Ado-trastuzumab emtansine

Name: Ado-trastuzumab emtansine

What special dietary instructions should I follow?

Talk to your doctor about eating grapefruit and drinking grapefruit juice while receiving this medication.

What side effects can this medication cause?

Ado-trastuzumab emtansine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

  • constipation
  • diarrhea
  • upset stomach
  • sores in the mouth and throat
  • dry mouth
  • changes in ability to taste
  • joint or muscle pain
  • headache
  • dry, red, or teary eyes
  • blurry vision
  • trouble falling asleep or staying asleep

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately:

  • pain, itching, redness, swelling, blisters, or sores in the place where the medication was injected
  • fever, sore throat, chills, difficulty urinating, pain when urinating, and other signs of infection
  • nosebleeds and other unusual bleeding or bruising
  • bloody or black, tarry stools
  • vomiting blood or brown material that resembles coffee grounds
  • pain, burning, or tingling in the hands or feet
  • hives
  • rash
  • itching
  • difficulty breathing or swallowing

Ado-trastuzumab emtansine may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

In case of emergency/overdose

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following:

  • nosebleeds and other unusual bleeding or bruising
  • bloody or black, tarry stools
  • vomiting blood or brown material that resembles coffee grounds

What is ado-trastuzumab emtansine?

Ado-trastuzumab emtansine is a cancer medicine 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.

Kadcyla (ado-trastuzumab) should not be used in place of Herceptin (trastuzumab).

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

Actions

  • An anti-HER2 antibody (trastuzumab; a humanized IgG1) conjugated via stable thioether linker (MCC) with microtubule inhibitor DM1 (maytansine derivative).1 12 Resultant complex, MCC-DM1, referred to as emtansine.1 12

  • Antibody-drug conjugate binds to extracellular domain (subdomain IV) of HER2 protein; resultant complex internalized by the cell, and DM1 released via lysosomal degradation.1 8 9 DM1 then binds to tubulin, disrupting microtubule activity, and resulting in cell cycle arrest and apoptosis.1 9

  • Ado-trastuzumab emtansine exhibits similar activity and binding affinity to the HER2 receptor as trastuzumab.1 9 10 12

  • DM1 approximately 2- to 17-fold more potent than paclitaxel on a molar basis in several breast cancer cell lines in vitro.12

How is this medicine (Ado-Trastuzumab Emtansine) best taken?

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • It is given as an infusion into a vein over a period of time.

What do I do if I miss a dose?

  • Call your doctor to find out what to do.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
  • Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
  • Signs of low potassium levels like muscle pain or weakness, muscle cramps, or a heartbeat that does not feel normal.
  • A burning, numbness, or tingling feeling that is not normal.
  • Feeling very tired or weak.
  • Swelling in the arms or legs.
  • Very bad and sometimes deadly lung problems have happened with ado-trastuzumab emtansine. Call your doctor right away if you have lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.
  • This medicine may irritate the vein. It may burn the skin if the drug leaks from the vein when it is given. Tell your nurse if you have any redness, burning, pain, swelling, or leaking of fluid where the drug is going into your body.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Ado-trastuzumab Emtansine Drug Class

Ado-trastuzumab Emtansine is part of the drug class:

  • OTHER ANTINEOPLASTIC AGENTS

Ado-trastuzumab Emtansine and Pregnancy

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. Ado-trastuzumab emtansine may harm your unborn baby. You should use birth control to prevent pregnancy during your treatment and for 6 months after your treatment. Talk to your doctor about birth control methods that will work for you. If you become pregnant during your treatment with ado-trastuzumab emtansine, call your doctor immediately.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Kadcyla: 100 mg (1 ea); 160 mg (1 ea) [contains mouse (murine) and/or hamster protein]

Pharmacologic Category

  • Antineoplastic Agent, Anti-HER2
  • Antineoplastic Agent, Antibody Drug Conjugate
  • Antineoplastic Agent, Antimicrotubular
  • Antineoplastic Agent, Monoclonal Antibody

Dosing Geriatric

Refer to adult dosing.

Reconstitution

Check vial labels to assure appropriate product is being reconstituted (ado-trastuzumab emtansine and conventional trastuzumab are different products and are NOT interchangeable).

Slowly inject sterile water for injection into the vial (5 mL for 100 mg vial or 8 mL for 160 mg vial) to a reconstituted concentration of 20 mg/mL. Gently swirl vial until completely dissolved. Reconstituted solution will be clear or slightly opalescent (there should be no visible particles) and colorless to pale brown. Dilute for infusion by adding to 250 mL sodium chloride 0.9%; gently invert bag to mix (do not shake).

ALERT U.S. Boxed Warning

Do not interchange:

Do not substitute ado-trastuzumab emtansine (Kadcyla) for or with trastuzumab (Herceptin).

Hepatotoxicity:

Serious hepatotoxicity has been reported, including liver failure and death. Monitor serum transaminases and bilirubin prior to initiation of treatment and prior to each dose. Reduce the dose or discontinue ado-trastuzumab emtansine as appropriate in cases of increased serum transaminases or total bilirubin.

Cardiotoxicity:

Ado-trastuzumab emtansine administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment. Withhold treatment for a clinically significant decrease in left ventricular function.

Pregnancy:

Exposure to ado-trastuzumab emtansine during pregnancy can result in embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Thrombocytopenia may occur (nadir achieved by day 8; generally resolves to ≤ grade 1 by the next scheduled dose). The incidence of thrombocytopenia may be higher in patients of Asian ancestry. Monitor platelet count at baseline and prior to each dose. May require treatment interruption or dose reduction. Monitor closely if at bleeding risk due to thrombocytopenia and/or concomitant anticoagulant use. Has not been studied in patients with platelets <100,000/mm3 at treatment initiation. Neutropenia and anemia have also occurred.

• Cardiotoxicity: [US Boxed Warning]: May result in left ventricular ejection fraction (LVEF) reductions. Evaluate left ventricular function (in all patients) prior to and at least every 3 months during treatment; withhold for clinically significant left ventricular function decreases. Treatment interruption or dosage reductions are required inpatients who develop decreased LVEF. Use has not been studied in patients with LVEF <50% at baseline, with a history of symptomatic CHF, serious arrhythmia, or recent history (within 6 months) of MI, or unstable angina.

• Extravasation reactions: May be a vesicant; avoid extravasation. Local reactions (erythema, irritation, pain, swelling, or tenderness) secondary to extravasation have been noted. These were generally mild and typically occurred within 24 hours of infusion. There is a case report of skin necrosis (delayed) following extravasation (Shafaee 2017). Monitor infusion site during infusion for possible infiltration.

• Hemorrhage: Hemorrhagic events, including central nervous system, respiratory, and gastrointestinal hemorrhage, have been observed; some hemorrhages were fatal. Some events occurred in patients who were receiving anticoagulation or antiplatelet therapy, or in patients with thrombocytopenia, although bleeding also occurred in patients without additional risk factors. Use caution when administering with antiplatelet agents or anticoagulants; consider additional monitoring when indicated.

• Hepatotoxicity: [US Boxed Warning]: Serious hepatotoxicity, including liver failure and death, has been reported. Monitor transaminases and bilirubin at baseline and prior to each dose. Increases (transaminases or total bilirubin) may require dose reductions or discontinuation. Hepatotoxicity is typically manifested by asymptomatic and transient increases in transaminases, although fatal cases of drug induced liver injury and hepatic encephalopathy have occurred; may be confounded by comorbidities or concomitant hepatotoxic medications. Use with caution in patients with hepatic impairment (has not been studied in patients with baseline serum transaminases >2.5 times ULN or bilirubin >1.5 times ULN, or in patients with active hepatitis B or C virus). Cases of idiopathic noncirrhotic portal hypertension (including nodular regenerative hyperplasia), a rare liver disorder characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules, have been observed (by biopsy). Idiopathic noncirrhotic portal hypertension (including nodular regenerative hyperplasia)may develop into noncirrhotic portal hypertension. Consider idiopathic noncirrhotic portal hypertension (including nodular regenerative hyperplasia) in patients with clinical symptoms of portal hypertension and/or cirrhosis-like pattern seen on liver CT scan, although without associated transaminase elevations or other manifestations of cirrhosis. Diagnosis of idiopathic noncirrhotic portal hypertension (including nodular regenerative hyperplasia) is confirmed by histopathology; permanently discontinue if histopathology confirms idiopathic noncirrhotic portal hypertension (including nodular regenerative hyperplasia).

• Hypersensitivity/infusion-related reactions: Infusion reactions (flushing, chills, fever, bronchospasm, dyspnea, wheezing, hypotension, and/or tachycardia) have been reported. After termination of infusion, these reactions generally resolved within several hours to a day. Medications for the treatment of reactions should be available for immediate use. Monitor closely for infusion reactions, especially during initial infusion. If reaction occurs, decrease infusion rate; for severe infusion reactions, interrupt infusion; permanently discontinue for life-threatening reactions. Serious allergic/anaphylactic reaction was observed (rare). Use is not recommended in patients who had trastuzumab permanently discontinued due to infusion reaction or hypersensitivity (has not been evaluated).

• Peripheral neuropathy: Sensory peripheral neuropathy has been reported, usually grade 1, although grade 3 peripheral neuropathy was also described. Monitor for signs and symptoms of neuropathy. May require treatment interruption and/or dose reduction.

• Pulmonary toxicity: Interstitial lung disease (ILD), including pneumonitis has been reported; some cases resulted in acute respiratory distress syndrome and/or fatalities. Permanently discontinue with diagnosis of ILD or pneumonitis. Signs and symptoms of pneumonitis include dyspnea, cough, fatigue, and pulmonary infiltrates; may or may not occur in correlation with infusion reaction. Patients with dyspnea at rest (due to advance malignancy complications or comorbidity) may be at increased risk for pulmonary toxicity.

Concurrent drug therapy issues:

• Drug-drug/drug-food interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Asian ancestry: The incidence of thrombocytopenia may be higher in patients of Asian ancestry.

• Pregnancy: [US Boxed Warning]: Exposure to ado-trastuzumab emtansine during pregnancy may cause embryo-fetal harm. Effective contraception must be used in women of reproductive potential. Pregnancy status should be verified prior to therapy. Effective contraception is recommended during therapy and for 7 months after the last dose for women of childbearing potential and for 4 months after the last dose in males with female partners of reproductive potential.

Dosage form specific issues:

• Do not interchange: [US Boxed Warning]: Ado-trastuzumab emtansine and conventional trastuzumab are NOT interchangeable. Do not substitute. In Canada, the generic name for Kadcyla is trastuzumab emtansine (ie, lacks Ado- prefix) and may be confused with conventional trastuzumab. Verify product label prior to reconstitution and administration to prevent medication errors.

Other warnings/precautions:

• HER2 expression: Establish HER2 overexpression or gene amplification status prior to treatment; has only been studied in patients with evidence of HER2 overexpression, either as 3+ IHC (Dako Herceptest) or FISH amplification ratio ≥2 (Dako HER2 FISH pharmDx test). There is only limited data on patients with breast cancer positive by FISH and 0 or 1+ by IHC.

Pregnancy Considerations

Animal reproduction studies have not been conducted. [US Boxed Warning]: Exposure to ado-trastuzumab emtansine during pregnancy may cause embryo-fetal harm. Effective contraception must be used in women of reproductive potential. Oligohydramnios and oligohydramnios sequence (manifested as pulmonary hypoplasia, skeletal malformations and neonatal death) were observed following trastuzumab exposure during pregnancy (trastuzumab is the antibody component of ado-trastuzumab emtansine). Monitor for oligohydramnios if trastuzumab exposure occurs during pregnancy or within 7 months prior to conception; conduct appropriate fetal testing if oligohydramnios occurs. Based on the mechanism of action, the DM1 component of the ado-trastuzumab emtansine formulation may also cause fetal harm if administered during pregnancy. Verify pregnancy status (in females of reproductive potential) prior to therapy. Effective contraception is recommended during therapy and for 7 months after the last dose for women of childbearing potential. Males with female partners of reproductive potential should use effective contraception during therapy and for 4 months after the last dose. Ado-trastuzumab emtansine may impair fertility in females and males.

If ado-trastuzumab emtansine exposure occurs during pregnancy or within 7 months prior to conception, healthcare providers should report the exposure to the Genentech Adverse Event Line (888-835-2555). Women exposed to ado-trastuzumab emtansine during pregnancy or within 7 months prior to conception are encouraged to enroll in MotHER Pregnancy Registry (1-800-690-6720).

European Society for Medical Oncology (ESMO) guidelines for cancer during pregnancy recommend delaying treatment with HER-2 targeted agents until after delivery in pregnant patients with HER-2 positive disease (Peccatori 2013).

Usual Adult Dose for Breast Cancer

Usual dose: 3.6 mg/kg IV every 3 weeks

Maximum dose: 3.6 mg/kg IV every 3 weeks

Duration of therapy: Until disease progression or unacceptable toxicity

Comments: Administer the first infusion over 90 minutes. Subsequent infusions may be administered over 30 minutes as tolerated.

Do not substitute ado-trastuzumab emtansine for or with trastuzumab.

Precautions

Consult WARNINGS section for dosing related precautions.

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