Alecensa 150 mg Hard Capsules

$0$0$0$0$07.       MARKETINGAUTHORISATION HOLDER$0$0 $0$0Roche Registration GmbH $0$0Emil-Barell-Strasse 1$0$079639 Grenzach-Wyhlen$0$0Germany$0$0Roche Registration Limited$0$06 Falcon Way$0$0Shire Park$0$0Welwyn Garden City$0$0AL7 1TW$0$0United Kingdom$0$0 $0$0 $0$010.     DATE OFREVISION OF THE TEXT$0$0 $0$015March 2018$0$0$0

4.       CLINICAL PARTICULARS

 

4.1     Therapeutic indications

 

Alecensa as monotherapy is indicated for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).

 

Alecensa as monotherapy 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.

 

 

 

4.4     Special warnings and precautions for use

 

Interstitial lung disease (ILD)/pneumonitis

Cases of ILD/pneumonitis have been reported in clinical trials with Alecensa (see section 4.8). Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Alecensa should be immediately interrupted in patients diagnosed with ILD/pneumonitis and should be permanently discontinued if no other potential causes of ILD/pneumonitis have been identified (see section 4.2).

 

Hepatotoxicity

Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 5 times the ULN as well as bilirubin elevations of more than 3 times the ULN occurred in patients in pivotal phase II clinical trials (NP28761, NP28673) with Alecensa (see section 4.8). The majority (76% of the patients with hepatic aminotransferase elevations and 60% of the patients with bilirubin elevations) of these events occurred during the first 3 months of treatment. In the pivotal phase IIAlecensa clinical trials (NP28761 and NP28673), two it was reported that three patients with Grade 3-4 AST/ALT elevations had documented drug induced liver injury by liver biopsy. Concurrent elevations in ALT or AST greater than or equal 3 times the ULN and total bilirubin greater than or equal 2 times the ULN, with normal alkaline phosphatase, occurred in one patient treated in Alecensa clinical trials.

 

[…]

 

Severe myalgia and creatine phosphokinase (CPK) elevation

Myalgia or musculoskeletal pain occurred in 31% of was reported in patients in pivotal phase II trials (NP28761, NP28673) with Alecensa, including Grade 3 events (see section 4.8). The incidence of Grade 3 myalgia/musculoskeletal pain was 1.2%. Dose modifications for myalgia/musculoskeletal pain were required in 0.8% of patients.

 

Elevations of CPK occurred in 46% of 219 patients with CPK laboratory data available in pivotal phase II trials (NP28761, NP28673) with Alecensa, including Grade 3 events (see section 4.8). The incidence of Grade 3 elevations of CPK was 5.0%.  Median time to Grade 3 CPK elevation was 14 days across clinical trials (NP28761, NP28673, BO28984). Dose modifications for elevation of CPK occurred in 4.0 % of patients (see section 4.8).

 

[…]

 

 

4.8       Undesirable effects

 

Summary of the safety profile

 

The data described below reflect exposure to Alecensa in 405 patients with ALK-positive advanced NSCLC who participated in one randomised Phase III clinical trial (BO28984) and in two single-arm phase II clinical trials (NP28761, NP28673). These patients were treated with the recommended dose of 600 mg twice daily. The safety of Alecensa has been evaluated in 253 patients iIn pivotal the phase II clinical trials (NP28761, NP28673; N=253),  with ALK-positive non-small cell lung cancer (NSCLC) treated with the recommended dose of 600 mg twice daily. Tthe median duration of exposure to Alecensa was 11 months. In BO28984 (ALEX; N=152) the median duration of exposure to Alecensa was 17.9 months, whereas the median duration of exposure to crizotinib was 10.7 months.

 

The most common adverse drug reactions (ADRs) (≥ 20%) were constipation (3635%), oedema (3430%, including oedema peripheral, oedema, generalised oedema, eyelid oedema, periorbital oedema, face oedema and localised oedema), and myalgia (3128%, including myalgia and musculoskeletal pain) and nausea (22%).

 

Tabulated list of adverse drug reactions

Table 3 summarises lists the ADRs occurring in patients who received Alecensa in pivotal across two phase II clinical trials (NP28761, NP28673) and one phase III clinical trial (BO28984; ALEX),  and during post-marketing.

 

The ADRs listed in Table 3 are presented by system organ class and frequency categories, defined using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency groupingsystem organ class, undesirable effects are presented in order of decreasing seriousnessfrequency.

 

Table 3 – updated

 

Description of selected adverse drug reactions

 

The safety profile of Alecensa was generally consistent across the pivotal phase III clinical trial BO28984 (ALEX) and phase II trials (NP28761, NP28673).

 

Interstitial lung disease (ILD) / pneumonitis

Severe ILD/pneumonitis occurred in patients treated with Alecensa. In the pivotal phase IIAcross clinical trials (NP28761, NP28673, BO28984), 1 out of 253 405 patients treated with Alecensa (0.40.2%) had a Grade 3 ILD. This event led to withdrawal from Alecensa treatment. In the phase III clinical trial BO28984, Grade 3 or 4 ILD/pneumonitis was not observed in patients receiving Alecensa versus 2.0% of patients receiving crizotinib. There were no fatal cases of ILD in any of the clinical trials. Patients should be monitored for pulmonary symptoms indicative of pneumonitis (see sections 4.2 and 4.4).

 

Hepatotoxicity

In the pivotal phase II Across clinical trials (NP28761, NP28673, BO28984) two patients with Grade 3-4 AST/ALT elevations had documented drug induced liver injury by liver biopsy. In addition, one patient experienced a Grade 4 adverse event of drug-induced liver injury. One Two of these cases led to withdrawal from Alecensa treatment. Adverse reactions of increased AST and ALT levels (1615% and 14% respectively) were reported in patients treated with Alecensa in pivotal phase II across clinical trials (NP28761, NP28673, BO28984). The majority of these events were of Grade 1 and 2 intensity, and events of Grade ≥ 3 were reported in 2.83.7% and 3.23.7% of the patients, respectively. The events generally occurred during the first 3 months of treatment, were usually transient and resolved upon temporary interruption of Alecensa treatment (reported for 1.21.5% and 3.23.0% of the patients, respectively) or dose reduction (1.62.2% and 0.81.2%, respectively). In 1.2% and 1.61.5% of the patients, AST and ALT elevations, respectively, led to withdrawal from Alecensa treatment. Grade 3 or 4 ALT or AST elevations were each observed in 5% of patients receiving Alecensa versus 15% and 11% of patients receiving crizotinib in the phase III clinical trial BO28984.

 

Adverse reactions of bilirubin elevations were reported in 1718% of the patients treated with Alecensa in pivotal phase II across clinical trials (NP28761, NP28673, BO28984). The majority of the events were of Grade 1 and 2 intensity; Grade 3 events were reported in 3.2% of the patients. The events generally occurred during the first 3 months of treatment, were usually transient and the majority resolved upon dose modification.upon temporary interruption of Alecensa treatment (4.7% of the patients) or dose reduction (2.8%). In 5.2% of patients, bilirubin elevations led to dose modifications and in 4 patients (1.61.5% of patients), bilirubin elevations led to withdrawal from Alecensa treatment. In the phase III clinical trial BO28984, Grade 3 or 4 bilirubin elevations occurred in 3.3% of patients receiving Alecensa versus no patient receiving crizotinib.

 

Concurrent elevations in ALT or AST greater than or equal to three times the ULN and total bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase, occurred in one patient (0.2%) treated in Alecensa clinical trials.

 

Patients should be monitored for liver function including ALT, AST, and total bilirubin as outlined in section 4.4 and managed as recommended in section 4.2.

 

Bradycardia

Cases of bradycardia (7.98.9%) of Grade 1 or 2 have been reported in patients treated with Alecensa in pivotal phase II across clinical trials (NP28761, NP28673, BO28984). No patients had events of Grade ³ 3 severity. There were 44 66 of 221 365 patients (2018%) treated with Alecensa who had post-dose heart rate values below 50 beats per minutes (bpm). In the phase III clinical trial BO28984 15% of patients treated with Alecensa had post-dose heart rate values below 50 bpm versus 20% of patients treated with crizotinib. Patients who develop symptomatic bradycardia should be managed as recommended in sections 4.2 and 4.4. No case of bradycardia led to withdrawal from Alecensa treatment.

 

Severe myalgia and CPK elevations

Cases of myalgia (3128%) including myalgia events (2522%) and musculoskeletal pain (7.57.4%) have been reported in patients treated with Alecensa in pivotal phase IIacross clinical trials (NP28761, NP28673, BO28984). The majority of events were Grades 1 or 2 and three patients (1.20.7%) had a Grade 3 event. Dose modifications of Alecensa treatment due to these adverse events were only required for two patients (0.80.5%); Alecensa treatment was not withdrawn due to these events of myalgia. Elevations of CPK occurred in 4643% of 219 362 patients with CPK laboratory data available in pivotal phase II across clinical trials (NP28761, NP28673, BO28984) with Alecensa. The incidence of Grade 3 elevations of CPK was 3.75.0%. Median time to Grade 3 CPK elevation was 14 days across trials (NP28761, NP28673, BO28984). Dose modifications for elevation of CPK occurred in 4.03.2% of patients; withdrawal from Alecensa treatment did not occur due to CPK elevations. Severe myalgia has not been reported in the clinical trial BO28984. Grade 3 elevation of CPK was reported for 2.6% of patients receiving Alecensa and 1.3% of patients receiving crizotinib;  and median time to Grade 3 CPK elevation was 27.5 days and 369 days, respectively, in the pivotal phase III clinical trial BO28984 (ALEX).  

 

Gastrointestinal effects

Constipation (3635%), nausea (2219%), diarrhoea (1816%) and vomiting (1311%) were the most commonly reported gastrointestinal (GI) reactions . Most of these events were of mild or moderate severity; Grade 3 events were reported for diarrhea (1.20.7%), nausea (0.40.5%), and vomiting (0.40.2%). These events did not lead to withdrawal from Alecensa treatment. Median time to onset for constipation, nausea, diarrhea, and/or vomiting events across clinical trials (NP28761, NP28673, BO28984) was 2118 days. The events declined in frequency after the first month of treatment. In the phase III clinical trial BO28984, one patient (0.2%) experienced a Grade 4 event of nausea in the Alecensa arm and the incidence of Grade 3 and 4 events for nausea, vomiting, and diarrhoea was 3.3%, 3.3%, and 2.0%, respectively, in the crizotinib arm.

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

[…]

 

ALK positive non-small cell lung cancer

 

Treatment-naïve patients

 

The safety and efficacy of Alecensa were studied in a global randomised Phase III open label clinical trial (BO28984, ALEX) in ALK-positive NSCLC patients who were treatment naïve. Central testing for ALK protein expression positivity of tissue samples from all patients by Ventana anti‑ALK (D5F3) immunohistochemistry (IHC) was required before randomisation into the study.

 

A total of 303 patients were included in the Phase III trial, 151 patients randomised to the crizotinib arm and 152 patients randomised to the Alecensa arm receiving Alecensa orally, at the recommended dose of 600 mg twice daily.

 

ECOG PS (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline (yes vs. no) were stratification factors for randomisation. The primary endpoint of the trial was to demonstrate superiority of Alecensa versus crizotinib based on Progression Free survival (PFS) as per investigator assessment using RECIST 1.1. Baseline demographic and disease characteristics for Alecensa were median age 58 years (54 years for crizotinib), 55% female (58% for crizotinib), 55% non-Asian (54% for crizotinib), 61% with no smoking history (65% for crizotinib), 93% ECOG PS of 0 or 1 (93% for crizotinib), 97% Stage IV disease (96% for crizotinib), 90% adenocarcinoma histology (94% for crizotinib), 40% CNS metastases at baseline (38% for crizotinib) and 17% having received prior CNS radiation (14% for crizotinib).

 

The trial met its primary endpoint at the primary analysis, demonstrating a statistically significant improvement in PFS by investigator. Efficacy data are summarised in Table 4 and the Kaplan-Meier curve for investigator assessed PFS is shown in Figure 1.

 

Table 4 – updated

 

The PFS benefit was consistent for patients with CNS metastases at baseline (HR = 0.40, 95% CI: 0.25-0.64, median PFS for Alecensa = NE, 95% CI: 9.2-NE, median PFS for crizotinib = 7.4 months, 95%CI: 6.6-9.6) and without CNS metastases at baseline (HR = 0.51, 95% CI: 0.33-0.80, median PFS for Alecensa = NE, 95% CI: NE, NE, median PFS for crizotinib = 14.8 months, 95% CI:10.8-20.3), indicating benefit of Alecensa over crizotinib in both subgroups.

 

4.8       Undesirable effects

 

[ … ]

 

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 (see details below).

 

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

 

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

 

United Kingdom

Yellow Card Scheme

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

 

 

 

6.4     Special precautions for storage

 

Blisters:

Store in the original package in order to protect from moisture.

 

Bottles:

Store in the original package and keep the bottle tightly closed in order to protect from moisture.

 

6.5       Nature and contents of container

 

Aluminium/aluminium (PA/Alu/PVC/Alu) perforated blisters containing 8 hard capsules.

Pack size: 224 (4 packs of 56) hard capsules.

 

HDPE bottle with a child-resistant closure and an integrated desiccant.

Pack size: 240 hard capsules.

 

Not all pack sizes may be marketed.

 

 

 

8.       MARKETING AUTHORISATION NUMBER(S)

 

EU/1/16/1169/001

EU/1/16/1169/002

 

10.     DATE OF REVISION OF THE TEXT

 

25 September 2017

 

 

 

Underlined text has been added:

4.8       Undesirable effects

 

Summary of the safety profile

 

The safety of Alecensa has been evaluated in 253 patients in pivotal phase II clinical trials (NP28761, NP28673) with ALK-positive non-small cell lung cancer (NSCLC) treated with the recommended dose of 600 mg twice daily. The median duration of exposure to Alecensa was 11 months.

 

The most common adverse drug reactions (ADRs) (≥ 20%) were constipation (36%), oedema (34%, including oedema peripheral, oedema, generalised oedema, eyelid oedema, periorbital oedema), myalgia (31%, including myalgia and musculoskeletal pain) and nausea (22%).

 

Tabulated list of adverse drug reactions

Table 3 summarises the ADRs occurring in patients who received Alecensa in pivotal clinical trials and during post-marketing.

 

The ADRs listed in Table 3 are presented by system organ class and frequency categories, defined using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

Table 3 Summary of ADRs occurring in patients treated with Alecensa in pivotal phase II clinical trials (NP28761, NP28673) and during post-marketing

 

System organ class     ADRs (MedDRA)	Alecensa N=253
	All grades (%)	Frequency category (all grades)	Grades 3-4* (%)
Blood and lymphatic system disorders
Anaemia1)	16	Very common	2.0
Eye disorders
Vision disorders2)	12	Very common	0
Cardiac disorders
Bradycardia3)	7.9	Common	0
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease / pneumonitis	0.4	Uncommon	0.4
Gastrointestinal disorders
Diarrhoea	18	Very common	1.2
Vomiting	13	Very common	0.4
Constipation	36	Very common	0
Nausea	22	Very common	0.4
Hepatobiliary disorders
Drug-induced liver injury4)	0.8	Uncommon	0.8
Increased AST	16	Very common	2.8
Increased ALT	14	Very common	3.2
Increased bilirubin5)	17	Very common	3.2
Increased alkaline phosphatase**	7.5	Common	0.4
Skin and subcutaneous tissue disorders
Rash6)	20	Very common	0.4
Photosensitivity	12	Very common	0
Musculoskeletal and connective tissues disorders
Myalgia7)	31	Very common	1.2
Increased blood creatine phosphokinase	13	Very common	3.6
Renal and urinary disorders
Blood creatinine increased	6.7	Common	0.4
General disorders and administration site conditions
Oedema8)	34	Very common	0.8

* No Grade 5 events observed

**Increased alkaline phosphatase was reported in the post-marketing period. Cases were also reported in pivotal Phase II clinical trials NP28761 and NP28673.

¹⁾ includes cases of anaemia and haemoglobin decreased

²⁾ includes cases of blurred vision, visual impairment, vitreous floaters, reduced visual acuity, asthenopia, and diplopia

³⁾ includes cases of bradycardia and sinus bradycardia

⁴⁾ includes one patient with reported MedDRA term of drug-induced liver injury as well as one patient with reported Grade 4 increased AST and ALT who had documented drug-induced liver injury by liver biopsy

⁵⁾ includes cases of blood bilirubin increased, hyperbilirubinaemia and bilirubin conjugated increased

⁶⁾ includes cases of rash, rash maculopapular, dermatitis acneiform, erythema, rash generalised, rash papular, rash pruritic and rash macular

⁷⁾ includes cases of myalgia and musculoskeletal pain

⁸⁾ includes cases of oedema peripheral, oedema, generalised oedema, eyelid oedema, periorbital oedema

 

10.     DATE OF REVISION OF THE TEXT

 

09 June 2017

 

 

6.3 Shelf-life

Updated from 2 to 3 years

10 Date of Revision of Text

18 April 2017

None provided