Verzenio

Verzenio™ (abemaciclib) is indicated:

• in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
• as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Diarrhea [see Warnings and Precautions (5.1)].
• Neutropenia [see Warnings and Precautions (5.2)].
• Hepatotoxicity [see Warnings and Precautions (5.3)].
• Venous Thromboembolism [see Warnings and Precautions (5.4)].

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

MONARCH 2: Verzenio in Combination with Fulvestrant

Women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy

The safety of Verzenio (150 mg twice daily) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in MONARCH 2. The data described below reflect exposure to Verzenio in 441 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of Verzenio plus fulvestrant in MONARCH 2.

Median duration of treatment was 12 months for patients receiving Verzenio plus fulvestrant and 8 months for patients receiving placebo plus fulvestrant.

Dose reductions due to an adverse reaction occurred in 43% of patients receiving Verzenio plus fulvestrant. Adverse reactions leading to dose reductions in ≥5% of patients were diarrhea and neutropenia. Verzenio dose reductions due to diarrhea of any grade occurred in 19% of patients receiving Verzenio plus fulvestrant compared to 0.4% of patients receiving placebo and fulvestrant. Verzenio dose reductions due to neutropenia of any grade occurred in 10% of patients receiving Verzenio plus fulvestrant compared to no patients receiving placebo plus fulvestrant.

Permanent study treatment discontinuation due to an adverse event were reported in 9% of patients receiving Verzenio plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Adverse reactions leading to permanent discontinuation for patients receiving Verzenio plus fulvestrant were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%), abdominal pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%).

Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of Verzenio plus fulvestrant treated patients versus 10 cases (5%) of placebo plus fulvestrant treated patients. Causes of death for patients receiving Verzenio plus fulvestrant included: 7 (2%) patient deaths due to underlying disease, 4 (0.9%) due to sepsis, 2 (0.5%) due to pneumonitis, 2 (0.5%) due to hepatotoxicity, and one (0.2%) due to cerebral infarction.

The most common adverse reactions reported (≥20%) in the Verzenio arm were diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache (Table 6). The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections.

Additional adverse reactions in MONARCH 2 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, and DVT inferior vena cava), which were reported in 5% of patients treated with Verzenio plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo.

Creatinine Increased

Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. In clinical studies, increases in serum creatinine (mean increase, 0.2 mg/dL) occurred within the first 28-day cycle of Verzenio dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated glomerular filtration rate (GFR), which are not based on creatinine, may be considered to determine whether renal function is impaired.

Verzenio Administered as a Monotherapy in Metastatic Breast Cancer (MONARCH 1)

Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic setting

Safety data below are based on MONARCH 1, a single-arm, open-label, multicenter study in 132 women with measurable HR-positive, HER2-negative metastatic breast cancer. Patients received 200 mg Verzenio orally twice daily until development of progressive disease or unmanageable toxicity. Median duration of treatment was 4.5 months.

Ten patients (8%) discontinued study treatment from adverse reactions due to (1 patient each) abdominal pain, arterial thrombosis, aspartate aminotransferase (AST) increased, blood creatinine increased, chronic kidney disease, diarrhea, ECG QT prolonged, fatigue, hip fracture, and lymphopenia. Forty-nine percent of patients had dose reductions due to an adverse reaction. The most frequent adverse reactions that led to dose reductions were diarrhea (20%), neutropenia (11%), and fatigue (9%).

Deaths during treatment or during the 30-day follow up were reported in 2% of patients. Cause of death in these patients was due to infection.

The most common reported adverse reactions (≥20%) were diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia (Table 8). Severe (Grade 3 and 4) neutropenia was observed in patients receiving abemaciclib [see Dosage and Administration (2.2)].

Creatinine Increased

Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function [see Clinical Pharmacology (12.3)]. In clinical studies, increases in serum creatinine (mean increase, 0.3 mg/dL) occurred within the first 28-day cycle of Verzenio dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.

Abemaciclib is a kinase inhibitor for oral administration. It is a white to yellow powder with the empirical formula C27H32F2N8 and a molecular weight 506.59.

The chemical name for abemaciclib is 2-Pyrimidinamine, N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-. Abemaciclib has the following structure:

Verzenio (abemaciclib) tablets are provided as immediate-release oval white, beige, or yellow tablets. Inactive ingredients are as follows: Excipientsmicrocrystalline cellulose 102, microcrystalline cellulose 101, lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate, silicon dioxide. Color mixture ingredientspolyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, and iron oxide red.

Verzenio in Combination with Fulvestrant (MONARCH 2)

Patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy

MONARCH 2 (NCT02107703) was a randomized, placebo-controlled, multicenter study in women with HR-positive, HER2-negative metastatic breast cancer in combination with fulvestrant in patients with disease progression following endocrine therapy who had not received chemotherapy in the metastatic setting. Randomization was stratified by disease site (visceral, bone only, or other) and by sensitivity to prior endocrine therapy (primary or secondary resistance). Primary endocrine therapy resistance was defined as relapse while on the first 2 years of adjuvant endocrine therapy or progressive disease within the first 6 months of first line endocrine therapy for metastatic breast cancer. A total of 669 patients were randomized to receive Verzenio or placebo orally twice daily plus intramuscular injection of 500 mg fulvestrant on days 1 and 15 of cycle 1 and then on day 1 of cycle 2 and beyond (28-day cycles). Pre/perimenopausal women were enrolled in the study and received the gonadotropin-releasing hormone agonist goserelin for at least 4 weeks prior to and for the duration of MONARCH 2. Patients remained on continuous treatment until development of progressive disease or unmanageable toxicity.

Patient median age was 60 years (range, 32-91 years), and 37% of patients were older than 65. The majority were White (56%), and 99% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Twenty percent (20%) of patients had de novo metastatic disease, 27% had bone only disease, and 56% had visceral disease. Twenty-five percent (25%) of patients had primary endocrine therapy resistance. Seventeen percent (17%) of patients were pre- or perimenopausal.

The efficacy results from the MONARCH 2 study are summarized in Table 10 and Figure 1. Median PFS assessment based on a blinded independent radiologic review was consistent with the investigator assessment. Consistent results were observed across patient stratification subgroups of disease site and endocrine therapy resistance. At the time of primary analysis of PFS, overall survival data were not mature (20% of patients had died).

Figure 1: Kaplan-Meier Curves of Progression-Free Survival: Verzenio plus Fulvestrant versus Placebo plus Fulvestrant (MONARCH 2)

Verzenio Administered as a Monotherapy in Metastatic Breast Cancer (MONARCH 1)

Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic setting

MONARCH 1 (NCT02102490) was a single-arm, open-label, multicenter study in women with measurable HR-positive, HER2-negative metastatic breast cancer whose disease progressed during or after endocrine therapy, had received a taxane in any setting, and who received 1 or 2 prior chemotherapy regimens in the metastatic setting. A total of 132 patients received 200 mg Verzenio orally twice daily on a continuous schedule until development of progressive disease or unmanageable toxicity.

Patient median age was 58 years (range, 36-89 years), and the majority of patients were White (85%). Patients had an Eastern Cooperative Oncology Group performance status of 0 (55% of patients) or 1 (45%). The median duration of metastatic disease was 27.6 months. Ninety percent (90%) of patients had visceral metastases, and 51% of patients had 3 or more sites of metastatic disease. Fifty-one percent (51%) of patients had had one line of chemotherapy in the metastatic setting. Sixty-nine percent (69%) of patients had received a taxane-based regimen in the metastatic setting and 55% had received capecitabine in the metastatic setting. Table 11 provides the efficacy results from MONARCH 1.

How Supplied

Verzenio 50 mg tablets are oval beige tablet with “Lilly” debossed on one side and “50” on the other side.

Verzenio 100 mg tablet are oval white to practically white tablet with “Lilly” debossed on one side and “100” on the other side.

Verzenio 150 mg tablets are oval yellow tablet with “Lilly” debossed on one side and “150” on the other side.

Verzenio 200 mg tablets are oval beige tablet with “Lilly” debossed on one side and “200” on the other side.

Verzenio tablets are supplied in 7-day dose pack configurations as follows:

• 200 mg dose pack (14 tablets) – each blister pack contains 14 tablets (200 mg per tablet) (200 mg twice daily)
  NDC 0002-6216-54
• 150 mg dose pack (14 tablets) – each blister pack contains 14 tablets (150 mg per tablet) (150 mg twice daily)
  NDC 0002-5337-54
• 100 mg dose pack (14 tablets) – each blister pack contains 14 tablets (100 mg per tablet) (100 mg twice daily)
  NDC 0002-4815-54
• 50 mg dose pack (14 tablets) – each blister pack contains 14 tablets (50 mg per tablet) (50 mg twice daily)
  NDC 0002-4483-54

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Before taking Verzenio, tell your healthcare provider about all of your medical conditions, including if you:

• have fever, chills, or any other signs of an infection.
• have liver or kidney problems.
• are pregnant or plan to become pregnant. Verzenio can harm your unborn baby.
  • If you are able to become pregnant, your healthcare provider may do a pregnancy test before you start treatment.
  • Females who are able to become pregnant should use effective birth control during treatment, and for at least three weeks after the last dose.
  • Talk to your healthcare provider about birth control methods to prevent pregnancy during treatment. If you become pregnant or think you may be pregnant, tell your healthcare provider right away.
• are breastfeeding or plan to breastfeed. It is not known if this medicine passes into your breast milk. Do not breastfeed during treatment, and for at least three weeks after the last dose.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Certain other medicines can affect how Verzenio works and cause serious side effects.

Especially tell your healthcare provider if you take a medicine that contains ketoconazole.

Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine, such as antibiotics, or medicines that treat fungus or HIV/AIDS, because your dose of Verzenio might need to be changed.

• Store the tablets at room temperature between 68°F to 77°F (20°C to 25°C).

Keep all medicines out of the reach of children and pets.

Active ingredient:strong> abemaciclib.

Inactive ingredients: microcrystalline cellulose 102, microcrystalline cellulose 101, lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate, silicon dioxide.

Color mixture ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, and iron oxide red.

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Loose stools (diarrhea).
• Feeling tired or weak.
• Upset stomach or throwing up.
• Not hungry.
• Belly pain.
• Headache.
• Hard stools (constipation).
• Dry mouth.
• Mouth irritation or mouth sores.
• Joint pain.
• Change in taste.
• Dizziness.
• Hair loss.
• Weight loss.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of abemaciclib in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of abemaciclib in the elderly.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Carbamazepine
• Enzalutamide
• Fosphenytoin
• Ketoconazole
• Lumacaftor
• Mitotane
• Phenytoin
• Rifampin
• St John's Wort

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Infection—May decrease your body's ability to fight infection.

• Liver disease, severe—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant during treatment with this medicine and for at least 3 weeks after your last dose. If you think you have become pregnant while using the medicine, tell your doctor right away.

If you plan to have children, talk with your doctor before using this medicine. Some men using this medicine have become infertile (unable to have children).

This medicine may cause diarrhea, which may be severe and lead to dehydration or infections. You may take antidiarrheal medicines (eg, loperamide) if you start to have loose stools. Check with your doctor right away for additional instructions.

Abemaciclib can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem.

This medicine may increase your risk of developing blood clots, which may be life-threatening. Check with your doctor right away if you or your child have swelling and pain in your arms, legs, or stomach, chest pain, shortness of breath, loss of sensation, confusion, or problems with muscle control or speech.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Abemaciclib is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Abemaciclib is used to treat advanced hormone-related breast cancer. Abemaciclib is used for this condition only if your tumor tests negative for a protein called human epidermal growth factor receptor 2 (HER2). HER2 protein can speed the growth of cancer cells.

Abemaciclib is sometimes given with other cancer medicines.

Abemaciclib may also be used for purposes not listed in this medication guide.

Abemaciclib can cause severe diarrhea, which can lead to dehydration or infection. Call your doctor right away if you have diarrhea. Drink extra fluids and start taking anti-diarrhea medicine such as loperamide (Imodium).

Abemaciclib can cause blood clots, liver problems, or serious and sometimes fatal infections. Call your doctor right away if you have symptoms such as: fever, chills, easy bruising or bleeding, unusual tiredness, loss of appetite, right-sided upper stomach pain, chest pain, shortness of breath, rapid breathing, fast heartbeats, or pain or swelling in your arms or legs.

You should not use abemaciclib if you are allergic to it.

Tell your doctor if you have ever had:

• a fever, chills, or other signs of infection; or
• liver or kidney disease.

You may need to have a negative pregnancy test before starting this treatment.

Using abemaciclib during pregnancy could harm the unborn baby. Use effective birth control to prevent pregnancy while you are using this medicine and for at least 3 weeks after your treatment ends. Tell your doctor right away if you become pregnant during this time.

It is not safe to breast-feed a baby while you are using this medicine. Also do not breast-feed for at least 3 weeks after your last dose.

You should not breast-feed while using this medicine and for at least 3 weeks after your last dose.BasicDescription Back to TopVerzenio Side Effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• severe or ongoing diarrhea;
• pain or burning when you urinate;
• liver problems--right-sided upper stomach pain, loss of appetite, easy bruising or bleeding, feeling very tired;
• low blood cell counts--fever, chills, tiredness, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands and feet, feeling light-headed or short of breath; or
• signs of a blood clot--pain or swelling in an arm or leg, chest pain, fast heartbeats, feeling short of breath.

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Common side effects may include:

• diarrhea, nausea, vomiting, stomach pain;
• loss of appetite;
• hair loss;
• infections;
• feeling tired;
• headache; or
• low blood cell counts.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.