4.1. Therapeutic indications

Early breast cancer

Verzenios in combination with endocrine therapy is indicated for the adjuvant treatment of adult patients with hormone receptor (HR)‑positive, human epidermal growth factor receptor 2 (HER2)‑negative, node‑positive early breast cancer at high risk of recurrence (see section 5.1).

In pre‑ or perimenopausal women, aromatase inhibitor endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.

Advanced or metastatic breast cancer

Verzenios is indicated for the treatment of women 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 as initial endocrine-based therapy, or in women who have received prior endocrine therapy.

In pre- or perimenopausal women, the endocrine therapy should be combined with a LHRH agonist.

4.2. Posology and method of administration

Verzenios therapy should be initiated and supervised by physicians experienced in the use of anti‑cancer therapies.

Posology

The recommended dose of abemaciclib is 150 mg twice daily when used in combination with endocrine therapy. Please refer to the summary of product characteristics of the endocrine therapy combination partner for the recommended posology.

Duration of treatment

Early breast cancer

Verzenios should be taken continuously for two years, or until disease recurrence or unacceptable toxicity occurs.

Advanced or metastatic breast cancer

Verzenios should be taken continuously as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs.

If a patient vomits or misses a dose of Verzenios, the patient should be instructed to take the next dose at its scheduled time; an additional dose should not be taken.

Dose adjustments

Management of some adverse reactions may require dose interruption and/or dose reduction as shown in Tables 1-7.

Table 1. Dose adjustment recommendations for adverse reactions

Verzenios dose

combination therapy

Recommended dose

150 mg twice daily

First dose adjustment

100 mg twice daily

Second dose adjustment

50 mg twice daily

Table 2. Management recommendations for haematologic toxicities

Complete blood counts should be monitored prior to the start of Verzenios therapy, every two weeks for the first two months, monthly for the next two months, and as clinically indicated. Before treatment initiation, absolute neutrophil counts (ANC) ≥ 1 500 / mm3, platelets ≥ 1 00 000 / mm3, and haemoglobin ≥ 8 g/dL are recommended.

Toxicitya, b

Management recommendations

Grade 1 or 2

No dose adjustment required.

Grade 3

Suspend dose until toxicity resolves to Grade 2 or less.

Dose reduction is not required.

Grade 3, recurrent; or Grade 4

Suspend dose until toxicity resolves to Grade 2 or less.

Resume at next lower dose.

Patient requires administration of blood cell growth factors

Suspend abemaciclib dose for at least 48 hours after the last dose of blood cell growth factors was administered and until toxicity resolves to Grade 2 or less.

Resume at next lower dose unless the dose was already reduced for the toxicity that led to the use of the growth factor.

a NCI Common Terminology Criteria for Adverse Events (CTCAE)

b ANC: Grade 1: ANC < LLN – 1 500 / mm3; Grade 2: ANC 1 000 - < 1 500 / mm3; Grade 3: ANC 500 - < 1 000 / mm3; Grade 4: ANC < 500 / mm3

LLN = lower limit of normal

Table 3. Management recommendations for diarrhoea

Treatment with antidiarrhoeal agents, such as loperamide, should be started at the first sign of loose stools.

Toxicity a

Management recommendations

Grade 1

No dose adjustment required.

Grade 2

If toxicity does not resolve within 24 hours to Grade 1 or less, suspend dose until resolution.

Dose reduction is not required.

Grade 2 that persists or recurs after resuming the same dose despite maximal supportive measures

Suspend dose until toxicity resolves to Grade 1 or less.

Resume at next lower dose.

Grade 3 or 4 or requires hospitalisation

a NCI CTCAE

Table 4. Management recommendations for increased aminotransferases

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be monitored prior to the start of Verzenios therapy, every two weeks for the first two months, monthly for the next two months, and as clinically indicated.

Toxicitya

Management recommendations

Grade 1 (> ULN - 3.0 x ULN)

Grade 2 (> 3.0 - 5.0 x ULN)

No dose adjustment required.

Persistent or Recurrent Grade 2, or Grade 3 (> 5.0 - 20.0 x ULN)

Suspend dose until toxicity resolves to baseline or Grade 1.

Resume at next lower dose.

Elevation in AST and/or ALT > 3 x ULN WITH total bilirubin > 2 x ULN, in the absence of cholestasis

Discontinue abemaciclib.

Grade 4 (> 20.0 x ULN)

Discontinue abemaciclib.

a NCI CTCAE

ULN = upper limit of normal

Table 5. Management recommendations for interstitial lung disease (ILD)/pneumonitis

Toxicitya

Management recommendations

Grade 1 or 2

No dose adjustment required.

Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1

Suspend dose until toxicity resolves to baseline or Grade 1.

Resume at next lower dose.

Grade 3 or 4

Discontinue abemaciclib.

a NCI CTCAE

Table 6. Management recommendations for venous thromboembolic events (VTEs)

Toxicitya

Management recommendations

Early breast cancer

All Grades (1, 2, 3, or 4)

Suspend dose and treat as clinically indicated. Abemaciclib may be resumed when the patient is clinically stable.

Advanced or metastatic breast cancer

Grade 1 or 2

No dose modification is required.

Grade 3 or 4

Suspend dose and treat as clinically indicated. Abemaciclib may be resumed when the patient is clinically stable.

a NCI CTCAE

Table 7. Management recommendations for non-haematologic toxicities (excluding diarrhoea, increased aminotransferases, and ILD/pneumonitis and VTEs)

Toxicity a

Management recommendations

Grade 1 or 2

No dose adjustment required.

Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures to baseline or Grade 1 within 7 days

Suspend dose until toxicity resolves to Grade 1 or less.

Resume at next lower dose.

Grade 3 or 4

a NCI CTCAE

CYP3A4 inhibitors

Concomitant use of strong CYP3A4 inhibitors should be avoided. If strong CYP3A4 inhibitors cannot be avoided, the abemaciclib dose should be reduced to 100 mg twice daily.

In patients who have had their dose reduced to 100 mg abemaciclib twice daily and in whom co‑administration of a strong CYP3A4 inhibitor cannot be avoided, the abemaciclib dose should be further reduced to 50 mg twice daily.

In patients who have had their dose reduced to 50 mg abemaciclib twice daily and in whom co‑administration of a strong CYP3A4 inhibitor cannot be avoided, the abemaciclib dose may be continued with close monitoring of signs of toxicity. Alternatively, the abemaciclib dose may be reduced to 50 mg once daily or discontinued.

If the CYP3A4 inhibitor is discontinued, the abemaciclib dose should be increased to the dose used prior to the initiation of the CYP3A4 inhibitor (after 3 to 5 half-lives of the CYP3A4 inhibitor).

Special populations

Elderly

No dose adjustment is required based on age (see section 5.2).

Renal impairment

No dose adjustments are necessary in patients with mild or moderate renal impairment. There are no data regarding abemaciclib administration in patients with severe renal impairment, end stage renal disease, or in patients on dialysis (see section 5.2). Abemaciclib should be administered with caution in patients with severe renal impairment, with close monitoring for signs of toxicity.

Hepatic impairment

No dose adjustments are necessary in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. In patients with severe (Child Pugh C) hepatic impairment, a decrease in dosing frequency to once daily is recommended (see section 5.2).

Paediatric population

The safety and efficacy of abemaciclib in children and adolescents aged less than 18 years has not been established. No data are available.

Method of administration

Verzenios is for oral use.

The dose can be taken with or without food. It should not be taken with grapefruit or grapefruit juice (see section 4.5).

Patients should take the doses at approximately the same times every day.

The tablet should be swallowed whole (patients should not chew, crush, or split tablets before swallowing).

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

Neutropenia

Neutropenia was reported in patients receiving abemaciclib. Dose modification is recommended for patients who develop Grade 3 or 4 neutropenia (see section 4.2). Fatal events of neutropenic sepsis occurred in < 1 % of patients with metastatic breast cancer. Patients should be instructed to report any episode of fever to their healthcare provider.

Infections/infestations

Infections were reported in patients receiving abemaciclib plus endocrine therapy at a higher rate than in patients treated with endocrine therapy. Lung infection was reported in patients receiving abemaciclib without concurrent neutropenia. Fatal events occurred in < 1 % of patients with metastatic breast cancer. Patients should be monitored for signs and symptoms of infection and treated as medically appropriate.

Venous thromboembolism

Venous thromboembolic events were reported in patients treated with abemaciclib plus endocrine therapy. Patients should be monitored for signs and symptoms of deep vein thrombosis and pulmonary embolism and treated as medically appropriate. Based on the grade of VTE, abemaciclib may require dose modification (see section 4.2).

Arterial Thromboembolic Events

A potential increased risk for serious arterial thromboembolic events (ATEs), including ischemic stroke and myocardial infarction, has been observed in metastatic breast cancer studies when abemaciclib was administered in combination with endocrine therapies. The benefits and risks of continuing abemaciclib in patients who experience a serious ATE should be considered.

Increased aminotransferases

Increases in ALT and AST were reported in patients receiving abemaciclib. Based on the level of ALT or AST elevation, abemaciclib may require dose modification (see section 4.2).

Diarrhoea

Diarrhoea is the most common adverse reaction. Across clinical studies, median time to onset of the first diarrhoea event was approximately 6 to 8 days, and median duration of diarrhoea was 7 to 12 days (Grade 2) and 5 to 8 days (Grade 3). Diarrhoea can be associated with dehydration. Patients should start treatment with antidiarrhoeal agents such as loperamide at the first sign of loose stools, increase oral fluids and notify their healthcare provider. Dose modification is recommended for patients who develop ≥ Grade 2 diarrhoea (see section 4.2).

ILD/Pneumonitis

ILD/pneumonitis was reported in patients receiving abemaciclib. Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis and treated as medically appropriate. Based on the grade of ILD/pneumonitis, abemaciclib may require dose modification (see section 4.2). Permanently discontinue abemaciclib in patients with Grade 3 or 4 ILD/pneumonitis.

Concomitant use of inducers of CYP3A4

Concomitant use of CYP3A4 inducers should be avoided due to the risk of decreased efficacy of abemaciclib (see section 4.5).

Visceral crisis

There are no data on the efficacy and safety of abemaciclib in patients with visceral crisis.

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

Effects of other medicinal products on the pharmacokinetics of abemaciclib

Abemaciclib is primarily metabolised by CYP3A4.

CYP3A4 inhibitors

Co-administration of abemaciclib with CYP3A4 inhibitors can increase plasma concentrations of abemaciclib. In patients with advanced and/or metastatic cancer, co‑administration of the CYP3A4 inhibitor clarithromycin resulted in a 3.4‑fold increase in the plasma exposure of abemaciclib and a 2.5‑fold increase in the combined unbound potency adjusted plasma exposure of abemaciclib and its active metabolites.

Use of strong CYP3A4 inhibitors together with abemaciclib should be avoided. If strong CYP3A4 inhibitors need to be co-administered, the dose of abemaciclib should be reduced (see section 4.2), followed by careful monitoring of toxicity. Examples of strong CYP3A4 inhibitors include, but not limited to: clarithromycin, itraconazole, ketoconazole, lopinavir/ritonavir, posaconazole or voriconazole. Avoid grapefruit or grapefruit juice.

No dose adjustment is necessary for patients treated with moderate or weak CYP3A4 inhibitors. There should, however, be close monitoring for signs of toxicity.

CYP3A4 inducers

Co-administration of abemaciclib with the strong CYP3A4 inducer rifampicin decreased the plasma concentration of abemaciclib by 95 % and unbound potency adjusted plasma concentration of abemaciclib plus its active metabolites by 77 % based on AUC0-∞. Concomitant use of strong CYP3A4 inducers (including, but not limited to: carbamazepine, phenytoin, rifampicin and St. John's wort) should be avoided due to the risk of decreased efficacy of abemaciclib.

Effects of abemaciclib on the pharmacokinetics of other medicinal products

Medicinal products that are substrates of transporters

Abemaciclib and its major active metabolites inhibit the renal transporters organic cation transporter 2 (OCT2), multidrug and extrusion toxin protein (MATE1), and MATE2‑K. In vivo interactions of abemaciclib with clinically relevant substrates of these transporters, such as dofetilide or creatinine, may occur (see section 4.8). In a clinical drug interaction study with metformin (substrate of OCT2, MATE1 and 2) co-administered with 400 mg abemaciclib, a small but not clinically relevant increase (37 %) in metformin plasma exposure was observed. This was found to be due to reduced renal secretion with unaffected glomerular filtration.

In healthy subjects, co-administration of abemaciclib and the P‑glycoprotein (P-gp) substrate loperamide resulted in an increase in loperamide plasma exposure of 9 % based on AUC0-∞ and 35 % based on Cmax. This was not considered to be clinically relevant. However, based on the in vitro inhibition of P-gp and breast cancer resistance protein (BCRP) observed with abemaciclib, in vivo interactions of abemaciclib with narrow therapeutic index substrates of these transporters, such as digoxin or dabigatran etexilate, may occur.

In a clinical study in patients with breast cancer, there was no clinically‑relevant pharmacokinetic drug interaction between abemaciclib and anastrozole, fulvestrant, exemestane, letrozole or tamoxifen.

It is currently unknown whether abemaciclib may reduce the effectiveness of systemically acting hormonal contraceptives.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in females

Women of childbearing potential should use highly effective contraception methods (e.g. double‑barrier contraception) during treatment and for at least 3 weeks after completing therapy (see section 4.5).

Pregnancy

There are no data from the use of abemaciclib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Verzenios is not recommended during pregnancy and in women of child-bearing potential not using contraception.

Breast-feeding

It is unknown whether abemaciclib is excreted in human milk. A risk to breast‑feeding children cannot be excluded. Patients receiving abemaciclib should not breast-feed.

Fertility

The effect of abemaciclib on fertility in humans is unknown. While in rats no effects on male fertility were noted, cytotoxic effects to the male reproductive tract in mice, rats, and dogs indicate that abemaciclib may impair fertility in males. No adverse effects on female reproductive organs in mice, rats, or dogs, nor effects on female fertility and early embryonic development in rats were observed (see section 5.3).

4.7. Effects on ability to drive and use machines

Verzenios has minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines in case they experience fatigue or dizziness during treatment with Verzenios (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The most commonly occurring adverse reactions are diarrhoea, infections, neutropenia, leukopenia, anaemia, fatigue, nausea, vomiting, alopecia and decreased appetite.

Of the most common adverse reactions, Grade ≥ 3 events were less than 5 % with the exception of neutropenia, leukopenia, and diarrhoea.

Tabulated list of adverse reactions

In the following table, adverse reactions are listed in order of MedDRA body system organ class and frequency. Frequency gradings are: very common (≥1 / 10), common (≥1 / 100 to < 1 / 10), uncommon (≥1 / 1 000 to < 1 / 100), rare (≥1 / 10 000 to < 1 / 1 000), very rare (< 1 / 10 000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 8. Adverse reactions reported in the phase 3 studies of abemaciclib in combination with endocrine therapya (N = 3 559) and during post-marketing experience

System organ class

Very common

Common

Uncommon

Rare

Infections and infestations

Infections b

Blood and lymphatic system disorders

Neutropenia

Leukopenia

Anaemia

Thrombocytopenia

Lymphopenia h

Febrile neutropenia e

Metabolism and nutrition disorders

Decreased appetite

Nervous system disorders

Headache f

Dysgeusia g

Dizziness g

Eye disorders

Lacrimation increased

Photopsia

Keratitis

Vascular disorders

Venous thromboembolism c

Respiratory, thoracic and mediastinal disorders

ILD/pneumonitis d

Gastrointestinal disorders

Diarrhoea

Vomiting

Nausea

Stomatitis f

Dyspepsia f

Skin and subcutaneous tissue disorders

Alopecia g

Pruritus g

Rash g

Nail disorder f

Dry skin e

Erythema multiforme

Musculoskeletal and connective tissue disorders

Muscular weakness e

General disorders and administration site conditions

Pyrexia e

Fatigue

Investigations

Alanine aminotransferase increased g

Aspartate aminotransferase increased g

a Abemaciclib in combination with anastrozole, letrozole, exemestane, tamoxifen, or fulvestrant.

b Infections include all reported preferred terms that are part of the system organ class infections and infestations.

c Venous thromboembolic events include deep vein thrombosis (DVT), pulmonary embolism, cerebral venous sinus thrombosis, subclavian, axillary vein thrombosis, DVT inferior vena cava and pelvic venous thrombosis.

d ILD/pneumonitis for early breast cancer (EBC) include all reported preferred terms that are part of the MedDRA SMQ interstitial lung disease. For metastatic breast cancer (mBC) preferred terms include interstitial lung disease, pneumonitis, organising pneumonia, pulmonary fibrosis and bronchiolitis obliterans.

e Considered ADRs in the mBC setting only (MONARCH 2 and MONARCH 3).

f Considered ADRs in the EBC setting only (monarchE).

g Common frequency in the EBC setting (monarchE), very common in the mBC setting (MONARCH 2 and MONARCH 3).

h Common frequency in mBC setting (MONARCH 2 and MONARCH 3), very common in the EBC setting (monarchE).

Description of selected adverse reactions

Neutropenia

Neutropenia was reported frequently across studies. In the monarchE study, neutropenia was reported in 45.8 % of patients. Grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 19.1 % of patients receiving abemaciclib in combination with endocrine therapy with a median time to onset of 30 days, and median time to resolution of 16 days. Febrile neutropenia was reported in 0.3 % patients. In MONARCH 2 and MONARCH 3 studies, neutropenia was reported in 45.1 % of patients. Grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 28.2 % of patients receiving abemaciclib in combination with aromatase inhibitors or fulvestrant. The median time to onset of Grade 3 or 4 neutropenia was 29 to 33 days, and median time to resolution was 11 to 15 days. Febrile neutropenia was reported in 0.9 % patients. Dose modification is recommended for patients who develop Grade 3 or 4 neutropenia (see section 4.2).

Diarrhoea

Diarrhoea was the most commonly reported adverse reaction (see Table 8). Incidence was greatest during the first month of abemaciclib treatment and was lower subsequently. In the monarchE study, the median time to onset of the first diarrhoea event of any grade was 8 days. The median duration of diarrhoea was 7 days for Grade 2 and 5 days for Grade 3. In MONARCH 2 and MONARCH 3 studies, the median time to onset of the first diarrhoea event of any grade was approximately 6 to 8 days. The median duration of diarrhoea was 9 to 12 days for Grade 2 and 6 to 8 days for Grade 3. Diarrhoea returned to baseline or lesser grade with supportive treatment such as loperamide and/or dose adjustment (see section 4.2).

Increased aminotransferases

In the monarchE study, ALT and AST elevations were reported frequently (12.3 % and 11.8 %, respectively) in patients receiving abemaciclib in combination with endocrine therapy. Grade 3 or 4 ALT or AST elevations (based on laboratory findings) were reported in 2.6 % and 1.6 % patients. The median time to onset of Grade 3 or 4 ALT elevation was 118 days, and median time to resolution was 14.5 days. The median time to onset of Grade 3 or 4 AST elevation was 90.5 days, and median time to resolution was 11 days. In MONARCH 2 and MONARCH 3 studies, ALT and AST elevations were reported frequently (15.1 % and 14.2 %, respectively) in patients receiving abemaciclib in combination with aromatase inhibitors or fulvestrant. Grade 3 or 4 ALT or AST elevations (based on laboratory findings) were reported in 6.1 % and 4.2 % patients. The median time to onset of Grade 3 or 4 ALT elevation was 57 to 61 days, and median time to resolution was 14 days. The median time to onset of Grade 3 or 4 AST elevation was 71 to 185 days, and median time to resolution was 13 to 15 days. Dose modification is recommended for patients who develop Grade 3 or 4 ALT or AST increase (see section 4.2).

Creatinine

Although not an adverse reaction, abemaciclib has been shown to increase serum creatinine. In the monarchE study, 99.3 % of patients had serum creatinine elevations (based on laboratory findings), and of these, 0.5 % of patients had Grade 3 or 4 elevations. In patients receiving endocrine therapy alone, 91.0 % reported an increase in serum creatinine (all laboratory grades). In MONARCH 2 and MONARCH 3 studies, 98.3 % of patients had serum creatinine elevations (based on laboratory findings), and of these, 1.9 % of patients had Grade 3 or 4 elevations. In patients receiving an aromatase inhibitor or fulvestrant alone, 78.4 % reported an increase in serum creatinine (all laboratory grades). Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters without affecting glomerular function (as measured by iohexol clearance) (see section 4.5). In clinical studies, increases in serum creatinine occurred within the first month of abemaciclib dosing, remained elevated but stable through the treatment period, were reversible upon treatment discontinuation, and were not accompanied by changes in markers of renal function, such as blood urea nitrogen (BUN), cystatin C, or calculated glomerular filtration rate based on cystatin C.

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

In the event of an abemaciclib overdose, fatigue and diarrhoea may occur. General supportive care should be provided.