Abemaciclib

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 AUC_0-∞ and 35% based on C_max. 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.

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.

Abemaciclib is primarily metabolised by CYP3A4.

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, 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.

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).

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

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 AUC_0-∞. 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.

There are no data regarding abemaciclib administration in patients with severe renal impairment, end stage renal disease, or in patients on dialysis. Abemaciclib should be administered with caution in patients with severe renal impairment, with close monitoring for signs of toxicity.

In patients with severe (Child Pugh C) hepatic impairment, a decrease in dosing frequency to once daily is recommended.

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.

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

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.

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.

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.

Abemaciclib 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 abemaciclib.

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.

Adverse reactions reported in the phase 3 studies of abemaciclib in combination with endocrine therapy^a (N=3 559) and during post-marketing experience:

^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.

Diarrhoea

Diarrhoea was the most commonly reported adverse reaction (see table). 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.

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 12 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.

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). 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.