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Alemtuzumab

Pronunciation

(ay lem TU zoo mab)

Index Terms

  • Anti-CD52 Monoclonal Antibody
  • Campath
  • Campath-1H
  • Humanized IgG1 Anti-CD52 Monoclonal Antibody
  • MoAb CD52
  • Monoclonal Antibody Campath-1H
  • Monoclonal Antibody CD52

Dosage Forms

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

Solution, Intravenous [preservative free]:

Campath: 30 mg/mL (1 mL) [contains edetate disodium dihydrate, mouse (murine) and/or hamster protein, polysorbate 80]

Lemtrada: 12 mg/1.2 mL (1.2 mL) [contains edetate disodium dihydrate, mouse (murine) and/or hamster protein, polysorbate 80]

Brand Names: U.S.

  • Campath [DSC]
  • Lemtrada

Pharmacologic Category

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

Pharmacology

Binds to CD52, a nonmodulating antigen present on the surface of B and T lymphocytes, a majority of monocytes, macrophages, NK cells, and a subpopulation of granulocytes. After binding to CD52+ cells, an antibody-dependent lysis of malignant cells occurs. In multiple sclerosis, alemtuzumab immunomodulatory effects may include alteration in the number, proportions, and properties of some lymphocyte subsets following treatment.

Distribution

Vd: IV: Campath: 0.18 L/kg (range: 0.1 to 0.4 L/kg); Lemtrada: 14.1 L

Metabolism

Campath: Clearance decreases with repeated dosing (due to loss of CD52 receptors in periphery), resulting in a sevenfold increase in AUC after 12 weeks of therapy.

Half-Life Elimination

IV: Campath: 11 hours (following first 30 mg dose; range: 2 to 32 hours); 6 days (following the last 30 mg dose; range: 1 to 14 days); Lemtrada: ~2 weeks

Use: Labeled Indications

B-cell chronic lymphocytic leukemia: Campath or MabCampath [Canadian product]: Treatment (as a single agent) of B-cell chronic lymphocytic leukemia (B-CLL)

Multiple sclerosis, relapsing: Lemtrada: Treatment of patients with relapsing forms of multiple sclerosis (MS), generally who have had an inadequate response to 2 or more medications indicated for the treatment of MS.

Use: Unlabeled

Conditioning regimen in stem cell transplant; prophylaxis of graft-versus-host disease (GVHD); treatment of steroid-refractory GVHD; treatment of T-cell prolymphocytic leukemia; treatment of autoimmune hemolytic anemia (CLL-induced); immunosuppressant in solid organ transplant (induction and steroid-refractory rejection)

Contraindications

U.S. labeling: There are no contraindications listed in the manufacturer's Campath labeling. Lemtrada is contraindicated in patients infected with HIV (due to prolonged reduction in CD4+ lymphocytes).

Canadian labeling:

Lemtrada: Hypersensitivity to alemtuzumab or any component of the formulation; HIV infection; active or latent tuberculosis; severe active infections; active malignancies; concurrent antineoplastic or immunosuppressive therapy; history of progressive multifocal leukoencephalopathy (PML)

MabCampath: Known type 1 hypersensitivity or anaphylactic reactions to alemtuzumab or any component of the formulation; active infections; underlying immunodeficiency (eg, seropositive for HIV); active secondary malignancies; current or history of progressive multifocal leukoencephalopathy (PML)

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 jiroveci 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)

Renal transplant, induction (off-label use): IV: 30 mg as a single dose at the time of transplant (Hanaway, 2011)

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: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Adjustment for Toxicity

Dosage adjustment for nonhematologic toxicity:

Treatment of B-CLL: Campath:

Note: If treatment is withheld ≥7 days, reinitiate at 3 mg with re-escalation to 10 mg and then 30 mg.

Grade 3 or 4 infusion reaction: Withhold infusion

Serious infection or other serious adverse reaction: Withhold alemtuzumab until resolution

Autoimmune anemia or autoimmune thrombocytopenia: Discontinue alemtuzumab

Treatment of MS: Lemtrada: Serious infusion reaction: Consider immediate discontinuation

Dosage adjustment for hematologic toxicity (severe neutropenia or thrombocytopenia, not autoimmune): Treatment of B-CLL: Campath:

Note: If treatment is withheld ≥7 days, reinitiate at 3 mg with re-escalation to 10 mg and then 30 mg.

ANC <250/mm3 and/or platelet count ≤25,000/mm3:

First occurrence: Withhold treatment; resume at 30 mg per dose when ANC ≥500/mm3 and platelet count ≥50,000/mm3

Second occurrence: Withhold treatment; resume at 10 mg per dose when ANC ≥500/mm3 and platelet count ≥50,000/mm3

Third occurrence: Discontinue alemtuzumab.

Patients with a baseline ANC ≤250/mm3 and/or a baseline platelet count ≤25,000/mm3 at initiation of therapy: If ANC and/or platelet counts decrease to ≤50% of the baseline value:

First occurrence: Withhold treatment; resume at 30 mg per dose upon return to baseline values

Second occurrence: Withhold treatment; resume at 10 mg per dose upon return to baseline values

Third occurrence: Discontinue alemtuzumab.

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).

Reconstitution

Campath, MabCampath [Canadian product]: Dilute for infusion in 100 mL NS or D5W. Compatible in polyvinylchloride (PVC) bags. Gently invert the bag to mix the solution. Do not shake prior to use.

Lemtrada: Withdraw 12 mg (1.2 mL) from vial and add to 100 mL bag of NS or D5W. Gently invert the bag to mix the solution.

Administration

Campath or MabCampath [Canadian product]: Administer by IV infusion over 2 hours. Premedicate with diphenhydramine 50 mg and acetaminophen 500 to 1000 mg 30 minutes before each infusion. IV glucocorticoids have been effective in decreasing severe infusion-related events. Start anti-infective prophylaxis. Other drugs should not be added to or simultaneously infused through the same IV line. Do not give IV push or bolus. Compatible in polyvinylchloride (PVC) or polyethylene lined administration sets or low protein binding filters.

Campath: SubQ (off-label route): SubQ administration has been studied (Lundin, 2002; Stilgenbauer, 2009); an increased rate of injection site reactions has been observed, with only rare incidences of chills or infusion-like reactions typically observed with IV infusion. A longer dose escalation time (1 to 2 weeks) may be needed due to injection site reactions (Lundin, 2002). Premedicate with diphenhydramine 50 mg and acetaminophen 500 to 1000 mg 30 minutes before dose. The subQ route should NOT be used for the treatment of T-PLL (Deardon, 2011).

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).

Lemtrada: Administer by IV infusion over 4 hours (beginning within 8 hours after dilution); do not administer by IV push or IV bolus. Do not infuse other medications through the same IV line. Premedicate with corticosteroids (methylprednisolone 1,000 mg or equivalent) for first 3 days of each treatment course. Administer in a setting with personnel and equipment appropriate to manage infusion reactions. Monitor vital signs prior to and periodically during the infusion. Infusion reactions should be managed symptomatically; consider discontinuing immediately for severe infusion reaction. Observe for at least 2 hours after each infusion, longer if clinically indicated.

Compatibility

Stable in D5W, NS. Medications should not be added to the solution or simultaneously infused through the same IV line.

Storage

Campath: Prior to dilution, store intact (30 mg/1 mL) vials at 2°C to 8°C (36°F to 46°F); do not freeze (if accidentally frozen, thaw in refrigerator prior to administration). Do not shake; protect from light. Following dilution, store at room temperature or refrigerate; protect from light; use within 8 hours. Discard unused portion in the vial.

Lemtrada: Prior to dilution, store intact vials at 2°C to 8°C (36°F to 46°F). Do not freeze. Do not shake; protect from light. Following dilution, store at room temperature or refrigerate; use within 8 hours.

MabCampath [Canadian product]: Prior to dilution, store vials at 2°C to 8°C (36°F to 46°F). Do not freeze (discard vial if frozen). Do not shake. Protect from light. Following dilution, store at room temperature or refrigerate; use within 8 hours.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Test Interactions

May interfere with diagnostic serum tests that utilize antibodies.

Adverse Reactions

Adverse reactions listed below are reflective of both the U.S. and Canadian product information.

>10%:

Central nervous system: Headache (44% to 52%), fatigue (8% to 21%), insomnia (11% to 17%), paresthesia (10% to 12%)

Dermatologic: Skin rash (43% to 53%), urticaria (15% to 17%), pruritus (13% to 17%)

Endocrine & metabolic: Thyroid disease (13% to 34%)

Gastrointestinal: Nausea (16% to 22%), diarrhea (12%), oral candidiasis (3% to 12%)

Genitourinary: Urinary tract infection (18% to 19%), vulvovaginal candidiasis (3% to 12%)

Hematologic & oncologic: Lymphocytopenia (6% to 100%)

Immunologic: Antibody development (8% to 85%; no effect on drug efficacy; anti-alemtuzumab: 2%)

Infection: Infection (71%), herpes virus infection (16%), fungal infection (12% to 13%)

Local: Infusion related reaction (92%)

Neuromuscular & skeletal: Arthralgia (12% to 13%), limb pain (13%), back pain (12%)

Respiratory: Nasopharyngitis (24% to 25%), upper respiratory tract infection (15% to 16%), oropharyngeal pain (11%), sinusitis (11%)

Miscellaneous: Fever (26% to 30%)

1% to 10%:

Cardiovascular: Flushing (10%), chest discomfort (7% to 8%), tachycardia (6% to 8%), peripheral edema (5%), palpitations (4%), bradycardia (3%), hypotension (3%), chest pain (2%), cold extremities (1%)

Central nervous system: Chills (9% to 10%), dizziness (10%), anxiety (7%), pain (5% to 7%), vertigo (4%), equilibrium disturbance (3%), hyperthermia (3%), increased body temperature (3%), drowsiness (2%), facial hypoesthesia (2%), hypertonia (2%)

Dermatologic: Skin rash (generalized; 7% to 8%), erythema (6%), acne vulgaris (3%), allergic dermatitis (3%), alopecia (3%), erythematous rash (3%), hyperhidrosis (3%), pruritic rash (3%), papular rash (2%), pruritus (generalized; 2%), skin blister (1%), xeroderma (1%)

Endocrine & metabolic: Hypothyroidism (5%), hypermenorrhea (4%), hyperthyroidism (4%), chronic lymphocytic thyroiditis (2%), Graves' disease (2%), thyroid stimulating hormone suppression (2%), goiter (1%)

Gastrointestinal: Vomiting (10%), abdominal pain (5% to 10%), oral herpes (9%), dyspepsia (6% to 9%), dysgeusia (8%), gastroenteritis (4%), upper abdominal pain (4%), abdominal distention (2%), oral mucosa ulcer (1%)

Genitourinary: Occult blood in urine (4% to 8%), uterine hemorrhage (5%), hematuria (3%), cystitis (2%), fungal vaginosis (2%), increase in urinary protein (2%), irregular menses (2%), proteinuria (2%), abnormal urinalysis (1%), herpes genitalis (1%), vaginal hemorrhage (1%)

Hematologic & oncologic: Bruise (10%), decreased CD-4 cell count (5% to 6%), decreased CD-8 cell counts (5% to 6%), decreased absolute lymphocyte count (4% to 5%), decreased T cell lymphocytes (4%), reduction of B-cells (4%), abnormal white blood cell differential (lymphocyte percentage decreased: 3%; lymphocyte percentage increased: 2%), immune thrombocytopenia (2%), nonthrombocytopenic purpura (2%), hematoma (1%), petechia (1%)

Hypersensitivity: Cytokine release syndrome (2%)

Infection: Influenza (8%), herpes zoster (4%), bacterial infection (3%), herpes simplex infection (2%), human papilloma virus infection (2%)

Local: Catheter pain (1%), infusion related reaction

Neuromuscular & skeletal: Myalgia (6% to 7%), myasthenia (7%), muscle spasm (6%), weakness (5% to 6%), neck pain (5%), joint sprain (2%), joint swelling (2%), musculoskeletal chest pain (2%)

Ophthalmic: Blurred vision (5%), conjunctivitis (2%), Graves' ophthalmopathy (1%)

Otic: Otalgia (3%), otic infection (3%)

Respiratory: Cough (9%), dyspnea (8% to 9%), bronchitis (7%), epistaxis (5%), pharyngitis (4%), rhinitis (4%), sinus congestion (3%), nasal congestion (2%), wheezing (2%), bronchospasm (1%)

<1% (Limited to important or life-threatening): Abnormal hepatic function tests, acquired blood coagulation disorder, allodynia, altered blood pressure, amenorrhea, anemia, anti-GBM disease, antithyroid antibody positive, aphthous stomatitis, asthma, ataxia, atrial fibrillation, autoimmune hemolytic anemia, autoimmune thrombocytopenia, bacterial vaginosis, candidiasis, cardiac failure, cellulitis, cervical dysplasia, cervicitis, chronic inflammatory demyelinating polyradiculoneuropathy, connective tissue disease (undifferentiated), decreased hematocrit, decreased hemoglobin, decreased monocytes, decreased neutrophils, dehydration, depression, desquamation, eosinopenia, eosinophilia, Epstein-Barr-associated lymphoproliferative disorder, Epstein-Barr infection, esophagitis, furuncle, gastroesophageal reflux disease, gastrointestinal disease, gingival hemorrhage, glycosuria, graft versus host disease (transfusion associated), Guillain-Barre syndrome, hemiparesis, hemophilia A (acquired [anti-Factor VIII antibodies]), hyperemia, hypersensitivity reaction, increased monocytes, infusion site reaction, labyrinthitis, leukocytosis, lymphoproliferative disorder, maculopapular rash, major hemorrhage, malignant lymphoma, malignant melanoma, malignant neoplasm of thyroid, membranous glomerulonephritis, memory impairment, meningitis due to listeria monocytogenes, meningitis (herpes), migraine, mucosal inflammation, multiple sclerosis, muscle spasticity, natural killer cell count increased, neutropenia, night sweats, onychomycosis, optic neuropathy, ostealgia, ovarian cyst, pancytopenia, papule, peripheral neuropathy, photophobia, pleurisy, pneumonia, pneumonitis, positive direct Coombs test, postherpetic neuralgia, progressive multifocal leukoencephalopathy, protozoal infection, psychomotor agitation, pyelonephritis, reactivation of disease, reduced ejection fraction, restless leg syndrome, retinal pigment changes (epitheliopathy), rheumatoid arthritis, serum sickness, skin hyperpigmentation, skin lesion, streptococcal pharyngitis, subacute thyroiditis, suicidal ideation, suicidal tendencies, syncope, tachypnea, thrombocytopenia, tongue discoloration, tonsillitis, tooth abscess, tracheobronchitis, tuberculosis, tumor lysis syndrome, type 1 diabetes mellitus, upper airway symptoms (cough syndrome), urethritis, urinary incontinence, varicella, viral infection, vitiligo, voice disorder, weight gain, weight loss

ALERT: U.S. Boxed Warning

Bone marrow suppression (Campath):

Serious, including fatal, pancytopenia/marrow hypoplasia, autoimmune idiopathic thrombocytopenia, and autoimmune hemolytic anemia can occur in patients receiving alemtuzumab. Single doses of alemtuzumab greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia.

Infusion reactions (Campath):

Alemtuzumab administration can result in serious, including fatal, infusion reactions. Carefully monitor patients during infusions and withhold alemtuzumab for Grade 3 or 4 infusion reactions. Gradually escalate alemtuzumab to the recommended dose at the initiation of therapy and after interruption of therapy for 7 or more days.

Infections (Campath):

Serious, including fatal, bacterial, viral, fungal, and protozoan infections can occur in patients receiving alemtuzumab. Administer prophylaxis against Pneumocystis jiroveci pneumonia (PCP) and herpes virus infections.

Autoimmune effects (Lemtrada):

Alemtuzumab causes serious, sometimes fatal, autoimmune conditions, such as immune thrombocytopenia and anti-glomerular basement membrane disease. Monitor complete blood counts with differential, serum creatinine levels, and urinalysis with urine cell counts at periodic intervals for 48 months after the last dose of alemtuzumab.

Infusion reactions (Lemtrada):

Alemtuzumab causes serious and life-threatening infusion reactions. Alemtuzumab must be administered in a setting with appropriate equipment and personnel to manage anaphylaxis or serious infusion reactions. Monitor patients for 2 hours after each infusion. Make patients aware that serious infusion reactions can also occur after the 2-hour monitoring period.

Malignancy (Lemtrada):

Alemtuzumab may cause an increased risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders. Perform baseline and yearly skin exams.

REMS program (Lemtrada):

Because of the risk of autoimmunity, infusion reactions, and malignancies, Lemtrada is available only through restricted distribution under a Risk Evaluation Mitigation Strategy (REMS) Program. Call 1-855-676-6326 to enroll in the Lemtrada REMS program.

Warnings/Precautions

Concerns related to adverse effects:

• Autoimmune effects: [U.S. Boxed Warning (Lemtrada)]: Alemtuzumab causes serious, sometimes fatal, autoimmune conditions, such as immune thrombocytopenia and antiglomerularantiglomerular basement membrane disease, in patients receiving alemtuzumab for the treatment of multiple sclerosis (MS). Monitor complete blood counts with differential, serum creatinine levels, and urinalysis with urine cell counts at periodic intervals for 48 months after the last dose of alemtuzumab. Monitor for symptoms of immune thrombocytopenia (easy bruising, petechiae, spontaneous mucocutaneous bleeding, heavy menstrual bleeding) in patients receiving alemtuzumab for MS. Monitor for nephropathy symptoms (eg, elevated serum creatinine, hematuria, proteinuria). Alveolar hemorrhage manifesting as hemoptysis may be present in anti-glomerular basement membrane disease. Glomerular nephropathies require urgent evaluation; may lead to renal failure if not treated. Prompt intervention is necessary for autoimmune cytopenias. Idiopathic thrombocytopenic purpura, thyroid disorders, autoimmune hemolytic anemia, autoimmune pancytopenia, undifferentiated connective tissue disorders, acquired hemophilia A, rheumatoid arthritis, vitiligo, and retinal pigment epitheliopathy have been reported in patients receiving alemtuzumab for MS. Guillain-Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy have been reported in patients receiving alemtuzumab for other uses. Alemtuzumab may increase the risk for other autoimmune conditions.

• Bone marrow suppression: [U.S. Boxed Warning (Campath)]: Serious and fatal cytopenias (including pancytopenia, bone marrow hypoplasia, autoimmune hemolytic anemia, and autoimmune idiopathic thrombocytopenia) have occurred. Single doses >30 mg or cumulative weekly doses >90 mg are associated with an increased incidence of pancytopenia. Severe prolonged myelosuppression, hemolytic anemia, pure red cell aplasia, bone marrow aplasia, and bone marrow hypoplasia have also been reported with use at the normal dose for the treatment of B-CLL. Discontinue for serious hematologic or other serious toxicity (except lymphopenia) until the event resolves. Permanently discontinue if autoimmune anemia or autoimmune thrombocytopenia occurs. Patients receiving blood products should only receive irradiated blood products due to the potential for transfusion-associated GVHD during lymphopenia.

• Gastrointestinal toxicity: 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).

• Infections: [U.S. Boxed Warning (Campath)]: Serious and potentially fatal infections (bacterial, viral, fungal, and protozoan) have been reported. Administer prophylactic medications against PCP pneumonia and herpes viral infections during treatment and for at least 2 months following last dose or until CD4+ counts are ≥200 cells/mm3 (whichever is later). Severe and prolonged lymphopenia may occur; CD4+ counts usually return to ≥200 cells/mm3 within 2 to 6 months; however, CD4+ and CD8+ lymphocyte counts may not return to baseline levels for more than 1 year. Withhold treatment during serious infections; may be reinitiated upon resolution of infection. Monitor for CMV infection (during and for at least 2 months after completion of therapy); initiate appropriate antiviral treatment and withhold alemtuzumab for CMV infection or confirmed CMV viremia (withhold alemtuzumab during CMV antiviral treatment). For patients being treated for MS, initiate antiviral prophylaxis (for herpetic viral infections) beginning on the first day of treatment and continue for at least 2 months or until CD4+ lymphocyte count is ≥200/mm3. In clinical trials for MS, infections seen more commonly in alemtuzumab-treated patients included nasopharyngitis, urinary tract infection, upper respiratory tract infection, sinusitis, herpetic infections, influenza, and bronchitis; serious cases of appendicitis, gastroenteritis, pneumonia, herpes zoster, and tooth infection also occurred. Consider delaying treatment in patients with active infection until infection is controlled. Patients should be screened for human papilloma virus (HPV) and tuberculosis as clinically necessary.

• Infusion reactions: [U.S. Boxed Warning]: Serious and potentially fatal infusion-related reactions may occur; monitor for infusion reaction; carefully monitor during infusion; withhold treatment for serious or grade 3 or 4 infusion reactions. For B-cell chronic lymphocytic leukemia (B-CLL), gradual escalation to the recommended maintenance dose is required at initiation and with treatment interruptions (for ≥7 days) to minimize infusion-related reactions. For multiple sclerosis, must be administered in a setting with appropriate equipment and personnel to manage anaphylaxis or serious infusion reaction; monitor for 2 hours after each infusion; inform patients that serious infusion reactions may also occur after the 2-hour monitoring period. Infusion reactions have been reported more than 24 hours after infusion. In patients treated for B-CLL, infusion reaction symptoms may include acute respiratory distress syndrome, anaphylactic shock, angioedema, bronchospasm, cardiac arrest, cardiac arrhythmias, chills, dyspnea, fever, hypotension, myocardial infarction, pulmonary infiltrates, rash, rigors, syncope, or urticaria. The incidence of infusion reaction is highest during the first week of B-CLL treatment. Premedicate with acetaminophen and an oral antihistamine. Medications for the treatment of reactions should be available for immediate use. Use caution and carefully monitor blood pressure in patients with ischemic heart disease and patients on antihypertensive therapy. For B-CLL, reinitiate with gradual dose escalation if treatment is withheld ≥7 days. Similar infusion reactions have been observed with use in the treatment of multiple sclerosis; premedication with corticosteroids for initial 3 days of each treatment course is recommended. Antihistamines and/or antipyretics may also be considered. Consider additional monitoring in patients with existing cardiovascular or respiratory compromise (the Canadian labeling recommends obtaining an ECG prior to each treatment course). Observe for infusion-related reactions; advise patients to monitor for signs/symptoms of infusion reaction, particularly during the 24 hours following infusion.

• Malignancy: [U.S. Boxed Warning (Lemtrada)]: Alemtuzumab may cause an increased risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders. Perform baseline and yearly skin exams. Other malignant neoplasm (breast cancer or basal cell carcinoma) has been observed (rarely) in patients receiving treatment for MS. Use of Lemtrada in patients with active malignancies is contraindicated; use caution if initiating treatment in patients with preexisting malignancy (Canadian labeling).

• Pneumonitis: Pneumonitis (hypersensitivity or fibrosis) has been reported. Monitor for symptoms (dyspnea, cough, wheezing, hemoptysis, chest pain/tightness).

• Progressive multifocal leukoencephalopathy (PML): Has been reported with use (rarely); withhold therapy immediately for signs/symptoms suggestive of PML. According to the Canadian labeling, alemtuzumab is contraindicated in patients with a history of PML.

• Thyroid disorders: Autoimmune thyroid disorders occurred in over one-third of patients receiving alemtuzumab for MS. In a trial evaluating alemtuzumab versus interferon beta-1a in patients with MS, thyroid dysfunction occurred more frequently in patients taking alemtuzumab (34% versus 6.5%) (Daniels, 2014). The incidence of the first episode of thyroid dysfunction increased annually the first 3 years (year 1: 4.6%; year 2: 13.3%; year 3: 16.1%) then gradually decreased thereafter. Among patients with alemtuzumab-related thyroid dysfunction, Graves’ hyperthyroidism occurred most commonly (23%), followed by hypothyroidism and subacute thyroiditis (7% and 4%, respectively). Thyroid dysfunction (thyroiditis, Graves’ disease) has also been reported with alemtuzumab use for the treatment of other conditions. For B-CLL treatment, TSH monitoring is recommended; monitor TSH at baseline and every 2 to 3 months during alemtuzumab treatment (Hamnvik, 2011). For MS, monitor TSH at baseline and every 3 months until 48 months after last infusion or longer or at any time during therapy if clinically indicated.

Concurrent drug therapy issues:

• Drug-drug 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:

• HBV or HCV infected patients: Alemtuzumab has not been studied in MS patients infected with HBV or HCV; consider screening patients at increased risk of infection prior to initiating treatment. Use with caution in HBV or HCV carriers; patients may be at risk for viral reactivation.

Other warnings/precautions:

• Appropriate use: Alemtuzumab is not recommended for use in MS patients with inactive disease or who are stable on other treatment. Patients should commit to at least 48 months of follow-up after the last infusion.

• Duplicate therapy: If considering Lemtrada treatment for use in a patient who has previously received Campath/MabCampath, consider the additive and long-lasting immune system effects.

• Immunizations: Patients should not be immunized with live, viral vaccines during or recently after treatment. The ability to respond to any vaccine following therapy is unknown. Testing for antibodies to varicella zoster virus (VZV) is recommended prior to initiation of Lemtrada if history of chickenpox or VZV vaccination status is unknown. When using for the treatment of multiple sclerosis, complete necessary immunizations at least 6 weeks prior to initiating alemtuzumab. Determine if patient has a history varicella or vaccination for VZV; if not, test for VZV antibodies and consider vaccinations for antibody-negative patients; postpone alemtuzumab treatment for 6 weeks following VZV vaccination.

• REMS Program: [U.S. Boxed Warning (Lemtrada)]: Due to the risk of autoimmunity, infusion reactions, and malignancies, alemtuzumab is available only through restricted distribution under a Risk Evaluation Mitigation Strategy (REMS) Program when used for the treatment of MS. Contact 1-855-676-6326 to enroll in the Lemtrada REMS program. Prescribers and pharmacies must be certified with the REMS program, and patients and healthcare facilities must be enrolled and comply with ongoing monitoring.

Monitoring Parameters

Campath: CBC with differential and platelets (weekly, more frequent if worsening); signs and symptoms of infection; CD4+ lymphocyte counts (after treatment until recovery); CMV antigen (routinely during and for 2 months after treatment); consider TSH at baseline and then every 2 to 3 months during alemtuzumab treatment (Hamnvik, 2011). Monitor closely for infusion reactions (including hypotension, rigors, fever, shortness of breath, bronchospasm, chills, and/or rash); vital signs (prior to and during infusion); carefully monitor BP especially in patients with ischemic heart disease or on antihypertensive medications;

Lemtrada: CBC with differential prior to initiation then monthly until 48 months after last infusion; serum creatinine prior to initiation then monthly until 48 months after last infusion or at any time during therapy if clinically indicated; urinalysis with urine cell counts (prior to initiation then monthly); signs/symptoms of infection; TSH at baseline and every 3 months until 48 months after last infusion or longer or at any time during therapy if clinically indicated; observe for at least 2 hours after each infusion, longer if clinically indicated; ECG prior to each treatment course; annual HPV screening; signs/symptoms of PML; baseline and annual skin exams (for melanoma).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Human IgG is known to cross the placental barrier; therefore, alemtuzumab may also cross the barrier and cause fetal B- and T-lymphocyte depletion. Use during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus. Effective contraception is recommended during and for at least 6 months (Campath) or 4 months (Lemtrada) after treatment for women of childbearing potential and men of reproductive potential.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience anxiety, back pain, painful extremities, neck pain, flushing, nausea, vomiting. diarrhea, muscle pain, joint pain, abdominal pain, rhinitis, pharyngitis, lack of appetite, muscle spasms, or insomnia. Have patient report immediately to prescriber signs of infusion reactions (chest pain, passing out, abnormal heartbeat, hives, trouble breathing, swelling of face or mouth, chest tightness, wheezing), signs of infection, signs of progressive multifocal leukoencephalopathy (confusion, depression, trouble with memory, behavioral changes, change in strength on one side, trouble speaking, change in balance, vision changes), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop), signs of breathing problems (shortness of breath, wheezing, coughing, or breathing gets worse), jaundice, dark urine, dyspnea, loss of strength and energy, enlarged lymph nodes, severe dizziness, passing out, redness or white patches in mouth or throat, severe headache, passing out, bradycardia, sweating a lot, angina, tachycardia, burning or numbness feeling, signs of tumor lysis syndrome (fast heartbeat or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; upset stomach, throwing up, loose stools or not able to eat; or feel sluggish), signs of thyroid problems (change in weight without trying, feeling nervous and excitable, feeling restless, feeling very weak, hair thinning, low mood [depression], neck swelling, not able to focus, not able to handle heat or cold, period [menstrual] changes, shakiness, or sweating), signs of thyroid cancer (new lump or swelling in the neck, pain in the front of the neck, cough that does not go away, change in voice that does not go away like hoarseness, or trouble swallowing or breathing), mole changes, depression, night sweats, suicidal ideation, swelling of arm or leg, or skin growths (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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