Alemtuzumab

Name: Alemtuzumab

What Is Alemtuzumab?

Alemtuzumab is an antibody made from animal DNA.

Alemtuzumab is used to treat chronic B-cell lymphocytic leukemia or relapsing forms of multiple sclerosis.

Lemtrada is available only from a certified pharmacy under a special program. You must be registered in the program and understand the risks of taking this medicine.

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

Alemtuzumab can cause your immune system to attack cells and organs in your body. This can lead to life-threatening medical problems such as severe bleeding or kidney damage. Call your doctor right away if you have unusual bruising or bleeding, blood in your urine, swelling in your legs or feet, or if you cough up blood.

Some side effects may occur during the injection or shortly afterward. You will be watched closely for at least 2 hours after receiving alemtuzumab, to make sure you do not have a serious reaction.

Serious and sometimes fatal infections may occur during treatment with alemtuzumab. Call your doctor right away if you have signs of infection such as: fever, chills, cough, mouth sores, or trouble breathing.

Alemtuzumab can have long lasting effects on your body, including an increased risk of developing other types of cancer (such as melanoma, thyroid cancer, or blood cancers). You may need frequent medical tests for as long as 4 years after you stop using this medicine.

You should not receive alemtuzumab if you are allergic to it. You should not be treated with Lemtrada if you have HIV (human immunodeficiency virus).

To make sure alemtuzumab is safe for you, tell your doctor if you have any of these other conditions:

  • an active or recent infection;
  • kidney disease;
  • a thyroid disorder;
  • a bleeding or blood clotting disorder such as hemophilia; or
  • if you have received a vaccine in the past 6 weeks.

Using alemtuzumab may increase your risk of developing other types of cancer, such as melanoma, thyroid cancer, or blood cancers. Ask your doctor about your specific risk.

It is not known whether alemtuzumab will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant. Use effective birth control to prevent pregnancy while you are receiving alemtuzumab, and for at least 4 months after each course of treatment.

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

Description

Campath (alemtuzumab) is a recombinant DNA-derived humanized monoclonal antibody (Campath-1H) directed against the 21-28 kD cell surface glycoprotein, CD52. Campath-1H is an IgG1 kappa antibody with human variable framework and constant regions, and complementarity-determining regions from a murine (rat) monoclonal antibody (Campath-1G). The Campath-1H antibody has an approximate molecular weight of 150 kD. Campath is produced in mammalian cell (Chinese hamster ovary) suspension culture in a medium containing neomycin. Neomycin is not detectable in the final product.

Campath is a sterile, clear, colorless, isotonic solution (pH 6.8-7.4) for injection. Each single use vial of Campath contains 30 mg alemtuzumab, 8.0 mg sodium chloride, 1.44 mg dibasic sodium phosphate, 0.2 mg potassium chloride, 0.2 mg monobasic potassium phosphate, 0.1 mg polysorbate 80, and 0.0187 mg disodium edetate dihydrate. No preservatives are added.

Clinical pharmacology

Mechanism Of Action

Campath binds to CD52, an antigen present on the surface of B and T lymphocytes, a majority of monocytes, macrophages, NK cells, and a subpopulation of granulocytes. A proportion of bone marrow cells, including some CD34+ cells, express variable levels of CD52. The proposed mechanism of action is antibody-dependent cellular-mediated lysis following cell surface binding of Campath to the leukemic cells.

Pharmacodynamics

Cardiac Electrophysiology

The effect of multiple doses of alemtuzumab (12 mg/day for 5 days) on the QTc interval was evaluated in a single-arm study in 53 patients without malignancy. No large changes in the mean QTc interval (i.e., > 20 ms) were detected in the study. A mean increase in heart rate of 22 to 26 beats/min was observed for at least 2 hours following the initial infusion of alemtuzumab. This increase in heart rate was not observed with subsequent doses.

Pharmacokinetics

Campath pharmacokinetics were characterized in a study of 30 previously treated B-CLL patients in whom Campath was administered at the recommended dose and schedule. Campath pharmacokinetics displayed nonlinear elimination kinetics. After the last 30 mg dose, the mean volume of distribution at steady-state was 0.18 L/kg (range 0.1 to 0.4 L/kg). Systemic clearance decreased with repeated administration due to decreased receptor-mediated clearance (i.e., loss of CD52 receptors in the periphery). After 12 weeks of dosing, patients exhibited a seven-fold increase in mean AUC. Mean half-life was 11 hours (range 2 to 32 hours) after the first 30 mg dose and was 6 days (range 1 to 14 days) after the last 30 mg dose.

Comparisons of AUC in patients ≥ 65 years (n=6) versus patients < 65 years (n=15) suggested that no dose adjustments are necessary for age. Comparisons of AUC in female patients (n=4) versus male patients (n=17) suggested that no dose adjustments are necessary for gender.

The pharmacokinetics of Campath in pediatric patients have not been studied. The effects of renal or hepatic impairment on the pharmacokinetics of Campath have not been studied.

Clinical Studies

Previously Untreated B-CLL Patients

Campath was evaluated in an open-label, randomized (1:1) active-controlled study in previously untreated patients with B-CLL, Rai Stage I-IV, with evidence of progressive disease requiring therapy. Patients received either Campath 30 mg IV 3 times/week for a maximum of 12 weeks or chlorambucil 40 mg/m PO once every 28 days, for a maximum of 12 cycles.

Of the 297 patients randomized, the median age was 60 years, 72% were male, 99% were Caucasian, 96% had a WHO performance status 0-1, 23% had maximum lymph node diameter ≥ 5cm, 34% were Rai Stage III/IV, and 8% were treated in the U.S.

Patients randomized to receive Campath experienced longer progression free survival (PFS) compared to those randomized to receive chlorambucil (median PFS 14.6 months vs. 11.7 months, respectively). The overall response rates were 83% and 55% (p < 0.0001) and the complete response rates were 24% and 2% (p < 0.0001) for Campath and chlorambucil arms, respectively. The Kaplan-Meier curve for PFS is shown in Figure 1.

Figure 1: Progression Free Survival in Previously Untreated B-CLL Patients1

1 Log-rank test adjusted for Rai Stage (I-II vs. III-IV).

Previously Treated B-CLL Patients

Campath was evaluated in three multicenter, open-label, single arm studies of 149 patients with B-CLL previously treated with alkylating agents, fludarabine, or other chemotherapies. Patients were treated with the recommended dose of Campath, 30 mg intravenously, three times per week for up to 12 weeks. Partial response rates of 21 to 31% and complete response rates of 0 to 2% were observed.

Uses of Alemtuzumab

Alemtuzumab is a prescription anti-cancer medication that is used to treat patients with B-cell chronic lymphocytic leukemia (a type of cancer of the blood). Alemtuzumab is also used for the treatment of patients with relapsing forms of multiple sclerosis (MS).

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

Alemtuzumab and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known if alemtuzumab passes into your breast milk. You and your doctor should decide whether you will stop breastfeeding or not take alemtuzumab.

Alemtuzumab Overdose

If you take too much this medication, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

How is alemtuzumab given?

Alemtuzumab is injected into a vein through an IV. A healthcare provider will give you this injection, which can take up to 4 hours to complete.

You may be given an antibiotic and other medicines to help prevent certain side effects of alemtuzumab. Take these medicines for the full prescribed length of time.

To treat chronic B-cell lymphocytic leukemia, alemtuzumab is usually given for a total of 12 weeks. You may receive the medicine every day or 3 days per week, depending on any side effects that occur.

For multiple sclerosis, alemtuzumab is given for 5 days followed by 12 months off the medicine. Then alemtuzumab is given for another 3 days. Your doctor will determine how long to treat you with this medicine.

You will be watched closely for at least 2 hours after receiving alemtuzumab, to make sure you do not have a serious reaction.

Serious and sometimes fatal infections may occur during treatment with alemtuzumab. Call your doctor right away if you have signs of infection such as: fever, chills, cough, mouth sores, or trouble breathing.

Your blood and urine will need to be tested often. Your cancer treatments may be delayed based on the results of these tests.

Alemtuzumab can have long lasting effects on your body. You may need frequent medical tests for as long as 4 years after you stop using this medicine.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Alemtuzumab 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.

Some side effects may occur during the injection or shortly afterward. Tell your caregiver right away if you feel weak, dizzy, itchy, nauseated, chilled or feverish, or if you have chest tightness or trouble breathing.

Alemtuzumab can cause your immune system to attack cells and organs in your body. This can lead to life-threatening medical problems such as severe bleeding or kidney damage. Call your doctor right away if you have:

  • unusual bruising or bleeding;

  • blood in your urine;

  • swelling in your legs or feet; or

  • if you cough up blood.

Also call your doctor at once if you have:

  • pain or swelling in your neck or throat, hoarse voice, trouble swallowing;

  • a mole that has changed in size or color;

  • lung problems--cough, wheezing, chest pain, feeling short of breath;

  • signs of infection--fever, swollen glands, weakness, pale or yellowed skin, dark colored urine, pain or burning when you urinate;

  • symptoms of herpes virus--cold sores around your mouth, skin sores or blisters, itching, tingling, burning pain in your thigh or lower back; or

  • thyroid problems--extreme tired feeling, nervousness, fast heartbeats, heavy sweating, weight gain or loss, swelling of your eyes, feeling more sensitive to cold temperatures, constipation.

Common side effects may include:

  • nausea, vomiting, stomach pain, diarrhea;

  • infections;

  • headache, joint pain, back pain;

  • itching, rash, tingling;

  • dizziness, tiredness, sleep problems (insomnia);

  • vaginal itching or discharge;

  • stuffy nose, throat pain or itching, white patches in your mouth or throat; or

  • flushing (warmth, redness, or tingly feeling).

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.

What other drugs will affect alemtuzumab?

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with alemtuzumab, especially:

  • drugs that weaken the immune system such as cancer medicine, or medicines to prevent organ transplant rejection.

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

Advice to Patients

  • Importance of advising patients receiving alemtuzumab (Lemtrada) for treatment of RRMS to read the manufacturer's patient information (medication guide) prior to each treatment course.a

  • Advise patients that alemtuzumab (Lemtrada) is available only through a restricted distribution program called the Lemtrada REMS Program.a Inform patients of the requirements of the program and provide them with information on how to locate a certified infusion site.a Advise patients to read the Lemtrada REMS educational materials and to carry the Patient Safety Information Card with them in case of an emergency.a

  • Risk of hematologic toxicity.1 a Importance of patients immediately informing clinician if signs or symptoms of cytopenias (bleeding, easy bruising, petechiae or purpura, pallor, weakness, or fatigue) occur.1

  • Risk of autoimmune diseases such as ITP and anti-glomerular basement membrane disease.a Importance of patients immediately informing clinician if any manifestations of potential autoimmunity (e.g., bleeding, easy bruising, petechiae, purpura, hematuria, edema, jaundice, hemoptysis) occur.a Importance of informing patients receiving alemtuzumab (Lemtrada) for treatment of RRMS that monthly monitoring of blood cell counts and urine tests is required during and for at least 48 months after completion of therapy.a

  • Risk of infusion-related reactions.1 a Importance of patients immediately informing clinician if any infusion-related reaction (e.g., swelling of the mouth or throat, difficulty breathing, weakness, abnormal heart rate, chest pain, rash) occurs.a Importance of informing patients receiving alemtuzumab (Lemtrada) that they will need to be monitored at the healthcare facility (e.g., infusion center) for at least 2 hours after each infusion.a Advise patients that infusion-related reactions may still occur after the 2-hour monitoring period.a

  • Risk of malignancies such as thyroid cancer and melanoma.a Advise patients to report any symptoms of thyroid cancer such as a new lump or swelling in the neck, pain in the front of the neck, persistent hoarseness or other voice changes, difficulty swallowing or breathing, or constant cough not due to upper respiratory tract infection.a Importance of annual skin examinations in patients receiving alemtuzumab (Lemtrada) to monitor for melanoma.a

  • Risk of infections.1 a Importance of taking prophylactic anti-infectives as prescribed.1 a Importance of advising patients to immediately contact their clinician if they develop any signs or symptoms of infection (e.g., fever, swollen glands).1 a Importance of advising patients to avoid or adequately heat foods that are potential sources of Listeria monocytogenes.a

  • Risk of thyroid disorders (e.g., hyperthyroidism, hypothyroidism).a Importance of advising patients to inform their clinician if they experience any manifestations of a potential thyroid disorder (e.g., unexplained weight loss or gain, rapid heart rate or palpitations, eye swelling, constipation, feeling cold).a

  • Advise patients that irradiation of blood products is required in the event that transfusions are necessary.1

  • Importance of patients completing any necessary vaccinations at least 6 weeks prior to the start of alemtuzumab therapy and to consult with their clinician prior to receiving any vaccination after recent use of alemtuzumab.a Advise patients that they should not be immunized with live viral vaccines if they have recently received alemtuzumab.1 a

  • Risk of pneumonitis; advise patients to report any symptoms such as shortness of breath, cough, wheezing, chest pain or tightness, or hemoptysis.a

  • Advise patients that alemtuzumab (Lemtrada) for the treatment of RRMS contains the same active ingredient as alemtuzumab (Campath) for the treatment of B-CLL; patients receiving Lemtrada should inform their clinician if they have previously received Campath.a

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 a Advise women of childbearing potential of the need for effective contraception during and for 4 months after a course of alemtuzumab (Lemtrada) therapy for treatment for MS.a Advise women of childbearing potential and men receiving alemtuzumab (Campath) to use effective contraceptive methods during therapy and for at least 6 months following completion of therapy.1

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1 a

  • Importance of informing patients of other important precautionary information.1 a (See Cautions.)

Preparations

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.

Distribution of alemtuzumab is restricted.1 37 (See Restricted Distribution Programs under Dosage and Administration.)

Alemtuzumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection concentrate, for IV infusion

10 mg/mL (12 mg)

Lemtrada

Genzyme

30 mg/mL

Campath

Genzyzme

Pharmacologic Category

  • Antineoplastic Agent, Anti-CD52
  • Antineoplastic Agent, Monoclonal Antibody
  • Monoclonal Antibody

Dosing Adult

B-cell chronic lymphocytic leukemia (B-CLL): Campath: IV: Gradually escalate to a maintenance of 30 mg per dose 3 times weekly on alternate days for a total duration of therapy of up to 12 weeks (Hillmen 2007; Keating 2002)

Note: Dose escalation is required; usually accomplished in 3 to 7 days. Single doses >30 mg or cumulative doses >90 mg/week increase the incidence of pancytopenia. Pretreatment (with acetaminophen 500 to 1,000 mg and diphenhydramine 50 mg) is recommended prior to the first dose, with dose escalations, and as clinically indicated; IV glucocorticoids may be used for severe infusion-related reactions. Administer antiviral prophylaxis (for herpetic viral infections) and Pneumocystis jirovecii pneumonia (PCP) prophylaxis; continue for at least 2 months after completion of alemtuzumab and until CD4+ lymphocyte count is ≥200/mm3. Reinitiate with gradual dose escalation if treatment is withheld ≥7 days. Alemtuzumab is associated with a moderate emetic potential in the oncology setting; antiemetics may be recommended to prevent nausea and vomiting (Basch 2011; Roila 2010).

Dose escalation: Initial: 3 mg daily beginning on day 1; if tolerated (infusion reaction ≤ grade 2), increase to 10 mg daily; if tolerated (infusion reaction ≤ grade 2), may increase to maintenance of 30 mg per dose 3 times weekly if required.

B-CLL (off-label route): SubQ: Initial: 3 mg on day 1; if tolerated 10 mg on day 3; if tolerated increase to 30 mg on day 5; maintenance: 30 mg per dose 3 times weekly for a maximum of 18 weeks (Lundin 2002) or 3 mg on day 1; if tolerated 10 mg on day 2; if tolerated 30 mg on day 3, followed by 30 mg per dose 3 times weekly for 4 to 12 weeks (Stilgenbauer 2009)

Multiple sclerosis, relapsing: Lemtrada: IV: 12 mg daily for 5 consecutive days (total 60 mg), followed 12 months later by 12 mg daily for 3 consecutive days (total 36 mg); total duration of therapy: 24 months.

Note: Premedicate with corticosteroids (methylprednisolone 1,000 mg or equivalent) immediately prior to alemtuzumab for the first 3 days of each treatment course. Antihistamines and/or antipyretics may also be considered. Administer antiviral prophylaxis (for herpetic viral infections) beginning on the first day of treatment and continue for at least 2 months after completion of alemtuzumab and until CD4+ lymphocyte count is ≥200/mm3. In some clinical trials patients received an additional 12 mg daily for 3 consecutive days 12 months later (total duration of 36 months) (CAMMS223 2008; Coles 2012).

Autoimmune cytopenias, CLL-induced, refractory (off-label use): IV, SubQ: Gradually escalate to a maintenance of 10 to 30 mg per dose 3 times weekly for 4 to 12 weeks (Karlsson 2007; Osterborg 2009)

Graft versus host disease (GVHD), acute, steroid refractory, treatment (off-label use): IV: 10 mg daily for 5 consecutive days, then 10 mg weekly on days 8, 15, and 22 if CR not achieved (Martinez 2009) or 10 mg weekly until symptom resolution (Schnitzler 2009)

Solid organ transplantation:

Heart transplant, induction (off-label use): IV: 30 mg once intra-operatively at the time of transplant followed by minimized maintenance immunosuppression (Teuteberg 2010). Additional data may be necessary to further define the role of alemtuzumab in this condition.

Lung transplant, induction (off-label use): IV, SubQ: 30 mg once either immediately before allograft reperfusion or immediately following transplant; followed by minimized maintenance immunosuppression (Jaksch 2014; Shyu 2011; Whited 2015). Additional data may be necessary to further define the role of alemtuzumab in this condition.

Renal transplant, induction (off-label use): IV: 30 mg as a single dose at the time of transplant (immediately following reperfusion) followed by a second 30 mg dose 24 hours later (the second dose was omitted in patients >60 years of age); followed by minimized maintenance immunosuppression (Haynes 2014).

Stem cell transplant (allogeneic) conditioning regimen (off-label use): IV: 20 mg daily for 5 days (in combination with fludarabine and melphalan) beginning 8 days prior to transplant (Mead 2010) or beginning 7 days prior to transplant (Van Besien 2009)

T-cell prolymphocytic leukemia (T-PLL; off-label use): IV: Initial test dose 3 mg or 10 mg, followed by dose escalation to 30 mg per dose 3 times weekly as tolerated until maximum response (Dearden 2001) or Initial dose: 3 mg day 1, if tolerated increase to 10 mg day 2, if tolerated increase to 30 mg on day 3 (days 1, 2, and 3 are consecutive days), followed by 30 mg per dose every Monday, Wednesday, Friday for a total of 4 to 12 weeks (Keating 2002)

Dosing Geriatric

Refer to adult dosing.

Dosing Obesity

American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity: Utilize a flat dose based on the regimen selected for hematopoietic stem cell transplant conditioning in adults (Bubalo 2014).

Test Interactions

May interfere with diagnostic serum tests that utilize antibodies.

Usual Adult Dose for Chronic Lymphocytic Leukemia

3 mg IV daily over 2 hours until infusion reactions are Grade 2 or less; then 10 mg IV daily over 2 hours until infusion reactions are Grade 2 or less; then 30 mg IV daily over 2 hours 3 times per week on alternate days (e.g., Monday, Wednesday, Friday).
-Duration of therapy: 12 weeks

Comments:
-Note: Consult manufacturer product information for approved indications. Different products have different approved indications.
-Escalation is required at initiation of dosing or if dosing is held for 7 days or longer during treatment.
-Escalation to 30 mg IV daily usually can be accomplished in 3 to 7 days.
-Single doses of greater than 30 mg 3 times per week or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia.
-Patients should be premedicated before the infusion is started. Consult manufacturer recommended concomitant medications or local protocol.

Use: As a single agent for the treatment of B-cell chronic lymphocytic leukemia (B-CLL)

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