetite

Common

Hypophosphataemia

Hyperglycaemia

Hyponatraemia

Hypokalaemia

Decreased appetite

Psychiatric disorders

Common

Insomnia

Nervous system disorders

Very common

Headached

Peripheral neuropathye

Dizziness

Common

Memory impairment

Dysgeusia

Headached

Peripheral neuropathye

Uncommon

Dizziness

Eye disorders

Very common

Visual disturbancef

Common

Visual disturbancef

Cardiac disorders

Common

Bradycardiag

Electrocardiogram QT prolonged

Tachycardiah

Palpitations

Electrocardiogram QT prolonged

Uncommon

Bradycardiag

Vascular disorders

Very common

Hypertensioni

Hypertensioni

Respiratory, thoracic and mediastinal disorders

Very common

Cough

Dyspnoeaj

Common

Pneumonitisk

Pneumonitisk

Dyspnoeaj

Gastrointestinal disorders

Very common

Lipase increased

Diarrhoea

Amylase increased

Nausea

Vomiting

Abdominal painl

Constipation

Stomatitism

Lipase increased

Common

Dry mouth

Dyspepsia

Flatulence

Amylase increased

Nausea

Abdominal painl

Diarrhoea

Uncommon

Pancreatitis

Vomiting

Stomatitism

Dyspepsia

Pancreatitis

Hepatobiliary disorders

Very common

AST increased

ALT increased

Alkaline phosphatase increased

Common

Blood lactate dehydrogenase increased

Hyperbilirubinaemia

ALT increased

AST increased

Alkaline phosphatase increased

Uncommon

Hyperbilirubinaemia

Skin and subcutaneous tissue disorders

Very common

Rashn

Prurituso

Common

Dry skin

Photosensitivity reactionp

Rashn

Photosensitivity reactionp

Uncommon

Dry skin

Prurituso

Musculoskeletal and connective tissue disorders

Very common

Blood CPK increased

Myalgiaq

Arthralgia

Blood CPK increased

Common

Musculoskeletal chest pain

Pain in extremity

Musculoskeletal stiffness

Uncommon

Pain in extremity

Musculoskeletal chest pain

Myalgiaq

Renal and urinary disorders

Very common

Blood creatinine increased

General disorders and administration site conditions

Very common

Fatiguer

Oedemas

Pyrexia

Common

Non-cardiac chest pain

Chest discomfort

Pain

Fatiguer

Uncommon

Pyrexia

Oedemas

Non-cardiac chest pain

Investigations

Common

Blood cholesterol increasedt

Weight decreased

Uncommon

Weight decreased

† 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

hIncludes 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

o Includes pruritus, pruritus allergic, pruritus generalised, pruritus genital, vulvovaginal pruritus

p Includes photosensitivity reaction, polymorphic light eruption, solar dermatitis

q Includes musculoskeletal pain, myalgia, muscle spasms, muscle tightness, muscle twitching, musculoskeletal discomfort

r Includes asthenia, fatigue

s 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

t 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 16 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.

Photosensitivity and photodermatosis

A pooled analysis from seven clinical trials with data from 804 patients, treated with Alunbrig at different dosing regimens, showed that photosensitivity and photodermatosis was reported in 5.8% of patients and Grade 3-4 occurred in 0.7% of patients. Dose reduction occurred in 0.4% of patients (see sections 4.2 and 4.4).

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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no specific antidote for overdose with Alunbrig. In the event of an overdose, the patient should be monitored for adverse reactions (see section 4.8) and appropriate supportive care should be provided.