Ado-trastuzumab emtansine

Ado-trastuzumab emtansine is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Ado-trastuzumab emtansine is used to treat a certain type of breast cancer that has spread to other parts of the body.

Ado-trastuzumab emtansine is usually given after other cancer medications have been tried without success.

Ado-trastuzumab emtansine may also be used for purposes not listed in this medication guide.

Do not use ado-trastuzumab emtansine if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

Ado-trastuzumab emtansine can harm your liver. Call your doctor at once if you have upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Before you receive each ado-trastuzumab emtansine injection, your heart function may need to be checked using an electrocardiograph or ECG (sometimes called an EKG).

You should not use ado-trastuzumab emtansine if you are allergic to it, or if you are pregnant.

To make sure ado-trastuzumab emtansine is safe for you, tell your doctor if you have:

• bleeding or blood clotting disorder such as hemophilia; or
• asthma, chronic obstructive pulmonary disease (COPD), sleep apnea, or other breathing disorder.

Do not use ado-trastuzumab emtansine if you are pregnant. It could harm the unborn baby. Tell your doctor if you become pregnant during treatment. Use effective birth control while you are using this medication and for at least 6 months after your treatment ends.

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

It is not known whether ado-trastuzumab emtansine passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

This medicine can pass into body fluids (urine, feces, vomit). For at least 48 hours after you receive a dose, avoid allowing your body fluids to come into contact with your hands or other surfaces. Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• imatinib;
• isoniazid;
• nefazodone;
• an antibiotic--clarithromycin, telithromycin;
• a blood thinner--warfarin, Coumadin, Jantoven;
• antifungal medication--itraconazole, ketoconazole, posaconazole, voriconazole;
• heart medication--nicardipine, quinidine;
• hepatitis C medications--boceprevir, telaprevir;
• HIV/AIDS medication--atazanavir, delavirdine, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir; or
• medicine used to prevent blood clots--alteplase, clopidogrel, dipyridamole, ticlopidine, urokinase.

This list is not complete. Other drugs may interact with ado-trastuzumab emtansine, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Before you receive this medicine, your doctor will perform blood tests to make sure ado-trastuzumab emtansine is the right medication to treat your cancer.

Ado-trastuzumab emtansine is injected into a vein through an IV. A healthcare provider will give you this injection.

Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when ado-trastuzumab emtansine is injected.

Ado-trastuzumab emtansine is usually given once every 3 weeks until your body no longer responds to the medication. Your doctor will determine how long to treat you with ado-trastuzumab emtansine.

You may need frequent medical tests at your doctor's office to be sure this medication is not causing harmful effects. Your cancer treatments may be delayed based on the results of these tests.

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Call your doctor for instructions if you miss an appointment for your ado-trastuzumab emtansine injection.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Do not use ado-trastuzumab emtansine if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

Ado-trastuzumab emtansine can harm your liver. Call your doctor at once if you have upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Before you receive each ado-trastuzumab emtansine injection, your heart function may need to be checked using an electrocardiograph or ECG (sometimes called an EKG).

Call your doctor for instructions if you miss an appointment for your ado-trastuzumab emtansine injection.

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

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Systemic exposure (AUC) was ~38% and ~67% lower in patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) impairment, respectively, compared to patients with normal hepatic function during cycles 1 and 2 of a 3.6 mg/kg ado-trastuzumab dose.

Hepatic impairment prior to treatment initiation:

Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary; use with caution.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Hepatotoxicity during treatment: Refer to dosage adjustment for toxicity for dose level reductions:

Grade 2 ALT, AST elevations (>2.5 to ≤5 times ULN): Continue at same dose level.

Grade 3 ALT, AST elevations (>5 to ≤20 times ULN): Withhold until ALT, AST recover to ≤ grade 2, then resume with one dose level reduction.

Grade 4 ALT, AST elevations (>20 times ULN): Permanently discontinue treatment.

Grade 2 hyperbilirubinemia (>1.5 to ≤3 times ULN): Withhold until bilirubin recovers to ≤ grade 1 (≤1.5 times ULN), then resume at the same dose level.

Grade 3 hyperbilirubinemia (>3 to ≤10 times ULN): Withhold until bilirubin recovers to ≤ grade 1, then resume with one dose level reduction.

Grade 4 hyperbilirubinemia (>10 times ULN): Permanently discontinue treatment.

Concomitant ALT, AST >3 times ULN and total bilirubin >2 times ULN: Permanently discontinue treatment.

Idiopathic noncirrhotic portal hypertension (including nodular regenerative hyperplasia): Permanently discontinue treatment.

Note: After a dose reduction is implemented, do not re-escalate dose.

Infusion-related reaction: Slow infusion rate or interrupt infusion. Permanently discontinue if life-threatening infusion reactions occur.

Dose levels for dosage reductions and/or discontinuation:

Starting dose: 3.6 mg/kg

First dose reduction: Reduce dose to 3 mg/kg

Second dose reduction: Reduce dose to 2.4 mg/kg

Further reductions necessary: Discontinue treatment.

Hematologic toxicity:

Grade 3 thrombocytopenia (platelets 25,000/mm3 to <50,000/mm3): Withhold treatment until platelet count recovers to ≤ grade 1 (platelets ≥75,000/mm3), then resume treatment at the same dose level.

Grade 4 thrombocytopenia (platelets <25,000/mm3): Withhold treatment until platelet count recovers to ≤ grade 1 (platelets ≥75,000/mm3), then resume treatment with one dose level reduction.

Cardiotoxicity:

LVEF >45%: Continue treatment.

LVEF 40% to ≤45% and decrease is <10% points from baseline: Continue treatment and repeat LVEF assessment within 3 weeks.

LVEF 40% to ≤45% and decrease is ≥10% points from baseline: Withhold treatment and repeat LVEF assessment within 3 weeks; if repeat LVEF has not recovered to within 10% points from baseline, discontinue treatment.

LVEF <40%: Withhold treatment and repeat LVEF assessment within 3 weeks; if repeat LVEF is confirmed <40%, discontinue treatment.

HF (symptomatic): Discontinue treatment.

Peripheral neuropathy, grade 3 or 4: Temporarily discontinue until resolves to ≤ grade 2.

Pulmonary toxicity: Interstitial lung disease or pneumonitis: Permanently discontinue.

Applies to ado-trastuzumab emtansine: intravenous powder for solution

Along with its needed effects, ado-trastuzumab emtansine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking ado-trastuzumab emtansine:

• Black, tarry stools
• bladder pain
• bleeding gums
• bloating or swelling of the face, arms, hands, lower legs, or feet
• bloody or cloudy urine
• blurred vision
• burning, numbness, tingling, or painful sensations
• chills
• convulsions
• cough
• decreased urine
• difficult or labored breathing
• difficult, burning, or painful urination
• dizziness
• dry mouth
• fever
• frequent urge to urinate
• headache
• increased thirst
• irregular heartbeat
• loss of appetite
• lower back or side pain
• mood changes
• muscle pain or cramps
• nausea or vomiting
• nervousness
• nosebleeds
• numbness or tingling in the hands, feet, or lips
• pale skin
• pinpoint red spots on the skin
• pounding in the ears
• rapid weight gain
• slow or fast heartbeat
• sore throat
• tightness in the chest
• troubled breathing with exertion
• ulcers, sores, or white spots in the mouth
• unsteadiness or awkwardness
• unusual bleeding or bruising
• unusual tiredness or weakness
• unusual weight gain or loss
• weakness in the arms, hands, legs, or feet

• Chest pain
• dilated neck veins
• extreme fatigue
• general feeling of discomfort or illness
• irregular breathing
• irregular heartbeat
• skin rash
• thickening of bronchial secretions

• Dark-colored urine
• general feeling of tiredness or weakness
• light-colored stools
• stomach bloating or pain
• vomiting blood
• yellow eyes or skin

• Abdominal or stomach tenderness
• itching

Some side effects of ado-trastuzumab emtansine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• change in taste
• constipation
• diarrhea
• difficulty with moving
• heartburn
• indigestion
• lack or loss of strength
• loss of taste
• muscle pain or stiffness
• pain in the joints
• stomach discomfort or upset
• swelling or inflammation of the mouth
• trouble sleeping

• Burning, dry, or itching eyes
• discharge or excessive tearing
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid

Applies to ado-trastuzumab emtansine: intravenous powder for injection

General

The most frequently reported side effects included nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation.[Ref]

Cardiovascular

Common (1% to 10%): Hypertension (5.1%), left ventricular dysfunction (1.8%)[Ref]

Dermatologic

Very common (10% or more): Rash (11.6%)
Common (1% to 10%): Pruritus (5.5%)[Ref]

Gastrointestinal

Very common (10% or more): Nausea (39.8%), constipation (26.5%), diarrhea (24.1%), vomiting (19.2%), abdominal pain (18.6%), dry mouth (16.7%), stomatitis (14.1%)
Common (1% to 10%): Dyspepsia (9.2%)[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection (9.4%)[Ref]

Hematologic

Very common (10% or more): Decreased platelet count (83%), decreased hemoglobin (60%), decreased neutrophils (39%), thrombocytopenia (31.2%), anemia (14.2%)
Common (1% to 10%): Neutropenia (6.7%)[Ref]

Hepatic

Very common (10% or more): Increased AST (98%), increased ALT (82%), increased transaminases (28.8%), increased bilirubin (17%)
Uncommon (0.1% to 1%): Nodular regenerative hyperplasia (0.4%), portal hypertension (0.4%)[Ref]

Hypersensitivity

Common (1% to 10%): Drug hypersensitivity (2.2%)[Ref]

Immunologic

Common (1% to 10%): Positive test for anti-ado-trastuzumab emtansine antibodies (5.3%)[Ref]

Metabolic

Very common (10% or more): Decreased potassium (33%), hypokalemia (10.2%)
Common (1% to 10%): Alkaline phosphatase increased (4.7%)[Ref]

Musculoskeletal

Very common (10% or more): Musculoskeletal pain (36.1%), arthralgia (19.2%), myalgia (14.1%)[Ref]

Nervous system

Very common (10% or more): Headache (28.2%), peripheral neuropathy (21.2%), dizziness (10.2%)
Common (1% to 10%): Dysgeusia (8.0%)[Ref]

Ocular

Common (1% to 10%): Vision blurred (4.5%), dry eye (3.9%), conjunctivitis (3.9%), lacrimation increased (3.3%)[Ref]

Other

Very common (10% or more): Fatigue (36.3%), pyrexia (18.6%), asthenia (17.8%)
Common (1% to 10%): Chills (7.6%), peripheral edema (7.1%), infusion related reaction (1.4%)[Ref]

Psychiatric

Very common (10% or more): Insomnia (12.0%)[Ref]

Respiratory

Very common (10% or more): Epistaxis (22.5%), cough (18.2%), dyspnea (12.0%),
Common (1% to 10%): Pneumonitis (1.2%)[Ref]

Some side effects of ado-trastuzumab emtansine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Mild to moderate renal dysfunction (CrCl 30 - 89 mL/min): No adjustment recommended
Severe renal dysfunction (CrCl less than 30 mL/min): Data not available

Dosing information is not available for patients with preexisting liver dysfunction.

A reduction in dose is recommended for increases in serum transaminases and/or hyperbilirubinemia that develop while on ado-trastuzumab emtansine as follows:

Serum Transaminase (AST/ALT) increases:
-Grade 2 increase (greater than 2.5 to less than or equal to 5 times ULN): No dose adjustment
-Grade 3 increase (greater than 5 to less than or equal to 20 times ULN): Hold further doses until AST/ALT recovers to Grade 2 or less and then reduce dose one level.
-Grade 4 increase (greater than 20 times ULN): Permanently discontinue treatment.

Hyperbilirubinemia:
-Grade 2 (greater than 1.5 to less than or equal to 3 times ULN): Hold further doses until total bilirubin is Grade 1 or lower and then resume treatment at same dose level.

-Grade 3 (greater than 3 to less than or equal to 10 times ULN): Hold further doses until total bilirubin is Grade 1 or lower and then reduce one dose level.

-Grade 4 (greater than 10 times ULN): Permanently discontinue ado-trastuzumab emtansine.

Permanently discontinue for concomitant serum transaminases greater than 3 times ULN and total bilirubin greater than two times ULN or for patients diagnosed with nodular regenerative hyperplasia (NRH).