Kryxana 200 mg FC tablet.

Kryxana is indicated for the treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant.

In pre- or perimenopausal women, or men the endocrine based therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.

Treatment with Kryxana should be initiated by a medical practitioner experienced in the use of anticancer therapies.

Posology

The recommended dose is 600 mg (three 200 mg film-coated tablets) of ribociclib once daily for 21 consecutive days followed by 7 days off treatment, resulting in a complete cycle of 28 days. The treatment should be continued as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs.

Kryxana should be used together with 2.5 mg letrozole or another aromatase inhibitor or with 500 mg fulvestrant. When Kryxana is used in combination with an aromatase inhibitor, the aromatase inhibitor should be taken orally once daily continuously throughout the 28-day cycle. Please refer to the Professional Information (PI) of the particular aromatase inhibitor for additional details. When Kryxana is used in combination with fulvestrant, fulvestrant is administered intramuscularly on days 1, 15 and 29, and once monthly thereafter. Please refer to the Professional Information (PI) of fulvestrant for additional details.

Treatment of pre- and perimenopausal women, or men with the approved Kryxana combinations should also include a LHRH agonist in accordance with local clinical practice. Kryxana can be taken with or without food (see section 4.5).

Patients should be encouraged to take their dose at approximately the same time each day, preferably in the morning. If the patient vomits after taking the dose or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time.

Dose modifications

Management of severe or intolerable adverse drug reactions (ADRs) may require temporary dose interruption, reduction or discontinuation of Kryxana. If dose reduction is required, the recommended dose reduction guidelines are listed in Table 1.

Table 1 Recommended dose modification guidelines

Kryxana

Starting dose 600 mg/day 3

First dose reduction 400 mg/day 2

Second dose reduction 200 mg*/day 1

* If further dose reduction below 200 mg/day is required, the treatment should be permanently discontinued.

Tables 2, 3, 4, 5 and 6 summarise recommendations for dose interruption, reduction or discontinuation of Kryxana in the management of specific ADRs. The clinical judgement of the treating medical practitioner should guide the management plan of each patient based on individual benefit/risk assessment (see section 4.4).

Complete blood counts (CBC) should be performed before initiating treatment with Kryxana. After initiating treatment CBC should be monitored every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, then as clinically indicated.

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

Concomitant use of Kryxana with medicines that have a known potential to prolong the QTcF interval to u2265 500 ms, or u2265 60 ms from the pre-treatment QTcF, increasing the risk to develop serious dysrhythmias (e.g. tamoxifen, moxifloxacin).

Congenital long QT syndrome.

Concomitant use of Kryxana with strong CYP3A inhibitors (e.g. ritonavir/lopinovir, itraconazole).

Concomitant use of Kryxana with CYP3A substrates with a narrow therapeutic index (e.g. midazolam, fentanyl).

Concomitant use with strong CYP3A4 inducers (e.g. rifampicin, phenytoin).

Pregnancy and lactation.

Difficult to control/unstable severe cardiac conditions including dysrhythmias, congestive cardiac failure, recent myocardial infarction and unstable angina pectoris.

Critical visceral disease

The efficacy and safety of ribociclib have not been studied in patients with critical visceral disease.

Neutropenia

Based on the severity of the neutropenia, treatment with Kryxana may have to be interrupted, reduced or discontinued as described in Table 2 (see sections 4.2 and 4.8).

Hepatobiliary toxicity

Liver function tests should be performed before initiating treatment with Kryxana. After initiating treatment, liver function should be monitored (see sections 4.2 and 4.8). Based on the severity of the transaminase elevations, treatment with Kryxana may have to be interrupted, reduced or discontinued as described in Table 3 (see sections 4.2 and 4.8). Recommendations for patients who have elevated AST/ALT grade u2265 3 at baseline have not been established.

QT interval prolongation

In the phase III clinical studies, in patients with advanced or metastatic breast cancer who received Kryxana plus any combination partners, review of ECG data showed that 15 patients (1.4 %) had >500 ms post-baseline QTcF interval value and 61 patients (5.8 %) had a >60 ms QTcF interval increase from baseline. There were no reported cases of Torsade de Pointes.

In study E2301 (MONALEESA-7), a QTcF interval increase > 60 msec from baseline was observed in 14/87 (16.1%) patients receiving Kryxana plus tamoxifen and in 18/245 (7.3%) patients receiving Kryxana plus a non-steroidal aromatase inhibitor (NSAI). Kryxana is not recommended to be used in combination with tamoxifen (see sections 4.8 and 5.1) (See Interactions with other medicines and contraindications).

ECG should be assessed before initiating treatment with Kryxana. Treatment with Kryxana should be initiated only in patients with QTcF values less than 450 msec. ECG should be repeated at approximately day 14 of the first cycle and at the beginning of the second cycle, then as clinically indicated (see sections 4.2 and 4.8).

Appropriate monitoring of serum electrolytes (including potassium, calcium, phosphorus and magnesium) should be performed before initiating treatment, at the beginning of the first 6 cycles and then as clinically indicated. Any abnormality should be corrected before initiating treatment with Kryxana and during treatment with Kryxana.

The use of Kryxana should be avoided in patients who already have or who are at significant risk of developing QTc prolongation. (See Interactions with other medicines and contraindications).

This includes patients:

• with long QT syndrome;
• with uncontrolled or significant cardiac disease, including recent myocardial infarction, congestive heart failure, unstable angina and bradyarrhythmias;
• with electrolyte abnormalities.

The use of Kryxana with medicines known to prolong QTc interval and/or strong CYP3A4 inhibitors should be avoided as this may lead to clinically meaningful prolongation of the QTcF interval (see sections 4.2, 4.5 and 5.1) (See Interactions with other medicines and contraindications).

If treatment with a strong CYP3A4 inhibitor cannot be avoided, the dose should be reduced to 400 mg once daily (see sections 4.2 and 4.5).

Based on the observed QT prolongation during treatment, treatment with Kryxana may have to be interrupted, reduced or discontinued as described in Table 4 (see sections 4.2, 4.8 and 5.2).

Interstitial lung disease/pneumonitis

ILD/pneumonitis has been reported with CDK4/6 inhibitors including reports of fatal cases. In the 3 phase III clinical studies (MONALEESA-2 [A2301], MONALEESA-7 [E2301-NSAI] and MONALEESA-3 [F2301]), ILD (any grade 0.3%, including 0.1% grade 3) was reported in the Kryxana treated group, with no cases in the placebo treated group. Pneumonitis (any grade 0.6 % vs. 0.4 %) was reported in the Kryxana and the placebo treated groups respectively with no grade 3 or 4 in either treatment group. Additional cases of ILD/pneumonitis have been observed with Kryxana in the post-marketing setting (see section 4.8).

Based on the severity of the ILD/pneumonitis, Kryxana may require dose interruption, reduction or discontinuation as described in Table 5 (see section 4.2). Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough and dyspnoea and dose modifications should be managed in accordance with Table 5 (see section 4.2).

Severe cutaneous reactions

Toxic epidermal necrolysis (TEN) has been reported with Kryxana treatment. If signs and symptoms suggestive of severe cutaneous reactions (e.g. progressive widespread skin rash often with blisters or mucosal lesions) appear, Kryxana should be immediately and permanently discontinued.

CYP3A4 substrates

Ribociclib is a strong CYP3A4 inhibitor at the 600 mg dose and a moderate CYP3A4 inhibitor at the 400 mg dose. Thus, ribociclib may interact with medicines which are metabolised via CYP3A4, which may lead to increased serum concentrations of CYP3A4 substrates (see section 4.5). Caution is recommended in case of concomitant use with sensitive CYP3A4 substrates with a narrow therapeutic index and the PIs of the other medicines should be consulted for the recommendations regarding co-administration with CYP3A4 inhibitors (See Interactions with other medicines and contraindications).

Women of childbearing potential

Women of childbearing potential should be advised to use an effective method of contraception while taking Kryxana and for at least 21 days after the last dose (see section 4.6).

Soya lecithin

Kryxana contains soya lecithin. Patients who are hypersensitive to peanut or soya should not take Kryxana (see section 4.3).

Substances that may increase ribociclib plasma concentrations

Ribociclib is primarily metabolised by CYP3A4. Therefore, medicines that can influence CYP3A4 enzyme activity may alter the pharmacokinetics of ribociclib. Co-administration of the strong CYP3A4 inhibitor ritonavir (100 mg twice daily for 14 days) with a single 400 mg dose of ribociclib increased ribociclib exposure (AUC inf) and the peak concentration (C max) in healthy subjects 3.2 and 1.7-fold, respectively, relative to a single 400 mg ribociclib dose given alone. C max and AUC last for LEQ803 (a prominent metabolite of ribociclib accounting for less than 10 % of parent exposure) decreased by 96 % and 98 %, respectively.

The concomitant use of strong CYP3A4 inhibitors including, but not limited to, the following must be avoided: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, verapamil and voriconazole (see section 4.4) (See Special warnings and precautions for use and contraindications).

Alternative concomitant medicines with less potential to inhibit CYP3A4 should be considered and patients should be monitored for ribociclib-related AEs (see sections 4.2, 4.4 and 5.2). If co-administration of Kryxana with a strong CYP3A4 inhibitor cannot be avoided, the dose of Kryxana should be reduced as described in section 4.2. (See Special warnings and precautions for use and contraindications).

However, there are no clinical data with these dose adjustments. Due to inter-patient variability, the recommended dose adjustments may not be optimal in all patients, therefore close monitoring for ribociclib-related AEs is recommended. In the event of ribociclib-related toxicity, the dose should be modified or treatment should be interrupted until toxicity is resolved (see sections 4.2 and 5.2). If the strong CYP3A4 inhibitor is discontinued, and after at least 5 half-lives of the CYP3A4 inhibitor (refer to the PI of the CYP3A4 inhibitor in question), Kryxana should be resumed at the same dose used prior to the initiation of the strong CYP3A4 inhibitor.

Substances that may decrease ribociclib plasma concentrations

Co-administration of the strong CYP3A4 inducer rifampicin (600 mg daily for 14 days) with a single 600 mg dose of ribociclib decreased the ribociclib AUC inf and C max by 89 % and 81 %, respectively, relative to a single 600 mg ribociclib dose given alone in healthy subjects. LEQ803 C max increased 1.7-fold and AUC inf decreased by 27 %, respectively. The concomitant use of strong CYP3A4 inducers may therefore lead to decreased exposure and consequently a risk for lack of efficacy. The concomitant use of strong CYP3A4 inducers should be avoided, including, but not limited to, phenytoin, rifampicin, carbamazepine and St Johnu2019s Wort (Hypericum perforatum). An alternative concomitant medicinal product with no or minimal potential to induce CYP3A4 should be considered (See Special warnings and precautions for use and contraindications).

The effect of a moderate CYP3A4 inducer on ribociclib exposure has not been studied. Physiologically-based pharmacokinetic simulations suggested that a moderate CYP3A4 inducer (efavirenz) may decrease steady-state ribociclib C max and AUC by 51 % and 70 %, respectively. The concomitant use of moderate CYP3A4 inducers may therefore lead to decreased exposure and consequently a risk for impaired efficacy, in particular in patients treated with ribociclib at 400 mg or 200 mg once daily.

Substances that may have plasma concentrations altered by Kryxana

Ribociclib is a moderate to strong CYP3A4 inhibitor and may interact with medicinal substrates that are metabolised via CYP3A4, which can lead to increased serum concentrations of the concomitantly used medicine. Co-administration of midazolam (CYP3A4 substrate) with multiple doses of Kryxana (400 mg) increased the midazolam exposure by 280 % (3.80-fold) in healthy subjects, compared with administration of midazolam alone. Simulations using physiologically-based pharmacokinetic models suggested that Kryxana given at the clinically relevant dose of 600 mg is expected to increase the midazolam AUC by 5.2-fold. Therefore, when ribociclib is co-administered with other medicines the PI of the other medicinal product must be consulted for the recommendations regarding co-administration with CYP3A4 inhibitors. (See section 4.3 and 4.4).

Caution is recommended in case of concomitant use with sensitive CYP3A4 substrates with a narrow therapeutic index (see section 4.4). The dose of a sensitive CYP3A4 substrate with a narrow therapeutic index, including but not limited to alfentanil, ciclosporin, everolimus, fentanyl, sirolimus and tacrolimus, may need to be reduced as ribociclib can increase their exposure. (See section 4.3 and 4.4).

Concomitant administration of ribociclib at the 600 mg dose with the following CYP3A4 substrates should be avoided: alfuzosin, amiodarone, cisapride, pimozide, quinidine, ergotamine, dihydroergotamine, quetiapine, lovastatin, simvastatin, sildenafil, midazolam, triazolam. (See section 4.3 and 4.4).

Co-administration of caffeine (CYP1A2 substrate) with multiple doses of Kryxana (400 mg) increased the caffeine exposure by 20 % (1.20-fold) in healthy subjects, compared with administration of caffeine alone. At the clinically relevant dose of 600 mg, simulations using PBPK models predicted only weak inhibitory effects of ribociclib on CYP1A2 substrates (< 2-fold increase in AUC).

Substances that are substrates of transporters

In vitro evaluations indicated that ribociclib has a potential to inhibit the activities of drug transporters P-gp, BCRP, OATP1B1/1B3, OCT1, OCT2, MATE1 and BSEP. Caution and monitoring for toxicity are advised during concomitant treatment with sensitive substrates of these transporters which exhibit a narrow therapeutic index, including but not limited to digoxin, pitavastatin, pravastatin, rosuvastatin and metformin.

Drug-food interactions

Kryxana can be administered with or without food (see sections 4.2 and 5.2).

Medicines that elevate gastric pH

Ribociclib exhibits high solubility at or below pH 4.5 and in bio-relevant media (at pH 5.0 and 6.5). Co-administration of ribociclib with medicines that elevate the gastric pH was not evaluated in a clinical study; however, altered ribociclib absorption was not observed in population pharmacokinetic and non-compartmental pharmacokinetic analyses.

Interaction between ribociclib and letrozole

Data from a clinical study in patients with breast cancer and population pharmacokinetic analysis indicated no interaction between ribociclib and letrozole following co-administration of these medicines.

Interaction between ribociclib and anastrozole

Data from a clinical study in patients with breast cancer indicated no clinically relevant interaction between ribociclib and anastrozole following co-administration of these medicines.

Interaction between ribociclib and fulvestrant

Data from a clinical study in patients with breast cancer indicated no clinically relevant effects of fulvestrant on ribociclib exposure following co-administration of these medicines.

Interaction between ribociclib and tamoxifen

Data from a clinical study in patients with breast cancer indicated that tamoxifen exposure was increased approximately 2-fold following co-administration of ribociclib and tamoxifen.

Interaction between ribociclib and oral contraceptives

Interaction studies between ribociclib and oral contraceptives have not been conducted (see section 4.6).

Anticipated interactions

Antidysrhythmic medicines and other medicines that may prolong the QT interval

Co-administration of Kryxana with medicines with a known potential to prolong the QT interval such as antidysrhythmic medicines (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine and sotalol), and other medicines that are known to prolong the QT interval (including, but not limited to, chloroquine, halofantrine, clarithromycin, ciprofloxacin, levofloxacin, azithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide and intravenous ondansetron) should be avoided (see section 4.4) (See Special warnings and precautions for use and contraindications). Kryxana is also not recommended to be used in combination with tamoxifen (see sections 4.1, 4.4 and 5.1).

Women of childbearing potential/Contraception

Pregnancy status should be verified prior to starting treatment with Kryxana. Women of childbearing potential who are receiving Kryxana should use effective contraception (e.g. double-barrier contraception) during therapy and for at least 21 days after stopping treatment with Kryxana.

Pregnancy

Kryxana is teratogenic and contraindicated in pregnancy and lactation. There are no adequate and well-controlled studies in pregnant women. Based on findings in animals, ribociclib can cause foetal harm when administered to a pregnant woman (see section 5.3). Kryxana is contraindicated during pregnancy and in women of childbearing potential not using contraception. (See Special warnings and precautions for use and contraindications).

Breast-feeding

It is not known if ribociclib is present in human milk. There are no data on the effects of ribociclib on the breast-fed infant or the effects of ribociclib on milk production. Ribociclib and its metabolites readily passed into the milk of lactating rats. Mothers on treatment with Kryxana should not breast-feed their infants (See Special warnings and precautions for use and contraindications). Mothers receiving Kryxana should not breast-feed for at least 21 days after the last dose.

Fertility

There are no clinical data available regarding effects of ribociclib on fertility. Based on animal studies, ribociclib may impair fertility in males of reproductive potential (see section 5.3).

Kryxana may have an influence on the ability of patients to drive and use machines. Patients should be advised to be cautious when driving or using machines in case they experience fatigue, dizziness or vertigo during treatment with Kryxana (see section 4.8).

Summary of the safety profile

The most common ADRs and the most common grade 3/4 ADRs (reported at a frequency u2265 20% and u2265 2%, respectively) in the pooled dataset for which the frequency for Kryxana plus any combination exceeds the frequency for placebo plus any combination were infections, neutropenia, leukopenia, headache, cough, nausea, fatigue, diarrhoea, vomiting, constipation, alopecia and rash, and infections, neutropenia, leukopenia, back pain, anaemia, abnormal liver function tests, lymphopenia, hypophosphataemia and vomiting respectively.

Dose reduction due to adverse events, regardless of causality, occurred in 37.3 % of patients receiving Kryxana in the phase III clinical studies regardless of the combination and permanent discontinuation was reported in 7.0 % of patients receiving Kryxana and any combination in the phase III clinical studies.

Tabulated list of adverse reactions

The overall safety evaluation of Kryxana is based on the pooled dataset from 1,065 patients who received Kryxana in combination with endocrine therapy (N = 582 in combination with an aromatase inhibitor and N = 483 in combination with fulvestrant) and who were included in the randomised, double blind, placebo-controlled phase III clinical studies (MONALEESA 2, MONALEESA 7 NSAI subgroup and MONALEESA 3) in HR positive, HER2 negative advanced or metastatic breast cancer. Additional ADRs were identified post-marketing.

The median duration of exposure to Kryxana treatment across the pooled phase III studies dataset was 19.2 months, with 61.7 % patients exposed u2265 12 months.

Adverse drug reactions from the phase III clinical studies (Table 7) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1,000 to < 1/100); rare (u2265 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot be estimated from the available data).

Table 7 Adverse drug reactions observed in the three phase III clinical studies

Adverse drug reactions Frequency category All Grades Infections and infestations Infections 1 Very common Blood and lymphatic system disorders Neutropenia Very common Leukopenia Very common Anaemia Very common Lymphopenia Very common Thrombocytopenia Common Febrile neutropenia Common Eye disorders Lacrimation increased Common Dry eye Common Metabolism and nutrition disorders Decreased appetite Very common Hypocalcaemia Common Hypokalaemia Common Hypophosphataemia Common Nervous system disorders Headache Very common Dizziness Very common Vertigo Common Cardiac disorders Syncope Common Respiratory, thoracic and mediastinal disorders Cough Very common Dyspnoea Very common Musculoskeletal and connective tissue disorders Back pain Very common Gastrointestinal disorders Nausea Very common Diarrhoea Very common Vomiting Very common Constipation Very common Stomatitis Very common Abdominal pain 2 Very common Dysgeusia Common Dyspepsia Very common Hepatobiliary disorders Hepatotoxicity 3 Common Skin and subcutaneous tissue disorders Alopecia Very common Rash 4 Very common Pruritus Very common Erythema Common Dry skin Common Vitiligo Common General disorders and administration site conditions Fatigue Very common Peripheral oedema Very common Asthenia Very common Pyrexia Very common Dry mouth Common Oropharyngeal pain Common Investigations Abnormal liver function tests 5 Very common Blood creatinine increased Common Electrocardiogram QT prolonged Common

1 Infections: Urinary tract infections; respiratory tract infections; gastroenteritis; sepsis (< 1 %).

2 Abdominal pain: Abdominal pain, abdominal pain upper.

3 Hepatotoxicity: hepatic cytosis, hepatocellular injury, drug induced liver injury, hepatotoxicity, hepatic failure, autoimmune hepatitis (single case).

4 Rash: rash, rash maculopapular, rash pruritic.

5 Abnormal liver function tests: ALT increased, AST increased, blood bilirubin increased.

Post marketing data

The following ADRu2019s are derived from post-marketing experience with Kryxana via spontaneous case reports and literature cases. As these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known.

Table 8 Adverse drug reactions derived from spontaneous reports and literature (frequency not known)

Respiratory, thoracic and mediastinal disorders Interstitial lung disease (ILD)/pneumonitis Skin and subcutaneous tissue disorders Toxic epidermal necrolysis (TEN)

Description of selected adverse drug reactions

Neutropenia

Neutropenia was the most frequently reported adverse drug reaction (73.7 %) and a grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 58.6 % of patients receiving Kryxana plus any combination in the phase III studies. Among the patients who had grade 2, 3 or 4 neutropenia, the median time to onset was 16 days, for those patients who had an event. The median time to resolution of grade u2265 3 (to normalisation or grade < 3) was 12 days in the Kryxana plus any combination arms following treatment interruption and/or reduction and/or discontinuation. Febrile neutropenia was reported in about 1.4 % of patients exposed to Kryxana in the phase III studies. Patients should be instructed to report any fever promptly. Based on its severity, neutropenia was managed by laboratory monitoring, dose interruption and/or dose modification. Treatment discontinuation due to neutropenia was low (0.8 %) (See sections 4.2 and 4.4).

Hepatobiliary toxicity

In the phase III clinical studies, hepatobiliary toxicity events occurred in a higher proportion of patients in the Kryxana plus any combination arms compared with the placebo plus any combination arms (27.3 % versus 19.6 %, respectively), with more grade 3/4 adverse events reported in the patients treated with Kryxana plus any combination (13.2 % versus 6.1 %, respectively). Increases in transaminases were observed. Grade 3 or 4 increases in ALT (9.7 % versus 1.5 %) and AST (6.7 % versus 2.1 %) were reported in the Kryxana and placebo arms, respectively. Concurrent elevations in ALT or AST greater than three times the upper limit of normal and total bilirubin greater than two times the upper limit of normal, with normal alkaline phosphatase, in the absence of cholestasis, occurred in 6 patients, (4 patients, whose levels recovered to normal within 154 days and 2 patients whose levels recovered to normal in 121 and 532 days, respectively, after discontinuation of Kryxana). Dose interruptions and/or adjustments due to hepatobiliary toxicity events were reported in 12.3 % of Kryxana plus any combination treated patients, primarily due to ALT increased (7.9 %) and/or AST increased (7.3 %). Discontinuation of treatment with Kryxana plus any combination due to abnormal liver function tests or hepatotoxicity occurred in 2.4 % and 0.3 % of patients respectively (see sections 4.2 and 4.4).

In the phase III clinical studies, 83.2 % (89/107) of grade 3 or 4 ALT or AST elevation events occurred within the first 6 months of treatment. Among the patients who had grade 3 or 4 ALT/AST elevation, the median time to onset was 85 days for the Kryxana plus any combination arms. The median time to resolution (to normalisation or grade u2264 2) was 22 days in the Kryxana plus any combination arms.

QT prolongation

In study E2301 (MONALEESA 7), the observed mean QTcF increase from baseline was approximately 10 msec higher in the tamoxifen plus placebo subgroup compared with the NSAI plus placebo subgroup, suggesting that tamoxifen alone had a QTcF prolongation effect which can contribute to the QTcF values observed in the Kryxana plus tamoxifen group. In the placebo arm, a QTcF interval increase of > 60 msec from baseline occurred in 6/90 (6.7 %) patients receiving tamoxifen and in no patients receiving a NSAI (see section 5.2). A QTcF interval increase of > 60 msec from baseline was observed in 14/87 (16.1 %) patients receiving Kryxana plus tamoxifen and in 18/245 (7.3 %) patients receiving Kryxana plus a NSAI. Kryxana is not recommended to be used in combination with tamoxifen (see section 5.1).

In the phase III clinical studies 9.3 % of patients in the Kryxana plus aromatase inhibitor or fulvestrant arms and 3.5 % in the placebo plus aromatase inhibitor or fulvestrant arms had at least one event of QT interval prolongation (including ECG QT prolonged and syncope). Review of ECG data showed 14 patients (1.3 %) had >500 msec post-baseline QTcF value, and 59 patients (5.6 %) had a > 60 msec increase from baseline in QTcF intervals. There were no reported cases of torsade de pointes. Dose interruptions/adjustments were reported in 2.3 % of Kryxana plus aromatase inhibitor or fulvestrant treated patients due to electrocardiogram QT prolonged and syncope. The analysis of ECG data showed 55 patients (5.2 %) and 12 patients (1.5 %) with at least one > 480 msec post-baseline QTcF for the Kryxana plus aromatase inhibitor or fulvestrant arms and the placebo plus aromatase inhibitor or fulvestrant arms, respectively. Amongst the patients who had QTcF prolongation > 480 msec, the median time to onset was 15 days regardless of the combination and these changes were reversible with dose interruption and/or dose reduction (see sections 4.2, 4.4 and 5.2).